Boring but useful because it's often the first information you get about a bug, perhaps 24 hours before full identification, and you can work out what antibiotic is likely to work.
Streps, staphs, enterococcus. Enterococcus faecalis used to be called Strep faecalis or Group D strep. Catalase test distinguishes Staph, Coagulase test distinguishes S aureus from S epidermidis. Haemolysis pattern on blood agar distinguishes Strep viridans from Strep pyogenes (alpha vs beta haemolysis respectively).
Neisseria (diplococci), Moraxella. Note some coccobacilli that might sneak in here eg Haemophilus, Acinetobacter.
Fastidious ie fussy to grow so needs enriched agar eg chocolate, cooked meat broth - Acinetobacter (coccobacillus), Bordetella pertussis (used to be Bordet-Gengou medium but Charcoal Cephalexin Blood agar has better shelf life), Brucella, Campylobacter, Francisella tularensis (tularaemia), Haemophilus (X and V discs identify influenze vs parainfluenze), Helicobacter, Kingella (kind of in between cocci and bacilli, increasingly recognized as a pathogen in joint and bone sepsis), Legionella, Pasteurella multocida (animal bites).
Carbohydrate fermentation: different patterns, can be automated eg Vitek machine but only after pure growth obtained first on agar {Vitek also does sensitivity, takes 6-8 hrs}. MacConkey agar contains lactose so helps identify the enteric coliforms. Basically:
Non glucose fermenting (some are fastidious too) - Acinetobacter, Pseudomonas, Burkholderia pseudomallei (meliodosis), B cepacia, Stenotrophomonas (previously Xanthomonas) maltophila.
Oxidase positive - (if gram negative) Pseudomonas mostly, look for multiple antibiotic resistance. Else Aeromonas, Vibrio.
Strict anaerobes (culture in gas jar, metronidazole sensitivity) - Bacteroides, fusobacterium
Anaerobes - Actinomyces (filamentous, characteristic "sulphur granules" in pus), Clostridium (tetanus, botulism, gangrene, pseudomembranous colitis).
Aerobes -
Borrelia, chlamydia, bartonella, leptospirum, mycobacteria, rickettsia, treponema
Resistance will always tend to develop because bacteria replicate so much faster than humans can, and with each new generation more genetic diversity will occur, with the potential for antibiotic resistance mechanisms to appear. The genes for antibiotic resistance can be found on the bacterial chromosome or else on separate DNA segments called plasmids. Plasmids have the ability to be shared with other bacteria, even other species, which is an important way in which antibiotic resistance spreads.
Resistance genes also become associated with one another, forming cassettes with multiple genes. These cassettes can be incorporated into integrons, which include a promoter so facilitate expression and exchange of the genes. For example, an integron in Enterobacteriaceae confers resistance to piperacillin, cephalosporins, aminoglycosides, and quinolones. N Engl J Med. 2006 Apr 20;354(16):1671-84.
Use of third-generation cephalosporins has been associated with the emergence of ESBL (extended-spectrum beta-lactamase) and AmpC beta-lactamase-producing Enterobacteriaceae, and vancomycin-resistant enterococci. Conversely, use of beta-lactams (eg piperacillin-tazobactam) have not. Fourth-generation cephalosporins, such as cefepime, seem not to have the same problem when used as part of an overall strategy (probably because time above MIC higher than for ceftazidime re ESBL).
Strategies to control outbreaks of multidrug-resistant bacteria are infection-control measures and interventional programs eg Stewardship program to minimize use of broad spectrum antibiotics esp 3rd gen cephs - education, review of prescriptions, audit and feedback. Other measures would include formulary interventions (therapeutic substitutions), formulary restrictions.
Clin Infect Dis. 2006 Apr 15;42 Suppl 4:S173-81.
The golden colour of staphylococcus aureus is due to a carotenoid that impairs neutrophil function! Other factors include haemolysins and DNAses; the former cause tissue necrosis, the latter disrupts extracellular neutrophil nets which are designed to snare bugs. Cloning and mutagenesis techniques can identify new virulence factors. In the lab, knocking out just 1 factor (even if the bug has multiple) can be enough to prevent virulence, so potential targets for antimicrobials.
HPA has evidence based guidelines on a range of infectious disease eg how long to exclude from school.
Not all microorganisms induce an acute phase response. Viral infections might be associated with a reduced rather than enhanced acute phase response. Very sick and malnourished children might not respond with an intensive inflammatory response despite infection with potentially lethal microorganisms. Certain bacterial pathogens, eg pneumococcus, elicit more inflammation than others. Not all acute phase response markers are predictably increased to the same degree. Consider the extent of the inflamed/infected tissue: a large pulmonary infiltrate or an extensive cellulitis are expected to have a larger effect on the inflammatory response than a similar process that takes place in a more limited area. Stressful conditions at the time of examination might also be a potential confounder due to the demargination of leukocytes, which does not necessarily reflect the intensity of the inflammatory response. For all these reasons, burdens of infection and of inflammation may not correlate.
Uncontrolled hyperinflammation can be detrimental. Early detection could prompt administration of antibiotics as well as antiinflammatory medications, such as activated protein C. The utility of most biomarkers depends on the clinical scenario. For example the WBC has a relatively low predictive value in predicting most serious bacterial diseases, but sensitivity is fairly high in the setting of occult bacteremia. Although it is reported that serum CRP cannot differentiate bacterial from viral etiology of community-acquired pneumonia in children in primary health care settings (Heiskanen-Kosma T, Scand J Infect Dis 2000; 32: 399-402), it may be useful in distinguishing bacterial from viral acute otitis media (Tejani NR, Pediatrics 1995; 95: 664-9).
The possibility of using a multimarker strategy for the detection of acute bacterial infection may improve sensitivity and specificity.
Differentiating viral from bacterial infections is of special relevance. Alternative markers have been suggested, including procalcitonin (PTC), calprotectin, MxA protein, interferon-[alpha] and 2'-5' oligoadenylate synthetase. PTC is a recognized marker of bacterial infections, and high concentrations correlate with severity of infection. In a prospective study of 455 febrile children 1-36 months old, presenting to ER, Lopez et al. found that PTC was slightly more specific than CRP for differentiating between viral and bacterial infections (94.3% vs. 84.3%). The sensitivity of both tests was ~70%. They also found that PCT might be useful for differentiating between invasive and noninvasive infections in infants with fever with onset at <12 h.
Gendrel studied 360 infants and children hospitalized for bacterial or viral infection and found that PCT had better specificity, sensitivity and predictive value than CRP, IL-6 and interferon-[alpha] in children, in distinguishing between viral and bacterial infections.
Erythrocyte aggregation correlates with that of leukocytes and can easily be detected by image analysis. In this test the degree of adhesiveness/aggregation correlates significantly with the intensity of both acute and chronic infl mmation. This approach has been used successfully both for the differentiation of bacterial from viral meningitis in children and for other bacterial and viral infections. Michelow et al. explored the value of cerebrospinal fluid leukocyte aggregation in distinguishing the etiologies of meningitis in children. They found that the WBC, CRP, CSF leukocyte count, blood culture, CSF Gram strain and CSF culture were inferior to the leukocyte aggregation test when compared individually. The leukocyte aggregation test was as effective as CSF protein, TNF-[alpha], IL-1[beta], IL-6 and IL-8 in predicting bacterial meningitis. In a logistic regression model that included routine laboratory tests, the best predictor of bacterial meningitis was the leukocyte aggregation score. It should be stressed that the volume needed for the test is minimal. Currently images must be read by a specialized center, but this can be accomplished easily by telemedicine.
Pediatric Infectious Disease Journal. 23(2):159-160, February 2004.
Procalcitonin is less sensitive than CRP but maybe more specific for pyelonephritis (Pediatrics. 2004 Aug;114(2):e249-54.)
See Congenital for congenital viral infections eg CMV, toxoplasma.
All emerging viruses related to animals eg avian flu, SARS so role of ecology, animal husbandry, economic development, dietary patterns all important. West Nile virus now in S America and Canada. Multiple bird species, mosquito species, animal species pretty damn versatile! Bioterrorism? Yes, a threat but nature will probably do worse things
See Influenza page.
Severe acute respiratory syndrome is caused by one of the coronavirus group. The virus probably originated in bats, then crossed into humans via masked palm civets.
The virus spread beyond its original outbreak in China when a businessman became on well on his flight out of China and died in Vietnam in 2003. Further outbreaks appeared rapidly, as far afield as Toronto. Eventually led to 8000 cases globally, but rapid surveillance and isolation measured brought the epidemic to an abrupt end within 4 months.
Super shedders exist, who have much higher infectivity (1 case on a plane infected 120 others, whereas another plane had 4 cases on board, but no secondary cases occurred!). On the other hand, there is no documented transmission by asymptomatic cases, or between children.
Incubation period is 5-7 but up to 14 days. Spread is by respiratory, fomites, and faecal-oral routes. Peak shedding occurs at peak of clinical disease hence outbreaks were often among health care workers.
Symptoms are 'flu-like, and non-specific. Fever is universal. Those who do badly have sudden deterioration on 10th day, with ARDS. Mortality is around 10%, but very age dependent, reaching over 50% in the over 65s. Children have lower viral loads, and generally have a benign course. Compared with adults, they perhaps get more gastrointestinal symptoms than respiratory.
Children under 5 yrs are hardly affected at all - perhaps because recent coronavirus infection protective, perhaps because of reduced immune reactivity.
No long term morbidity seen in children.
The diagnosis is suggested by the paucity of clinical signs (mild crepitations only, if anything) with an abnormal chest radiograph (non-specific), and laboratory evidence of leucopenia, lymphopenia, and thrombocytopenia. Raised AST/ALT also seen.
Definitive diagnosis is by ELISA or PCR, neither of which is very sensitive, or useful early on in disease.
Interferon alpha appears to be of benefit in vitro. Otherwise supportive.
Protective measures effective if used properly - so buddy system.
More hospitalizations in young children than influenza in one study! PIV 1 and 3 responsible for most serious illness, PIV 1 is epidemic, biennial (odd years) and autumnal; PIV 3 is endemic throughout year although more in spring.
Usually croup, often coexistent otitis media, but also pneumonia, bronchiolitis and nonspecific fever.
The main cause of exanthema subitum, also called roseola, also called 6th disease! HHV7 can also cause it, and is very closely related, but with 1 important difference. But increasingly recognised as agents in febile infants, and suspected in central nervous infections of the immunocompromised. Infection is almost universal by the age of 2yrs, and like other herpesviruses, remains latent for life.
HHV 6 is responsible for a third of all febrile seizures in children up to 2yrs old. These primary infections seem to be more likely to cause atypical or recurrent seizures. Occasionally encephalitis has been reported. HHV7 probably does the same but this is not as well documented. DNA is not always found in the CSF so standard antibody tests are used.
Asymptomatic infection is unusual, although more common under 6 months of age. Over that age, fever is common, but only a minority get exanthema subitum. Persistence and later reactivation however can be asymptomatic. HHV6/7 encephalitis has been reported in immunosuppressed children and treated with ganciclovir, foscarnet and donor lymphocytes.
HHV6, but not HHV 7, is capable of chromosome integration, meaning that it can insert its DNA into the chromosomes of the host, thus becoming immortalized, and it can then be passed on to children. This is probably the main cause for "congenital HHV6 infection", which appears to affect 1% of births. Where diagnosed in babies, it appears to be asymptomatic, but antibody develops and mRNA has been found, so it does appear that active replication is occurring rather than DNA being produced from degraded chromosomes. The clinical course is not known, however.
Prime target is CD4 cells, as per HIV. Other immune cells can be affected functionally. Attractive candidate for chronic fatigue syndrome! Liver dysfunction is known to occur; fulminant hepatitis has been reported but causality has not been established.
Cross reactions occur when testing for HHV6/7 antibodies! Avidity tests can distinguish recent infection from established.
Current Opinion in Infectious Diseases. 18(3):247-52, 2005. PMID: 15864103, Pediatrics 2008, PMID: 18762520
HHV-8 (Kaposi sarcoma assoc herpesvirus) is endemic in Africa and the Amazon basin, common in the Mediterranean and Middle East but rare in the rest of Europe and most of Asia. In endemic areas most transmission occurs in childhood, but otherwise it would appear to be sexual esp homosexuals. No evidence of transfusion borne or vertical infection. Infection causes fever, macpap rash and URTI. KS is rare in children with immunodeficiency, suggesting multiple factors in aetiology. HHV-8 has also been associated with AIDS related lymphoma and post-transplant haemophagocytic syndrome. KS can be treated with radio/laser/cryotherapy. No information on effectiveness of ganciclovir. PIDJ January 2005, 81-82
= Chickenpox (Latin). Caused by Varicella Zoster Virus, a systemic viral illness characterised by widespread vesicles. Like other herpes viruses, it retains the ability to lie dormant in ganglions after initial infection, possibly reactivating in the future as Herpes Zoster (= shingles).
Age and immunodeficiency are the most important predictors of severity, with adults and infants having more severe disease. Cellular rather than humoral immunodeficiency is associated with more severe disease. Numerically, most cases of severe disease (and 90% of the deaths) occur in previously healthy people.
Average age is falling, now under 5 (presumably increased day care). cf underdeveloped countries, where average age is older eg teens. Peak incidence March to May.
There are 3 genotypes but they are virtually identical, and only 1 circulates in Europe; it remains theoretically possible, therefore, to get chickenpox twice!
Starts as small spots, spreading over the trunk within 24 hr. There is no prodrome. Within 24-48 hours the classic pustules develop. Burst to leave a scab which falls off after 4-5 days. There may be several crops of these blisters which follow the same pattern. The classical distribution is on the trunk but lesions can be widespread and can affect the mouth, the eyes and the urethra.
Onset of the rash is often associated with fever and other systemic symptoms. The disease can however be subclinical (or at least unrecognized) in some cases. Secondary cases in a household on the other hand tend to be more severe, probably due to increased viral load.
In the immunocompromised, there may be a prodrome ie symptoms may occur at the time of initial viraemia, around day 7 of the incubation period. The classic prodrome is of abdominal symptoms and/or hyponatraemia, and can precede the classic vesicular rash by several days (up to 3 weeks). Abdominal manifestations include severe pain, diarrhoea, or vomiting which are explained by hepatitis, gastritis, oesophagitis, pancreatitis, and paralytic ileus owing to viral spreading from the posterior nerve roots that supply abdominal organs. The mechanism of hyponatraemia is presumed to be SIADH.
Usually clinical. If in doubt, PCR and culture can be done on skin scrapings (particularly from the base of lesions, but potentially also from the crust) or from other sites eg CSF.
IgM can be positive from as early as 1-2 days after appearance of the rash. But serology is not 100% sensitive. Antibodies persist lifelong and are useful for indicating previous exposure and hence immunity; they may however be passed on passively through transfusion. Not very good for confirming response to vaccination, as levels are 10 times lower than after disease.
Complications of varicella occur in the immunocompetent, as well as the immunocompromised :
Encephalitis usually occurs a week into the illness, and can be acute or gradual in onset. It can however develop before onset of the rash. Other CNS manifestations are benign cerebellar ataxia and vasculitis (potentially leading to stroke, possibly months after disease, VZV IgG Ab more sensitive than DNA Neurology. 68(13):1069-73, 2007).
See also Congenital varicella.
Incubation period is 10-21 days, typically 14 days. Infectivity (by aerosol spread) begins up to 48 hours before onset of the rash and persists until all lesions have dried (crusted), usually 1-2 weeks but may be longer in the immunocompromised. In theory transmission from a moist spot can occur but infection is generally by respiratory route.
Infectious or isolation period is until all lesions crusted, or else 5 days after the last spot appears. UK ,a href="http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1210922353756">HPA guidance is available on exclusion periods from school or nursery on health grounds. Infectivity can persist in the immunocompromised for up to several weeks. Note also that after VZIG administration, incubation period is prolonged.
Chickenpox can be treated with aciclovir or the like. Oral aciclovir in the healthy child reduces fever by 1 day and symptoms by 15-30%; not clear if complications are reduced. NEJM 1991;325(22):1539-44. Not standard practice, however! Oral aciclovir only works if given in first 24 hours; IV most effective if given within 72 hours of onset of the rash.
See Vaccines for details on live attenuated vaccine.
Post-exposure prophylaxis is required for at risk groups who have had significant exposure. This includes:
Specific Varicella Zoster Immunoglobulin (VZIG) is effective at reducing the likelihood of disease, and where disease occurs it tends to be less severe. It is an intramuscular product and should be given within 10 days of exposure. Protection lasts 3 weeks, after which a further dose should be considered if re-exposure occurs and antibody has not persisted. See Greenbook for more details.
There is evidence that varicella vaccine can be used up to 3 days after exposure to prevent disease, and Varivax is licensed for this indication. This is not, however, policy although active immunisation should be considered for anyone in whom ongoing exposure is likely.
Local reactivation due to waning immunity, but actually not uncommon in children and rarely due to immunodeficiency - ophthalmic and otic zoster are more common in immunocompetent children! But multidermatomal zoster does suggest immunodeficiency - see Derm. Once immune, exposure to chickenpox or zoster boosts immunity and makes zoster less likely.
Aciclovir started within 72 hrs reduces severity and duration of episode, as well as incidence of PHN. Oral steroids help acute episode but have not been shown to prevent post herpetic neuralgia. Single dose gabapentin reduces acute pain of zoster. Tramadol is efficacious in post herpetic neuralgia; role for topical capsaicin?
ZIG is actually different from VZIG prepared from people convalescing from zoster, rather than high titres of VZV antibody. Not used in UK.
Adenovirus infections in immunocompetent individuals are usually mild and self-limited. Clinical manifestations are generally limited to conjunctivitis, URTI or pharyngitis, although up to 7% of pneumonias requiring hospitalization in children have been attributed to adenoviruses. Gastroenteritis and cystitis may also be seen. Additionally more severe manifestations, including hepatitis, myocarditis, meningoencephalitis and nephritis, have been reported rarely. Adenovirus infections are more common in children, with a peak incidence between 6 months and 5 years of age. Currently 6 distinct species or subgenera, A to F, with different clinical syndromes associated with different species. For example, epidemic keratoconjunctivitis is associated with group D adenoviruses, whereas adenovirus pharyngitis and pharyngoconjunctival fever are most often caused by group B isolates.
In immunosuppressed patients, adenoviral disease presents as fulminant hepatitis, pneumonia and/or encephalitis. Gastroenteritis and hemorrhagic cystitis may also occur. As in CMV disease, isolation of adenovirus from multiple sites and/or peripheral blood has been associated with increased risk for adenoviral disease. Monitoring of rising adenovirus copies by PCR is an effective method of early detection of invasive disease. Serotypes B and C are most often isolated as the cause of severe disease in bone marrow transplant recipients. To date, no antiviral treatment of adenovirus infection has proven clinically effective, although a number of agents with in vitro activity against adenoviruses have been used in small numbers of patients. Ribavirin (IV and/or by aerosol) has had a number of successful outcomes. Cidofovir is a nucleoside analog with activity against CMV, herpes simplex virus, varicella-zoster virus and adenoviruses. Nephrotoxicity related to cidfovir is a concern, however (use probenecid for protection). Ganciclovir has only weak in vitro activity against adenoviruses, but transplant patients receiving CMV prophylaxis with ganciclovir had lower rates of adenovirus infections than other patients. Additional considerations in treating adenoviral infections in transplant recipients might include reduction in immunosuppression if possible, administration of intravenous immunoglobulin or transfusion of donor lymphocytes.
Pediatric Infectious Disease Journal. 24(6):555-556
Mild: fever +/- rash, hand/foot/mouth, herpangina, pleurodynia, pharyngitis, conjunctivitis, croup.
Serious: meningitis, encephalitis, acute paralysis, neonatal sepsis, myo/pericarditis, hepatitis, chronic infection (immunocompromised).
Meningitis in neonates usually associated with other organ involvement. In adolescents headache can be severe and symptoms last several weeks. Early CSF can show around 1000 neutrophils! Prognosis good cf encephalitis eg EV71 outbreak in Taiwan in assoc with hand/foot/mouth (78 deaths). Acute flaccid paralysis can occur cf polio. Neonatal disease can be severe, mimicking bacterial sepsis or HSV. Maternal history is often elusive. Virus is shed in throat and stool (rectal swab quicker than stool!), can also be detected in CSF, blood and urine.
Role of IVIG is unproven but antibody plays an important role in immune response to EV. Pleconaril in enteroviral meningitis RCT, 38% to 50% improvement in symptoms in the drug-treated group with improvement noted as early as 24 hours after initiation of therapy - no longer available.
Current Opinion in Pediatrics. 13(1):65-9, 2001
Human Parechovirus has been described in Japan, Canada and now the Netherlands, causing neonatal sepsis or encephalitis in about 10% of cases where culture suggests enterovirus but PCR is negative. Clin Infect Dis. 2006 Jan 15;42(2):204-10
RCT of Nitazoxanide, n=38 children hospitalized with rotavirus diarrhea in Cairo, 3 days therapy BD 200 mg in aged 411 years, 100 mg in patients aged 1247 months, 7.5 mg/kg in patients aged <12 months). Most were moderately to severely malnourished. The median time to resolution of illness was 31 hours cf 75 hours. No significant adverse events.
Nitazoxanide is a nitrothiazole benzamide compound with activity against a profoundly broad range of pathogens including giardia, Entamoeba, Ascaris lumbricoides, Bacteroides species, Clostridium species and Helicobacter pylori!
Lancet. 2006;368:124129
The main cause of Glandular fever, a syndrome of fever and lymphadenopathy. Often sore throat, characteristic rash if given amoxicillin (non-allergic), splenomegaly with risk of traumatic rupture. Atypical lymphocytosis seen. Steroids may be used for airway obstruction/thrombocytopenia.
Ampicillin type non-allergic rash with EBV has also been described with tazocin, azithromycin, levofloxacin and cefalexin.
Infection in early life is usually asymptomatic! At age 5yrs about half will be symptomatic.
Monospot (=Paul-Bunnell, heterophil antibody) test uses sheep red cells to find IgG antibodies; usually only positive after a week, peaks in the second week and persists for months. Not very sensitive, false negatives with rubella, hepatitis, SLE, lymphoma. But a quick test to do. More reliable is serology for specific antigens, of which there several: EA = early antigen, in fact the IgG may preced IgM. VCA (viral capsid antigen) is another early antigen. NA (nuclear antigen) is the slowest to generate antibodies but persists.
Also causes oral hairy leukoplakia in patients with T cell deficiency. Responds to aciclovir.
Like other Herpes viruses, once you have acquired EBV it lies dormant in your lymphocytes - specifically CD21 marked B cells. It may become active again following immunosuppression eg Post transplant lymphoproliferative Disease (PTLD) - seen esp after solid organ transplants, and with Tacrolimus. The reason for this (and other cancer associations eg Burkitts) is that the EBNA protein actually protects DNA from degradation, while other proteins prohibit apoptosis, hence encouraging tumour potential. Not necessarily ill. Donor T cells? Rituximab?
Duncan's = X-linked lympoproliferative (XLP) syndrome, a selective immunodeficiency, leading to extensive liver necrosis, often fatal. See Immunology.
Incubation period is 8-14 days. Starts with a prodrome of cough, coryza, conjunctivitis and fever lasting 2-6 days. Then the rash appears: brick red, maculopapular, starts behind ears, spreads from face on to trunk and then everywhere including palms/soles. Discrete spots may then coalesce. With time the rash may darken ("stain") and may desquamate. The child is typically irritable.
Koplik's spots are pathognomic but easily missed as they appear early in the illness, disappearing within a few days of the rash starting. They are grey or white spots on the buccal mucosa opposite the 2nd molars.
Diagnosis is by saliva swab. Notifiable.
Measles after MMR occurs 7-14 days post-vaccination. Very rare after booster. Tends to be mild fever, rash and conjunctivitis.
Rubella has a long incubation period of approx 17 days. Tends not to have a prodrome although adults may get fever and headache. The rash is accompanied by a mild fever if any at all. Suboccipital/posterior auricular lymphadenopathy is common. Arthralgia/arthritis tends to be seen in adolescents.
or Fifth disease. Due to Erythrovirus (Parvovirus) B19. There is a characteristic slapped cheek appearance with circumoral pallor, folowed by a lacy (reticular) rash on the trunk. May come and go over 1-3 weeks.
Note risk in early pregnancy.
HHV6/7. 3-5 days of high fever then rash appears accompanied by defervescence. Common cause of febrile convulsions in infants.
Recently discovered parvovirus found in children with acute respiratory and diarrhoeal illnesses. In a community sample of infants in the first year of life, it was associated with winter birth, maternal smoking and development of asthma! Asymptomatic carriage is pretty common, and in many RTI cases there were other respiratory viruses isolated as well. ( Pediatric Infectious Disease Journal. 27(10):897-902, October 2008)
Groups identified by Rebecca Lancefield. Group B is seen in the genitourinary tract of women and is an important pathogen in neonates. Groups C and G both cause invasive disease, both have M proteins, more common throat carriage in developing countries. Maybe also responsible for acute rheumatic fever. Alpha-haemolytic (strep viridans) are associated with line infections and endocarditis. Gamma-haemolytic include enterococci, of which faecium is usually resistant to amoxicillin but faecalis is usually sensitive. Of note, some enterococci are now resistant to vancomycin (VRE).
M type proteins on GAS are the main virulence factors esp 1, 3.
Erysipelas - rapidly spreading skin infection with clear demarcation, can evolve over a few hours.
Necrotizing fasciitis - often normal skin, with small entry site. Early surgical debridement is key to control. IVIG may be of benefit.
Group A strep sepsis is provoked by varicella - not just skin! A quarter of all invasive strep infections in kids follow chickenpox esp toxic shock, osteomyelitis. ?Shifts T helper cells from Th2 (antibody) to Th1 (cellular).
Has never been resistant to penicillin! But clindamycin shows superior killing.
GAS vaccine - danger of priming for rheumatic fever! New 26 valent, effective for sore throats and invasive disease, probably not long term effective or appropriate for preventing rheumatic fever.
About 20 toxins, all superantigens (see Immunity). Antibodies to toxin are effective. Some HLA types appear more susceptible. Clindamycin inhibits protein synthesis including toxins, appears to be more effective than Penicillin in animal models (see below). IVIG effective against toxins.
An autoimmune vasculitis caused by Group A streptococcal infection that is the commonest cause of acquired heart disease in the world. Relapsing in nature. M-proteins on the bacterium cross sensitize to cardiac and other proteins. Clues to the diagnosis are:
Diagnosis is based on the Modified Jones criteria:
Positive diagnosis is made with 2 major or else 1 major and 2 minor criteria, plus positive test for GAS - culture/ASOT or equivalent.
See cardiology.
Eradicate first with 10 days penicillin (or single IM benzathine penicillin). Erythromycin for allergic.
NSAIDs provide symptomatic relief for arthritis. Aspirin 75mg/kg/d for 2 weeks is usually given too, but apart from helping defervescence there is little evidence of long term benefit. Similarly for steroids - if anything, Cochrane suggests higher risk of complications after steroids.
Then prophylaxis. For at least 5 yrs (where recurrence risk is highest), life long if carditis. IM benzathine penicillin 3-4 wkly is preferred, else oral pen V (sulphadiazine for allergic).
Long term damage is more likely with severe carditis at presentation, and with each relapse of carditis. Even if there is no carditis at presentation, it may appear with a relapse so prophylaxis is still indicated.
Young children do worse. Approximately 5% of children with RF were younger than 5 years at diagnosis. Compared with older patients, children under 5 were more likely to have moderate to severe carditis and to present with arthritis or the rash of erythema marginatum and were less likely to have chorea. Chronic rheumatic heart disease was common in young children who presented with carditis. Pediatrics. 2003 Nov;112(5):1065-8.
Hygiene measures such as introduction of swimming pools in aboriginal areas of Australia have reduced the incidence of strep related diseases. PMID 18484935
Lancet 1997 PMID9093263
Staph refers to a bunch of grapes, aureus to the golden yellow colour! Infected thrombus can be a source of recurrent staph septicaemia.
Methicillin-resistant Staphylococcus aureus. Methicillin resistance equates with flucloxacillin resistance. mecA is the methicillin resistance gene, which codes for a low affinity PBP (penicillin binding protein) - ie penicillin can't bind easily. The gene has probably crossed from coag neg staph on at least 5 occasions to create MRSA strains. As with Methicillin-sensitive staphylococcus aureus (MSSA), different strains exist, carrying a range of different pathogenic genes.
Traditionally MRSA was found in institutions and the elderly, but now can be seen frequently in the young and healthy, causing the same infections that MSSA causes eg skin/soft tissue. It can also be responsible for rarer, more severe diseases eg necrotizing fasciitis. The US Center for Disease Control details criteria for distinguishing hospital acquired and community acquired MRSA infections - community acquired strains are typically SCCmec type IV (this is the cassette that contains mecA), which are sensitive to most non-beta lactam antibiotics, but on the other hand is associated with Panton Valentine Leucocidin (PVL, a cytotoxin associated with necrotizing disease). But again, this distinction is becoming less clear with strains associated with community acquired infection becoming more frequent in hospital acquired cases, and having variable levels of non-beta lactam antibiotic resistance.
In itself, antibiotic resistance may not translate to increased virulence and pathogenicity - it may just make it harder to treat. Studies have shown that after correcting for other factors eg age and co-morbidity, mortality is not significantly different. However, one important factor is use of inappropriate antibiotics, which of course is more likely with MRSA. Furthermore, in the US many MRSA outbreaks are caused by the USA300 clone, which carries a number of genes (in common with Methicillin sensitive staphylococcus aureus) eg PVL, ACME which are associated with enhanced pathogenicity.
PVL seen in 50% of symptomatic (skin) community MRSA in the US. Now also being reported in hospital acquired MRSA. Prevalence much lower in Europe, but risk of spread. Geographical areas tend to have their own clones (eg type 80 in Europe), with occasional pandemic.
In the UK, most MRSA are resistant to quinolones and macrolides. Even if sensitive to quinolones, treatment is not recommended as resistance evolves rapidly. Most MRSAs are sensitive to tetracyclines, rifampicin, co-trimoxazole, and linezolid, all of which can be given orally. Clindamycin can be effective but beware inducible resistance - see below. For intravenous therapy, gentamicin, vancomycin and teicoplanin are effective, although vancomycin resistance has been described since 2002. Teicoplanin levels can be unpredictable, and treatment failure associcated with low levels has been seen; checking levels would make sense (aiming for trough of at least 10, 20 in endocarditis) but is rarely done. About 12% are resistant to mupirocin. See Antibiotics below.
Clindamycin resistance is sometimes only 1 mutation away from erythromycin resistance. If the bug is erythromycin sensitive, then there is no issue, and clindamycin is a good choice (and can be given orally). On the other hand, if erythromycin resistance is seen, then the D test should be done: if a D-shaped zone appears around the clindamycin disk when an erythromycin disk is placed nearby, then you have induced resistance and clindamycin should be avoided. The erm gene is responsible for erythromycin-inducible resistance; the mrsA gene also confers resistance to erythromycin but does not affect clindamycin.
In MRSA skin infections (cellulitis/abscesses), most will get better anyway, esp after I&D, but using the wrong antibiotic increases risk of treatment failure by odds ratio of 2.80 (87% success cf 95% of patients who received an active antibiotic). Doxycycline is effective in skin infections, and is suitable if the child is over 12. No evidence for trimethoprim alone (cf septrin); use in combination with rifampicin? Probably best not to give rifampicin or fusidic acid monotherapy anyway as resistance frequently induced. Topical agents will induce resistance if used for high load infections eg wounds, catheter sites so should be combined with systemic therapy.
In line infections, vancomycin or linezolid should be used if the infection is severe; if milder, then removal of the line and oral therapy may be sufficient.
In bone infection, linezolid is good but should be given for a maximum of 28 days. Fusidic acid and Rifampicin are good adjuncts (rifampicin has in vitro activity against biofilms). Clindamycin and co-trimoxazole have also been used for bone infections. Early surgery (eg within 2/7 of onset of symptoms) is important esp where a prosthesis is present.
Necrotising pneumonia with MRSA post-influenza has mortality up to 75%.
For bacteraemia/endocarditis, vancomycin is the drug of choice, as treatment failures have been described with teicoplanin. Rifampicin or fusidic acid can be considered as adjuncts; there is no evidence for adding an aminoglycoside. A minimum of 14 days treatment is required (although oral treatment may be appropriate for maintenance) but should be extended if vegetations seen on trans-oesophageal echo. Infected pacemakers should be considered the same as orthopaedic prostheses.
Once colonized, about 40% of patients develop persistence - commoner where skin breaks present. Vancomycin does not clear nose, throat or gut.
Eradication of S. aureus nasal colonization eg with 72 hour mupirocin has been successful. However, recolonization usually occurs within a relatively short time, and the Cochrane review did not find much evidence in favour. Use of mupirocin to prevent infection in endemic settings eg dialysis centers have shown conflicting results although metanalysis suggests benefit (but fear of mupirocin resistance). Neomycin is even less effective, but is an alternative where mupirocin resistance is seen.
Combined treatment seems sensible, and recent RCT of 2% chlorhexidine gluconate washes, 2% mupirocin ointment intranasally, oral rifampin and doxycycline for 7 days vs no treatment confirms. At 3 months of follow-up, 74% cf 32% had cleared. Still significant benefit at 8 months (54% of those treated culture negative). On multivariable analysis, having a mupirocin-resistant isolate increased the risk of treatment failure nearly 10 fold. Mupirocin resistance emerged in only 5% of follow-up isolates. Clin Infect Dis. 2007 Jan 15;44(2):178-85.
Other control measures include a combination of active surveillance cultures of high risk patients, improved health care worker hand hygiene, consistent use of contact precautions for colonized/infected patients, and directed treatment of health care workers implicated in transmission. PIDJ January 2005 pp 79-80
Screening patients seems to reduce hospital acquired infection in the Netherlands, but not in Switzerland. UK guidelines say do for high risk only eg previous carriers, transfers, ICU. Standard infection control procedures alone seem to have worked in UK although what do you compare with? Rapid test (PCR) did not help (in crossover trial) except in reducing inappropriate isolation. 3-4x as expensive.
UK guidelines, J antimicro chemo 2006 PMID 16507559
6 of these is a confirmed case. But toxic shock criteria are there for research rather than clinical work just treat if at all suspicious! For staph related TSS, blood culture usually (but not always) negative, although may be isolated from wound or trachea.
For strep, almost always associated with a healthy looking recent wound. Criteria are looser but microbiological confirmation required:
1A plus 2 is a confirmed strep TSS case, 1B plus 2 is probable.
TSST-1 found in 75% of cases, the rest feature enterotoxins B or C. Recurrence is very rare. 90% of the adult population have antibodies against TSST1, not surprising since 20% of staphs are TSST-1 positive!!! Test is genotype based, not toxin based, so other factors must affect whether toxins are released, or how much disease is caused.
Females outnumber males 3:1.
Clindamycin has added benefit due to ability to reduce toxin production. IVIG has theoretical benefit but the only trial was stopped because of slow recruitment.
Not a pathogen, more a commensal! Most people have been infected on multiple occasions. Hence no evolutionary pressure on pathogenic types. Carriage rate peaks at 30% in 19 yr olds, but on multivariate analysis age is not signficant! Cf going out, number of kissing partners, smoking etc.
More genetic diversity among meningococci than in mammals! Small group of clonal complexes cause most disease, but changes with time and not associated with prevalence among carriers. Clonal complex is not the same as serotype, in fact most complexes show a mix of serotypes, but serotype is what we usually talk about! Overall incidence has been increasing since WWII. Historically, MenC caused epidemics in teenagers, but C isolates now have totally different clonal complexes to previous isolates. In US army, pre Vietnam war disease was gp B, then switched to C, no known reason. But genetically, almost identical isolates.
Despite antimicrobial therapy and supportive care, meningococcal sepsis is often fatal. Endotoxin (lipopolysaccharide (LPS) component of the Gram-negative outer membrane) initiates a cascade, including activation of complement and release of cytokines, leading to endothelial cell injury, capillary leak, loss of vasomotor tone, disseminated intravascular coagulation, myocardial depression and circulatory collapse (initial plasma endotoxin levels correspond with morbidity and mortality). LPS acts on Toll like Receptor 4. Also exposes Tissue Factor (leading to coagulation). Inflammatory response actually falls below normal ("hypoimmune") by day 4, associated with shift from Th1 to Th2 response (apoptosis of CD4/B/dendritic cells). Recombinant bactericidal permeability-increasing (rBPI21) protein neutralizes endotoxin. In RCT (n=393) fewer amputations, decreased blood product transfusions and improved functional outcome. No difference in mortality unless you look only at the subgroup of kids who survived long enough to get the full 24-hour infusion (2% versus 6%, even then P = 0.07). Human IgM monoclonal antibody-binding endotoxin (HA-1A) did not show any reduction in 28-day mortality (in vitro data raise questions about affinity of HA-1A for LPS). Activated Protein C is an anticoagulant consumed by inflammatory process, also counteracts apoptosis. In adults infusion led to small improvement in mortality (NNT=16) but dosing regimen crucial.
In Scott's meningococcal study 1 child looked well with normal markers cf Mandl/Brogan data, so treat all? Logistic regression based on PT, Hb, Wcc. Flea bitten rash pathognomic (petechia in centre of macule).
Case control study shows that inadequate supervision of junior staff plus inadequate inotropes gives an OR for death of 9 (95% CI up to 33). Hence management according to protocol is a significant influence on outcome. BMJ. 2005 Jun 25;330(7506):1475.
Strong family history or atypical illness may suggest complement or properdin deficiency.
Normal flora! 91 strains and counting but about a dozen responsible for the vast majority of disease. Some serotypes show cyclical or outbreak behaviour. Now that conjugate pneumococcal vaccine is part of universal schedule, epidemiology will probably change significantly, as it has done in US. Concern that vaccine use will simply cause replacement of vaccine strain bugs in population with non-vaccine strains (although since the vaccine strains are the ones associated with penicillin resistance, these new strains would be more susceptible). This has not been the case in most but not all studies so far. See Vaccines.
Causes pneumonia (obviously), but also otitis media, sinusitis, meningitis (nasty), septicaemia (especially in the very young).
Risk of invasive pneumococcal disease higher for children with a chronic disease, but also in children with multiple hospital contacts for any other reason. Children with a history of cancer, chronic renal disease, splenectomy, and transplantation are particularly susceptible to invasive pneumococcal disease. For children with other chronic diseases, their excess risk seemed to be attributable mostly repeated hospital contact rather than their underlying condition. PMID 18595971
`Penicillin resistance varies across the world, high in Spain, low in UK so some guidelines now suggest vancomycin first line. Not mediated by beta lactamase, so Co-amox is of no use. Not clear if Meropenem has benefit. But only 1 documented case of microbiological failure in pneumococcal pneumonia, so does in vitro resistance translate to in vivo?
Occult pneumococcal bacteraemia, the most common etiology of occult bacterial infection, occurs in approximately 1.9%-3% of children younger than 3 months with fever under 39degC but in approximately 10% when the temperature is 39.5 or greater and the WBC count is 15,000/mm3 or greater. But of course that depends on what criteria you use to select your study group. With the introduction of pneumococcal conjugate vaccine into the universal schedule, the risk now is likely to be much less. See Unexplained fever.
H influenzae so called because misidentified as cause of flu! Non typeable forms are pathogenic including LRI and meningitis/septicaemia, just less common. Natural infection does not induce good antibody levels (vaccine better!). Less invasive disease and less carriage with immunization. Late immunity memory seems to persist, and even vaccine failures do have higher antibody levels than non vaccinated. No evidence of replacement cf above although capsule switching documented.
Inherently resistant to wide range of antibiotics. Co-trimoxazole is drug of choice! Rarely epidemic. Usually affects immunodeficient.
2 billion people worldwide infected... Only 0.5% get disease in any given year! So usually controlled, by monocyte/NK/T cell interactions. Those who get disease probably have polymorphisms in multiple genes that increase susceptibility, hence different susceptibilities in different populations.
On first exposure to TB, the acid/alcohol fast bug beds down, usually in the lung hilum, to create a Gohn focus - an acute inflammatory reaction. The patient is infected, but may not have any symptoms. The Gohn focus is usually transient, although in HIV may become cavitating. Disseminating infection, causing miliary lung disease (widespread granular changes) or TB meningitis usually only seen between 1 and 6 months of age. Pulmonary lymph node disease or empyema is seen at 3-8 months after infection, and is a result of direct spread from the Gohn focus [in adults, disease may not develop for up to 2 years after infection].
The risk to children is highest under 1 year of age, and most cases seen under the age of 3. They themselves rarely transmit TB - primary infection seems less infectious than reactivation, less cough & less forceful cough (only 5 cases of children under 10 yrs with TB infecting others, mostly nurses doing ET suction on infants). Cavity disease should be considered high risk, like sputum positivity - although it may be that one of the adults who visit the child was the original source! Sputum positivity may persist for several weeks, but in practice there is no infection risk after 2 weeks.
Even in adults, although infection is common, the transmissibility is low. A man with highly active TB traveled by train and bus from Chicago to Florida, a journey of 35 hours. Only 2 other people were infected! Airline exposure under NICE is usually only taken on as a public health problem if the flight was more than 8 hours and the case was MDR or else coughed frequently.
Most CSF disease is meningitis, but about 5% will have tuberculomas +/- meningitis. Single/multiple mass lesions which enhance on CT esp basal ganglia, often hydrocephalus. Focal signs, abnormal movements, are suggestive. CSF and skin testing is not very sensitive - CXR best (including parents)!
Congenital TB usually disseminated, tubercles on placenta, HSM. TB in pregnancy Rx Rif, pyraz, isoniazid. Rx baby prophylactically, CXR & mantoux for baby @3/12. BCG if neg.
Symptom based diagnosis pretty good for S Africa viz HIV neg, cough >3/52, fatigue and FTT.
Mantoux test is a way of looking for hypersensitivity, and is effectively inducing erythema nodosum! Usually requires 1 in 1000 PPD. Grade 2 response is 5-14mm of induration (NOT erythema), Grade 3 is 15mm+, Grade 4 is with vesiculation or ulceration. Grade 2 is considered a positive response, whereas 3 or 4 are considered strongly positive. But since hypersensitivity takes 2 weeks to 3 months to develop after exposure, a negative result done before 3 months is not reliable (hence no use for neonates). False negatives occur with viral infections esp infectious mononucleosis, live vaccines in the preceding 3/52, immunosuppression incl malignancy. Grade 2 is suspicious only if patient has not had BCG.
Interferon tests eg Elispot look for ESAT6, almost but not completely specific for M. tuberculosis. Found in M. Bovis, which accounts for 1% of TB (clinically indistinguishable, but pyrazinamide resistant). Not found in BCG, at any rate. In BCG vaccinated patients, mantoux pos occurs in 51% of controls cf 78% of those with confirmed TB, cf 4% and 80% for IFN gamma test. JAMA. 2005 Jun 8;293(22):2756-61.
PCR is another rapid diagnostic test for TB: 90-95% sensitive in smear-positive, culture-positive TB cases, and 65-75% in smear-negative, culture-positive cases. May still result in false negative results due to low organism numbers eg in pleural fluid, or in some sample types, eg CSF, due to the presence of inhibitors. False positives may result from contamination.
NICE guidelines recommend that molecular tests (PCR or elispot) should only be used where:
ADA can be done on pleural fluid - T cell product. But non-specific, depending on population, no clear cut offs.
CXR (Pulmonary TB): dense unilat hilum (prominence alone prob not), Round shadows cf streaks, narrowing of adjacent airways. No predisposition towards upper lobe, except in adolescents cf adults. Lateral may be helpful (fluid in fissure, airway compression may be clues).
Induced sputum more effective for yielding TB in kids (S Africa) than gastric lavage, but note infection control implications, so needs specially engineered facilities! Lancet. 2005 Jan 8;365(9454):130-4. String test also good if sputum insufficient.
Close/household TB contacts - CDC now recommends IFN gamma tests for TB screening. Also useful where there is impaired cellular immune function. NICE guidance is to stick with Mantoux, but use IFN test to rule out the false positives for BCG. If BCG and over 35, go straight to CXR without Mantoux. Positive Mantoux (>=15 after BCG, >=6 without) gets IFN test; if negative then discharged. Positive IFN tests get CXR and examination; if normal, get treatment for latent infection (if BCG negative, then under 35yrs only, with opting out possible).
If BCG neg and mantoux negative but index was sputum positive, IFN test at 6 weeks. If nothing found, give BCG!
Newcastle emulation showed that about half of kids screened would need IFN-g testing, but with a 85% reduction in chemoprophylaxis, and with 2/120 "missed" (eg CXR changes but diagnosis uncertain). Only 1% had indeterminate responses (up to 17% in other studies, esp young children) 17350970
Other contacts would not routinely be offered anything unless index case especially infectious or if contact is especially susceptible. The preceding 3 month period is considered.
Do baseline LFTs and repeat after a week if starting Rif. Check urine colour is red or orange. Take at night if nausea.
Currently adults with mantoux 5-14mm with normal CXR do not get treatment, because historically this older patient group were at risk of hepatotoxicity. However cases of reactivation eg with pregnancy are seen with younger patients who are at less risk of side effects, so new guidelines will recommend treatment for latent infection.
There has been renewed interest in the treatment of latent infection esp as a TB-control strategy. The 2 broad categories of persons who should be tested for latent TB infection are those who are likely to have been recently infected (such as contacts to infectious TB cases) and persons who are at increased risk of progression to TB disease following infection with Mycobacterium tuberculosis (eg HIV etc; recent immigrants from high TB-burden countries).
NICE guidelines 2006. BTS guidelines in 2000 (Thorax 2000;55;887-901). WHO guidelines not v systematic. MMWR guidelines used in US.
H=isoniazid, Z=Pyrazinamide, E-ethambutol
Treatment is HRZE for 2 months then HR for 4 months (used to be 3 drugs only to begin with). Exceptions:
Reason for using 4 drugs is isoniazid resistance (among whites is 2%, among non-whites 6% but higher in London and India.
Streptomycin is another anti-TB drug, but injected. No comparison of streptomycin and ethambutol has ever been done. Strep CSF penetration good in theory but not proved to be superior.
Intermittent therapy (ie 2-3x weekly) appears to be as effective as daily but no RCT. 2x weekly seems intuitively a bit risky from point of view of resistance if doses missed. DOTS is recommended by WHO but seems overkill in UK so only if compliance doubtful.
Other issues:
Steroids: The American Academy of Pediatrics recommends adjuvant steroids in patients with:
Weird atypical mycobacterial disease suggests a problem with Interferon gamma, NEMO or IL12 - see Immunodeficiency.
Non TB mycobacteria (NTM) cause chronic localized cervicofacial lymphadenitis in young children (ie scrofula ). Presents as painless unilateral lymph node enlargement, followed by a dusky/purplish discoloration, then shining, thinning and flaking of the overlying skin. Without intervention, eventually these lymph nodes adhere to the overlying skin, and form a chronic draining sinus. Usually submandibular and submental but may also be parotid, cervical. Kids usually 1-5 years old (?macrophage immaturity ?oral exposure to soil) and rarely have systemic symptoms. Differential diagnosis: partially treated pyogenic adenitis, tuberculous scrofula, cat-scratch disease, lymphoma. Lack of systemic symptoms, no response to antibacterial therapy, young age, node location, normal chest radiograph, normal FBC/ESR, modest or negative Mantoux and lack of exposure to active tuberculosis support the diagnosis of NTM scrofula.
Definitive diagnosis of NTM scrofula requires a positive culture, PCR or histology. Only 30-80% of cases are culture-confirmed. M. avium complex organisms is most common, followed by M. scrofulaceum and M. kansasii. Several difficult-to-cultivate mycobacteria are being recognized esp with PCR, including M. genavense and M. hemophilum. Typical histology is stellate or serpiginous necrosis with nuclear debris, necrotizing granulomas, and/or acid-fact bacilli. Some series report increasing rate of NTM infections.
A case series from Israel of 92 culture positive cases showed that purulent discharge could continue for 3-8 weeks but that resolution occurred within 6 months in 71% and within 12 months in all cases. Typically a skin coloured flat scar was left. These cases probably reflected the milder end of the spectrum, with only 25% of cases showing the violaceous skin change. Zeharia et al, PIDJ 2008;27(10):920-2 PMID 18787500 Other reports have suggested that healing may take years but does eventually occur even in cases of incomplete surgical excision.
Before clarithromycin and azithromycin came along, medical therapy was ineffective; surgery was the only option. Surgery is still a primary treatment choice because:
Complete excision has a success rate of about 90%. Complications/recurrence after surgery more likely where:
The rate of facial nerve damage is about 14% but weakness often improves or resolves over 6-12 months. Other surgical options:
Definitive surgical intervention is sometimes impossible where resection may endanger the facial nerve. In many cases, incomplete resection still results in full healing.
For when complete surgical resection is impossible or unsuccessful. Various regimens, all include either clarithromycin or azithromycin; most include other drugs such as rifampin, rifabutin or ethambutol. Standard course is for 6 months. NB Sensitivity tests for mycobacteria not v reliable, resistance in vitro not always clinically significant.
Clarithromycin dose is 15mg/kg/d, max 500mg. The suspension of granules is well-tolerated as long as the granules do not open before swallowing. Rinsing the mouth and cleaning the face after dosing is strongly advised. Children do not report the postdose bad taste as often as adults. Families should be cautioned to observe for hearing loss. Brownish discoloration of the teeth has been reported but resolves after discontinuation of the drug.
Clarithromycin has the best in vitro activity, active against many NTM species. In cases of disseminated NTM disease, its use is associated with better outcome than non-clarithromycin-containing regimens.
Azithro dose is 10 mg/kg/d (maximum dose, 250 mg), and suspension is available. Families should be cautioned to observe for hearing loss.
Azithromycin has fewer drug interactions, better taste, once daily dosing and less taste problems. In vitro though, it has slightly less activity than clarithromycin, but clinical efficacy has not been compared prospectively.
Rifampicin dose is 10-20 mg/kg/d (maximum, 600 mg). The 150- and 300-mg capsules can be opened and contents sprinkled onto soft vehicles or into a small amount of simple syrup.
Rifampicin induces metabolism of clarithromycin (and many other drugs), rarely causes hepatotoxicity. Rifabutin has been used less in children; the dose is extrapolated to be 5 mg/kg/d (maximum, 300 mg). It has less effect on clarithromycin levels but is more expensive and has potential side effects including neutropenia, dose-related uveitis and pseudojaundice. Ethambutol is used cautiously in children due to dose-related optic toxicity in adults. A 15-mg/kg/d dose is probably safe if used under close observation. Tablets can be crushed into food.
Pediatric Infectious Disease Journal. 23(10):957-958, October 2004. Loeffler A
There has been only 1 reported randomized controlled trial of surgery vs medical therapy. `This found that surgery was 96% effective at 24 weeks cf only 66% for medical therapy with clarithromycin and rifabutin. Lindeboom, Clinical Infectious Diseases 2007;44:10571064 PMID 17366449 . But nearly a quarter of subjects refused randomization. The cure rate with medical therapy alone was not much different to the rate for spontaneous resolution described by Zeharia after needle aspiration.
Although a large randomized controlled trial would appear necessary to decide the best treatment modality, in practice patient variation and patient choice would make such a trial unfeasible. The natural history suggests that whatever treatment options are employed, healing will eventually occur. Factors such as patient preference, extent/skin involvement of lesion, progression, proximity to the facial nerve, compliance with long term medication, adverse effects to drugs will all tend to guide management decisions. Honest open discussion with the family and an agreed treatment plan, perhaps assisted by before/after photographs, is probably the best strategy in most cases.
Neutrophils and macrophages required to combat fungi, hence seen in CGD and Hyper IgE syndrome.
Rhinocerebral disease associated with sinus infection, presents with nasal congestion, epistaxis, palatal erythema, ocular signs. Diagnosis by deep sinus culture or biopsy.
Pulmonary disease classically shows infiltrates with central cavity on XR. On CT, macronodules +/- halo sign (macronodule surrounded by ground glass opacity, an early sign). More rarely consolidation, infarct-shaped nodules, cavitary lesions, air-crescent sign. Diagnosis by biopsy.
Peritoneal candidiasis is a well recognized complication of intestinal perforation, esp pancreatitis in adults, with high mortality.
Diagnosis of aspergillus - Precipitins are IgG antibodies, but their presence is not always clinically significant so interpret in clinical context eg ABPA vs invasive disease. Alternatively there is PCR - US has different cut offs from UK, who are more stringent. Galactomannan (a wall protein) assay has 70% sens, 90% spec in immunocomp so need to do serial screening.
Antifungal therapy failure is a major problem, despite a broader range of more effective drugs. Resistance is a problem eg some candida, but poor response to treatment may have more to do with host factors, low concentration of the drug at the site of infection, drug toxicities, wrong diagnosis, and misdiagnosis of failure because of the occurrence of immune reconstitution inflammatory syndrome. See antifungals below.
Indeed, emergence of resistant candida species seems to be related less to use of antifungals and more to changes in immunosuppression (severity, duration).
Now classified as a fungus, and renamed P jirovecii from carinii. Cannot be cultured. Unclear whether reactivation or airborne spread; isolation not usually recommended. Extremely rare to extend beyond lung! Typical CXR is bilateral perihilar interstitial infiltrates that become increasingly homogeneous and diffuse as the disease progresses. Less common findings include solitary or multiple nodules, pneumatoceles. Pleural effusions and thoracic lymphadenopathy are rare. If CXR is normal high-res CT may reveal extensive ground-glass attenuation or cystic lesions.
Diagnose by staining or PCR of sputum, else BAL. Depending on the degree of immunosuppression, there may be more or less organisms relative to neutrophils.
Prophylaxis should be used for CD4 counts below 200 or patients with history of oropharyngeal candidiasis. Even patients on 16mg Prednisolone for 8 weeks are at risk. Dapsone, atovaquone are alternatives.
Treat with Co-trimoxazole (NOT contraindicated with methotrexate, although give folate and monitor blood counts). Else primaquine/clindamycin, atovaquone, neb pentamidine. Give steroids if hypoxaemic - start with big dose eg 40mg BD pred, 1mg/kg methylpred BD then half each week, stop after 3 weeks. Risk of resistance, in theory. New England Journal of Medicine. 350(24):2487-2498, June 10, 2004.
(also known as zygomycosis) Typically rhino-oculo-cerebral invasion, but can be anywhere incl intracardiac. High mortality, diagnosis often only at autopsy. Distinctive micro appearance - angiotropic, ie invades vessels causing thrombosis.
Nocardia (asteroides) and Actinomyces (israelii) are gram positive bacilli that form filaments. Both are found in the soil. Actinomycosis is woody, painless mass lesions with sinus formation suggestive of tumours but with sulphur granules and filaments on microscopy. Treat with long term penicillin and surgery.
On agar, nocardia forms white colonies that are verrucous else heaped up or folded. Characteristic of Chronic Granulomatous Disease - always pulmonary, often disseminated. Prophylaxis (IFN or septrin) effective. Often coexistent fungal infection. Rx septrin, mero, amik - all effective, linezolid too.
Neutropenia defined as <0.5 in most units.
Organisms:
Outpatient Rx preferred by parents - less nosocomial infections, less broad spectrum antibiotics required. Obviously not for high risk eg previous septic neutropenic episode, inpatient stay beyond 1 week, post BMT or relapse, CRP>50.
Combined procalcitonin and IL8 can achieve 90% sensitivity and specificity.
More conservative regimens?
NB chemo is generally getting more rather than less intense so these more relaxed regimens may not be appropriate.
Treatment:
Streptococci (both aerobic and anaerobic) cause 50-70% of brain abscesses in children. Staphylococci (10-30%) and enteric bacteria (10-25%) are also commonly isolated. Mixed flora are found in up to 30%, and isolation of anaerobes is increasing. In neonates Gram-negative enterics are most common. Immunocompromised hosts can develop brain abscess caused by Nocardia, fungi or Myc bacterium tuberculosis. Toxoplasma gondii, the most common cause of parasitic brain abscess in adults with AIDS, is rarely encountered in children.
The most common predisposing conditions are cyanotic congenital heart disease (hematogenous spread) and direct spread from a contiguous site (middle ear, sinuses, teeth). Brain abscess uncommonly complicates bacterial meningitis or head trauma (usually with a significant delay from the time of injury). Although some other conditions (eg cystic fibrosis, bronchiectasis, following brain surgery, oesophageal dilatation) may predispose to brain abscess, no predisposing factor can be identified in up to 30%.
The location and predisposing condition of the abscess provide clues to the possible etiology. Frontal abscess may be related to a sinus or tooth focus and are caused by aerobic or anaerobic streptococci (including Streptococcus milleri), Enterobacter, Staph and anaerobes. Abscess secondary to ear infection is usually temporal or cerebellar, with mixed flora including anaerobes and streptococci (aerobic and anaerobic), Enterobacteriaceae and Pseudomonas aeruginosa. Posttraumatic brain abscess is commonly due to S. aureus, streptococci or Enterobacteriaceae. Hematogenous spread from a distant focus usually causes multiple monomicrobial abscesses in the distribution of the middle cerebral artery. Haemophilus aphrophilus is relatively common with cyanotic congenital heart disease (CCHD), whereas S. aureus or streptococci are major causes in abscesses from endocarditis or prolonged bacteremia.
Headache, fever and vomiting each occur in 60-70%. Seizures, altered mental status and focal neurologic signs occur in 25-50%. The classic triad of fever, headache and focal deficits occurs in under 30% and meningeal signs in at least 25%! Thus the presentation of brain abscess in infants and children can be nonspecific, and a high index of suspicion is required.
Only 10% of blood cultures are positive. CT scan with contrast may show a ring-enhancing hypodense lesion but may lag behind the clinical presentation. MRI is superior to CT because of greater sensitivity and better soft tissue details. CSF findings are generally nonspecific, and the cultures of CSF are usually sterile except in the unusual circumstance of abscess rupture into the CSF. If scans indicate a brain abscess, an LP is generally not indicated, because of the very low yield of microbiologic results from the CSF. If the CT and/or MRI fail to demonstrate a brain abscess, then consideration of the LP is determined by the remaining causes on the differential diagnosis (e.g. meningitis).
Surgical drainage with antimicrobial therapy is the treatment of choice for most brain abscesses. Although medical treatment is facilitated by the availability of CT and MRI, the chance of success is maximized when the etiologic agent is known and antimicrobial therapy is targeted. Thus CT- or MRI-guided stereotactic aspiration should be encouraged, and aspirated material should be sent for Gram's stain and cultures for aerobic and anaerobic bacteria, fungi and mycobacteria. Stereotactic aspiration is accurate, minimally invasive and associated with few complications. Surgical excision is reserved for reaccumulation of fluid, multiloculated abscesses or posterior fossa abscess. In fungal, Nocardia and helminthic infection, surgical intervention is frequently required due to failure of the medical treatment. Surgical procedures can reduce raised intracranial pressure, obtain pus for microbiologic diagnosis and enhance the antibiotic efficacy. In carefully selected patients (illness duration <2 weeks, neurologically intact, no signs of increased intracranial pressure and abscess <3 cm in diameter), medical therapy alone can be successful. However, such patients should be imaged frequently (once a week) during the acute illness to assure that the lesions are regressing in number and size.
For brain abscess associated with sinusitis, mastoiditis, otitis or CCHD, a third generation cephalosporin plus metronidazole is recommended. Ampicillin/sulbactam, meropenem or ciprofloxacin are reasonable alternatives. With the increasing prevalence of methicillin-resistant S. aureus and Staphylococcus epidermidis, vancomycin should be added to a third generation cephalosporin (possibly with metronidazole) in cases associated with penetrating head trauma, ventriculoperitoneal shunts or endocarditis. Vancomycin should also be added to a third generation cephalosporin if the abscess is associated with meningitis to cover cephalosporin-resistant Streptococcus pneumoniae. In neonatal brain abscess where Listeria monocytogenes is possible, ampicillin should be added to the cephalosporin.
The duration of therapy must be individualized, but intravenous antibiotics generally should be continued for 4-6 weeks. A 3- to 4-week course may be adequate for those who underwent surgical excision. Although some recommend an additional 2-3 months of oral antibiotics, the benefit is doubtful. Corticosteroids may decrease intracranial pressure but potentially can also decrease antibiotic penetration across the BBB and impair clearance of the pathogen.
Mortality remains relatively high (15% die). Two-thirds of survivors recover without neurologic sequelae, and one-third develop neurologic sequelae. Poor prognostic factors include infants, rapidly progressive neurologic impairment, multiple foci and coma at diagnosis.
Yogev, Ram; Pediatric Infectious Disease Journal. 23(2):157-159, February 2004.
Infection occuring within 10/7 of insertion mostly due to extraluminal spread of bacteria. Thereafter intraluminal - haematogenous spread is probably rare! Biofilm orgs need antibiotic levels of 100-1000x MIC to achieve kill. Risks include difficult placement (5x), lack of tunnel, multiluminal, contam of hub, duration >7/7, frequency of set change.
These lines should be for short term use only. Risk of resistance - but no data. Good economic argument in favour.
Diagnosis:
Pull line if short term! Pull a longterm line if complicated infection (ie tunnel infection, thrombosis, shock), Stenotrephomonas, B cepacia, Pseudomonas, multiresistant Acinetobacter baumannii, or Aspergillus infection. Candida & staph aureus debatable. Coag Neg Staph & gram neg enterics 60-90% can be cleared without line removal. Antibiotics via line, plus lock for 12hrs. May work for other bugs where line needed.
Duration of antibiotics? Adults have higher SBE risk. Probably 2/52 if removed and rapid defervescence. If left ?4/52, ?echo for staph.
Clinical Microbiology & Infection. 12(7):606-620, July 2006
Risk factors for haematogenous complications of staph aureus catheter infections include:
Clin Infect Dis 2005;40:695-703.
Uveitis usually presents with photophobia, tears, decreased vision. Often minimal redness but loss of red reflex, fuzzy retinal view, band keratopat y.
Do mantoux, syphilis, RF, lyme, rubella, cmv, toxoplasma, histoplasma.
Endophthalmitis has pain, loss of vision, oedema, hypopyon. Mostly postop staph, strep. But can be:
Aspirate for culture & micros. Intravitreal, topical & IV antibiotics then vitrectomy. Cyclopegics to prevent synechiae.
Note difference between occupational injuries (including porters, police, cleaners), hospital acquired and community acquired injuries (occurring outside of hospitals and health care settings, usually relating to injecting drug use). In addition to accidental occupational or non-occupational contact, children are known to play with found sharps and even to imitate drug taking behaviour (pmid: 16291833, 8135572, 17006290).
Guidelines exist on the prevention of tetanus and blood borne viruses from such injuries, generally in agreement with each other. (Greenbook, pmid: 15192899, EAGA guidance UK 2008, Red Book 2006, pmid: 12777574, CHIVA 2007). These are discussed in more detail below. The risks of blood borne virus transmission appear to be small, given prior immunization and use of post-exposure prophylaxis. But the high prevalence of Hepatitis C in the drug using population and the absence of a vaccine or post-exposure prophylaxis regimen will continue to cause concern.
Hepatitis A has spread in epidemic form among injecting drug users by unhygienic injection practices pmid: 8036466, Euro Surveill. 2005;10(10):pii=569.).
The more usual suspects are Hepatitis B, C and HIV.
Of the three viruses, HBV has the highest transmission risk as it has the highest virus titres in untreated individuals and is viable for the most prolonged periods in needle syringes stored at room temperature (pmid: 14723407). The risk of contracting disease from a single percutaneous exposure to HBV-infected blood without any post exposure prophylaxis is very high, ranging from 6% to more than 30%. High rates are associated with exposure to HBeAg-positive blood (pmid: 12170239)
There have been very few if any cases of HBV transmission in occupational settings since post-exposure prophylaxis with hepatitis B vaccine has been available, and now that immunisation of healthcare workers is routine (pmid: 10182555) Post-exposure prophylaxis may still be necessary where immunisation has been missed or ineffective. An accelerated course of hepatitis B vaccine with doses at 0, 1, and 2 months is recommended, ideally starting within 48 hours of exposure, and not longer than 7 days post exposure. A booster dose at 12 months is recommended for those at continuing risk. Specific immunoglobulin (HBIG) is recommended where the source is known to be hepatitis B positive. See Green book.
Estimates of the risk of acute HCV infection following a percutaneous injury from an HCV positive source vary between 0 and 10% across studies (pmid: 17684714) The risk obviously depends on the prevalence of the disease in the population. Where the source has a high viraemia, the risk is considerably higher.
There is no established post-exposure prophylaxis protocol. Some cases develop a transient viraemia and antibody response. Antivirals are used for HCV disease, and early treatment of new infections where spontaneous clearance does not take place has been validated (PMID 15710214).
There have been at least 5 cases of HIV infection occurring through needlestick injury, all occupational (PMID 3273755) The risk of transmission of HIV from a known source is estimated at 0.29-0.56% (PMID 15789967) Logistic-regression analysis based on 33 cases and 665 controls showed that significant risk factors for HIV seroconversion were:
Use of zidovudine post-exposure prophylaxis was about 80% protective (OR=0.19; 95% CI 0.06-0.52) (PMID 9366579) There have been at least 2 cases of fulminant hepatic failure with HIV post-exposure prophylaxis (PMID 9366579, 11198946) More recent protocols do not include nevirapine, the agent most likely responsible for hepatic failure, but instead recommend zidovudine (or stavudine) and lamivudine, with or without Kaletra or nelfinavir, for low risk cases (pmid: 15192899, 12777574) Post-exposure prophylaxis is probably of no benefit if started later than 72 hours after exposure and should ideally start as soon as possible.
Hepatitis viruses and HIV can be detected outside the human body for at least several weeks, and possibly for up to 12 months (PMID 14723407, 8603983). Detection of virus outside the body is influenced by virus titre, volume of blood, ambient temperature, exposure to sunlight and humidity. In a simulation study, blood borne viruses could be detected by enzyme linked immunosorbent assay (ELISA) in blood residues and from needle tips for up to 5 weeks (PMID 8921748)> In contrast, HIV proviral DNA could not be found in 28 syringes found outdoors or 10 syringes from needle exchange programme (PMID 9686738). But it is not clear whether a positive result (for DNA, enzymes, RNA, etc) equates to the virus actually retaining the ability to infect.
HBV post-exposure prophylaxis should be offered. Since the source is generally unknown, HBIG is not recommended. HIV post-exposure prophylaxis on the other hand should only be started in exceptional circumstances, eg if the source is known to be positive, if the injury was particularly deep or if there was fresh blood in the syringe. Where it is started, 16-96% of patients do not complete the full 4 week course, which may relate to side effects, the degree of parental motivation or cost considerations (pmid: 16291833, 17006290, 18676535, 17682761) Low motivation may relate to attempts to reassure families that there is minimal risk of infection.
There have been 13 studies looking at community acquired needlestick injury in children (PMID 16291833, 17006290, 18676535, 8948755, 9859551, 12047709, 15851438, 17682761, 14992057, 10830685, 17682761). Some of these studies describe mass exposure incidents, others describe a series of patients. In most, HBV vaccine was offered, and in some HBV immunoglobulin was offered. Most looked at all 3 viruses of interest. In only 1 study was seroconversion seen - a case of HBV in which post exposure prophylaxis was not given (PMID 9859551). Evidence of transient infection with HBV was seen in several other patients in this same study. However, follow up rates across the different studies were variable and sometimes poor.
There has been only 1 other report of CANSI associated with a blood borne virus infection in a child (PMID 9384355). In this case, a patient presented with hepatitis and HBV infection, and retrospectively CANSI was the most likely mode of transmission; HBV immunisation had not been offered.
There are only a few adult studies, and some relate to police officers which may reflect a different risk group (PMID 17682761, 14992057, 11957386, 15710272). To date there has not been a single report of HIV or HBV seroconversion from CANSI among adults. 3 cases of HCV seroconversion were reported recently (PMID 17914964, 15937781). So discarded needles appear to pose a small but not negligible risk.
The risk of an unknown source depends on background virus prevalence. Estimating the prevalence of blood borne viruses among injecting drug users (IDUs) is difficult, and different methods are used in different regions. The prevalence of HIV among current injecting drug users in 2007 was 1.1% in England and Wales, varying regionally. In London, the prevalence was 4.4%. In Scotland in 2005, 0.3% of injecting drug users undergoing HIV testing were positive (Health Protection Agency 2008). The prevalence of HCV antibodies among current injecting drug users in 2007 was 40% in England and Wales. In Scotland it varies from 28% in Dumfries & Galloway to 71% in Greater Glasgow, and is around 44% overall (PMID 16722130).
Data for HBV is even less informative. In England, Wales and Northern Ireland in 2007 15% of current and former injecting drug users were positive for HBV core antibody, demonstrating past exposure but not necessarily infectivity. There is no reliable data for the prevalence of HBV in Scotland - it is around 19% but again varies regionally (Health Protection Scotland 2008) Prevalence of HBV surface antigen is closely related to vaccination coverage which continues to increase; but new cases continue to be reported in the injecting drug user population (PMID 15531039).
CHIVA (part of BHIVA.org) for UK guidelines.
HIV 2 (west Africa, parts of India) is less aggressive with lower risks of disease progression and transmission.
HIV may now have peaked globally. Prevalence in Africa has been stable or even declining for some years eg Uganda, Kenya, Malawi and now in India and China it also appears to be stabilising. Incidence is hard to measure and usually has to be calculated from changes in prevalence, but prevalence lags behind. Probably due to: high risk individuals get infected first, so initial explosion but then reduced pool and transmission; behaviour change. Just means that the number of new cases matches the numbers of deaths - long way to go to reduce impact, and still potential for things to go backwards. Lancet Volume 367, Issue 9517 , 8 April 2006-14 April 2006, Pages 1120-1122
Testing for HIV is never urgent and should be done after careful consideration of the competency of the child and discussion with the family, with appropriate interpreter services (NOT family/friends) if necessary. Remember that a positive test in a child almost certainly means Mum is positive too, if not others.
Measuring CD4 counts as a surrogate marker is inappropriate. HIV antibody test is enough after the age of 18 months when maternal antibody has cleared, but a positive should probably be repeated for certainty. Before that, see Maternal for testing babies/infants; you can't make a diagnosis in the first month of life, and strictly you should wait till 18 months to confirm disappearance of maternal antibody before you can really declare a negative.
After diagnosis is made, or where diagnosis is not in doubt, there is a long list of staging investigations that should be done: see CHIVA guidelines.
There is bimodal pattern of disease progression: 10% are rapidly progressive and die within a year.
WHO gives clinical staging (children slightly different from adults):
Normal CD4 at 6 months is 3000. Advanced HIV (including AIDS) is defined in the over 5s as a CD4 count less than 350; but under 5yrs you have to look at percentage of CD4 cells by age - see below.
Viral load is not cleared by kids and is not as predictive as it is in adults.
Although mortality in infected infants is much lower now than in past, symptomatic disease rates remain high: associated with infrequent clinic attendance, poor compliance, late presentation. Worrying of course because resistance is likely to kick in quickly.
Infected infants appear to be at increased risk of developmental delay but studies inconsistent and short term. Wouldn't be surprising since HIV has a direct destructive effect on neuronal tissue in the CNS.
Even uninfected children born to mothers with HIV also manifest disturbances in their development eg attentional, social, and behavioural problems (but not in all studies). Important because uninfected outnumber infected. Presumably compromised parenting and childcare practices (eg depression and suicidal ideation), disruption of social and material support networks. Early psychosocial interventions in disadvantaged communities (without HIV), delivered during pregnancy and early childhood, have been shown to provide long term benefits to children and their families, should be at least as true for HIV. ArchDisChild 2005
Do CD4 count, viral load every 3 months if off treatment. Otherwise care as for T cell defects - avoid live vaccines, pneumococcal and flu vaccines.
Anti retroviral drug interactions in detail, including PDA versions.
Viral load and CD4% are the best predictors of disease progression but fluctuate with intercurrent illness, natural and test variability. Trend over 3-4 measurements better than single result, although rapid clinical deterioration or changing numbers are worrying.
Measure every 3-4 months. Large metanalysis gives estimates for risks of progression (Penta online calculator) but note strong calendar effect, ie risks now are probably less than before due to better drugs etc. CD4% and VL are independent predictors but CD4% is the better one. Percentage is also better for comparing children of different ages because CD4 total counts fall naturally with age, but total lymphocyte count and absolute CD4 counts important in older children. Risk estimates are less reliable for older children (small numbers) and infants (high variability).
A risk of progression to AIDS within 12 months of 10% is considered unacceptable, as is the risk of death within 12 months of 5%, but these are obviously arbitrary and will be revised with time. There is a need to assess the more subtle risks of HIV in untreated children esp cognitive impairment, and balance these with emerging toxicity data.
Cut off for AIDS risk of 10% at 6 months is hard to say: CD4 of 50% gives a risk of 35% so it's at least that. Cut off for AIDS risk of 10% at 6 months for 1 year old is about 40% (flat curve); 2 year old, 25%; 5 year old, 15%; 10 year old, 5-10% (steep curve). (table and graph don't match!)
VL under 4 logs are unlikely to progress rapidly (under 3% AIDS within 1 yr). Note lab variation esp at extremes of measurement so repeat. For infants, VL over 1 million gives an AIDS risk within 1 yr of over 10%. For 1-12 yrs, equivalent VL is 250 000.
Always triple. usually PI or NNRTI based. Protease inhibitors - lopinavir, nelfinavir (with or without boosting ie coadministrati n with ritonavir); metabolic toxicity. Non-Nucleoside Reverse Transcriptase Inhibitors - Efavirenz, Nevirapine - act fast to lower viral load but resistance develops easily (single mutation);
Recommended NRTI combinations are:
NVP has liquid, but resistance with single mutation, rash and hepatic side effects. EFV once daily, resistance with single mutation, neuropsych side effects. LPV/r low volume syrup (still poor taste however) but large capsules. NFV few adverse effects other than diarrhoea, needs to be given with food, high variability in blood levels, high pill burden.
PENPACT1 randomizes PI or NNRTI based triple regimen. Discussion with family should consider taste, volume/number of syrups/pills, crushability, storage and food requirements, frequency of administration. In adults, metanalysis shows initial tolerability is prognostic.
Lopinavir/ritonavir (Kaletra) liquid is safe, well tolerated and small volume. VL and CD4 seem to be better (69% achieve VL<50 at week 48) non-randomized) so ritonavir boosted PI regimens seem to be better than non boosted (as in adults). Concern about lipodystrophy. Major concerns about metabolic toxicity from PIs, so interest in NNRTI based regimens. EFV seems to be better than NFV in adults, few data in kids. Good response to NVP if high dose (use surface area calc). PACTG study combining nelfinavir with efavirenz achieved 63% VL<50 at week 48 but low baseline. CNS toxicity is the main issue with efavirenz.
Triple NRTI regimens in adults seem to have a worse outcome esp if very high VL or stage C disease. New strategy in adults is to start with 4 then simplify after response. May be appropriate to use triple regimens in kids on antituberculous Rx or adolescents where adherence is a problem (trizivir is one pill BD - AZT/3TC/ABC). In the future regimens will hopefully be once daily, once pharmacokinetics have been sorted out.
FORTE trial supports the idea of intensive induction followed by simplification (4 drugs to 3). One strategy could be a ritonavir boosted PI regimen switching to an NNRTI or triple NRTI regimen.
Planned (structured) treatment interruptions - make sense because of regenerative capacity of thymus, better CD4 response to reinitiation of ART cf adults, reduced toxicity and cost. But more resistance?. Cohort study showed widely varying rates of CD4 fall unrelated to initial values. PENTA 11 will evaluate.
Immune reconstitution syndrome - symptoms may be similar to opportunistic infection, occur around 6 weeks after starting ART with very low CD4 counts. CD4 rises rapidly. Difficult to diagnose! Steroids may be useful and ART should be continued.
New ART - Tenofovir and Emtricitabine (FTC) are NRTI, once daily. Atazanavir is once daily PI with little lipid disturbance. Tipranavir is active in PI resistant virus (must be boosted). Fosemprenavir is PI with lower pill burden (must be boosted). Enfuvirtide (T20) is fusion inhibitor, a new class so no cross resistance - painful subcut injection.
Usually virological first, then immunological and finally clinical (recurrence or non-disappearance of stage B/C disease). However lots of children maintain a detectable VL with high CD4% and remain clinically well. Danger is that the presence of continued vial replication will lead to more resistance mutations. PENPACT1 is randomizing switching therapy at VL of 1000 or 30000. Causes of failure are adherence, inadequate levels. Genetic/racial differences in drug metabolism significant with high variability, esp NNRTIs/PIs. Therapeutic drug monitoring may be useful (PENTA14). NNRTIs are particularly likely to lead to resistance to the whole class within only a few days of viral replication.
No resistance mutations suggests non-adherence! Virus replicates every 6 hours, mutants tend to be less fit so wild type predominates unless selection pressure exerted by therapy. Sometimes possible to reintroduce drugs previously prescribed if issue was poor tolerance rather than resistance. But beware selecting out resistant mutant which has become undetectable (PCR probably detects only a minority of virus present). An archive of latently infected CD4 cell develops very early in infection; the half-life of these cells is over 3 years, plus they retain the ability to proliferate. Presumably originate from when lymphoblasts that are in the process of reverting to a resting state become infected. The lack of detectable evolution in viral sequences during HAART argues against new genotypes entering the latent pool during successful treatment - persistence must depend primarily on the intrinsic stability of the infected cells.
Change all 3 if possible. Combinations of 4-5 drugs (Mega HAART) might be considered but interactions, poor tolerabiltiy, cumulative toxicity. Higher doses may overcome partial resistance. Planned treatment interruption may allow wild type sensitive virus to proliferate (evidence in adults against!). IL2 may boost CD4 even in presence of high levels of viral replication, may be useful if immunological failure predominates (PENPACT2).
Resistance testing can be done phenotypically, meaning actually culturing virus in the presence of drug, or more usually, genotypically. Here genetic mutations known to produce certain resistance patterns are looked for, giving a "virtual phenotype" - faster, more cost effective. The only problems are that rarer mutations may not be recognized, and at low viral loads there may be insufficient material to sequence.
To interpret these mutations, use a database eg Stanford. For some mutations resistance is absolute, but others esp TAMS (Thymidine Associate Mutation) relative and cumulative (need about 6 before resistance significant) so higher doses may be effective. Should be done in pregnancy, failure of regimen, before change in regimen. Consider in under 2s. If all VLs are archived, can go back and study previous resistance patterns. Using meds with known resistance selects out type which may be less fit eg reverse other mutations or more sens to other NRTIs, so may be useful eg 184 resist 3TC but more sens to tenofovir!
Adherence - in adults, more than 90% adherence required for sustained viral suppression. 4 drug and PI based regimens are the worst. Once daily are 3TC, ABC, ddI, FTC, EFV, TDF. Ask how many doses missed in previous week. Pharmacy records best, therapeutic drug monitoring (TDM) not totally sensitive.
Toxicity - lipodystrophy increasingly recognized, mostly facial and limb atrophy, but truncal obesity and buffalo hump also occur. Blood lipids may or may not be raised. DEXA may detect before clinical signs. Risk factors: puberty, females, advanced disease and duration of time on ART, PI use, D4T (Stavudine) use. Switch PI to NNRTI or abacavir in children with markedly abnormal blood lipids. Limited experience with statins. Mitochondrial toxicity manifest as lactic acidosis is rare but serious. Early symptoms are nonspecific, and random lactates are not predictive. NRTIs in utero are associated with transient hyperlactat emia, ?higher risk in future. Treatment with mitochondrial multivitamin rescue can be considered. Osteonecrosis of femoral and humeral heads occurs, with Perthes being 9x as common.Consider bisphosphonates in patholotgical fractures. Impaired glucose tolerance and hyperinsulinaemia not uncommon in PI treated adults, but rare in kids.
HIV Med 2004;5(Suppl 2):61-86, Mike Sharland et al
Protease inhibitor based HAART raises the percentage of CD4+ cells in HIV-infected children but is most effective when treatment is started at younger ages and before severe immunosuppression has occurred. Randomised trials are needed to establish the best time to start treatment. (Lancet 2004)
TB occurs in HIV patients even with relatively intact immunity. Suspicion that TB triggers enhanced viral replication. RCT of prednisolone therapy in Kampala - better immune activation and CD4 counts, quicker clearance of TB from sputum but outweighed by higher HIV RNA and adverse events (fluid retention, hyperglycaemia). J Infect Dis 2005;191:856-65.
CMV appears to be a co-factor for HIV, status has a strong bearing on outcome, almost more prognosis than HIV load.
AIDS progression and mortality in children in UK has fallen signficantly. However, total number of hospital admissions has only decreased by 25% due to increased survivors, so burden not changed much. Nearly a quarter of HIV pos kids aged over 10 - need for psychosocial support.
Quality of life among US children receiving PI therapy differed little from that among children receiving non-PI therapy, despite clinical indications of more advanced disease. No evidence of side effects other than an increased rate of diarrhea. Findings suggest that PI combination therapies slow or prevent disease progression and increase CD4 cell counts and height growth. Many children experience behavioral problems and clinical symptoms, equivalent to other chronically ill children with socio-economic disadvantage. Pediatrics. 2005 Jan 3
Bartonella henselae causes CSD, and has been recognized worldwide as a zoonosis with a wide clinical spectrum. It is emerging, particularly in immunocompromised patients. The organism is transmitted to humans by a kitten scratch, bite, lick or other intimate contact. The cat flea transmits B. henselae from one kitten to another 4 and is hypothesized to be responsible for direct transmission to humans. B. henselae is endemic in warm humid climates
CSD may present in a typical or atypical fashion in both immunocompetent and immunocompromised patients. Typical disease in immunocompetent persons includes a scratch, bite, lick or other contact with a kitten followed in 3-10 days by a round, red-brown, nontender papule within the scratch line. Regional, unilateral lymphadenopathy occurs 1-3 weeks later with gradual nodal enlargement. Unlike pyogenic lymphadenopathy, CSD does not progress rapidly, and patients are usually well-appearing with mild nonspecific symptoms such as anorexia, malaise, headache, arthralgia, myalgia or abdominal pain. Lymph nodes usually enlarge over 2-3 weeks, stabilize for 2-3 weeks and then resolve over 2-3 weeks. Any stage may be more prolonged; symptoms rarely exceed 6 months. Histologic examination reveals granulomas with central necrosis and multiple microabscesses. Up to 10% of lesions may suppurate and require needle or open drainage. CSD lymphadenopathy does not produce chronic draining fistulous tracts when incised and drained.
The most common atypical manifestation is Parinaud's oculoglandular syndrome (POGS) consisting of unilateral preauricular lymphadenopathy and conjunctivitis. Palpebral conjunctivas demonstrate a 2- to 3-mm red-yellow nodule or nodules, the equivalent of the inoculation papule seen with a scratch. Although POGS can be caused by other infections, B. henselae is the most common etiology. POGS is a predictable, self-limited infection with full recovery regardless of treatment in most cases.
Fever of unknown origin (FUO) and hepatosplenic CSD represent dissemination that may present in immunocompetent patients as daily spiking fevers lasting weeks to months. Frequently patients have an elevated erythrocyte sedimentation rate, but abdominal pain and lymphadenopathy are seen in less than one-half of cases. The diagnosis is likely with a history of kitten contact, dermal scratch scars and lytic lesions in the liver and/or spleen on ultrasound or computerized tomography (CT) scan and is suspect in patients who do not have these findings. In immunocompetent patients, insidious back pain is frequently the presenting sign of B. henselae vertebral osteomyelitis, with or without a paravertebral mass. Clinical and radiographic resolution appears to occur over months without intervention.
CSD causes many cases of endocarditis. Surgical intervention, including valve replacement, followed by months of antibiotics, is necessary in both pediatric and adult patients with Bartonella endocarditis. Neurologic complications of CSD include Leber's stellate neuroretinitis, characterized by painless, unilateral loss of vision with a macular star visible on retinal examination. Visual loss occurs abruptly over hours to days. Recovery occurs in weeks to months, with or without treatment. CSD encephalopathy is a severe complication frequently requiring admission to an intensive care facility and respiratory support. Progression from headache to coma typically develops within hours, often followed by rapid recovery. Cerebrospinal fluid and blood studies, as well as head CT scans, are often normal or nonspecific. Focal seizures or prolonged coma portend neurologic sequelae. Most immunocompetent patients recover fully without therapy.
Immunocompromised hosts may develop bacillary angiomatosis and peliosis. Bartonella stimulates endothelial vasoproliferation that can develop into large, pedunculated and painful tumors in skin, soft tissue, bone, bone marrow, respiratory or gastrointestinal tract, lymph nodes or brain. Severely immunosuppressed patients can form large blood-filled cysts in the liver and spleen. Bartonella bacilli can be demonstrated in these lesions by Warthin-Starry staining. Patients may present with gastrointestinal symptoms and malaise, but prolonged fever is the most common complaint.
A history of kitten contact supports the diagnosis of CSD. Fever and/or adenopathy should be prolonged. It is essential to examine the skin for scratches, bites, inoculation papules and adenopathy. A careful history and examination, along with serologic testing, can obviate the need for tissue diagnosis in immunocompetent patients with typical CSD. Atypical disease should be confirmed by serology or, if necessary, culture, by polymerase chain reaction (PCR) or by histology. Ultrasound or abdominal CT scan may be helpful in cases of FUO.
The IFA to detect IgG and IgM antibodies to Bartonella, remains the most widely used and reliable serologic test, reported sensitivity 88% and specificity 94% and performs well in recent omparison studies with enzyme immunoassay. There is wide variation in the Bartonella antibody responses in immunocompetent hosts. Although a Bartonella titre >1/64 is considered positive, some individuals with past disease may maintain this titre for long periods. One result of >=1/512, or a 4-fold rise over 2-4 weeks, has been proposed as diagnostic for acute CSD. PCR of infected tissues is far superior to histology or culture for detection of B. henselae.
Typical CSD is self-limited in immunocompetent individuals; resolution occurs in 1-3 months with or without treatment. RCT by Bass et al showed a modest hastening in resolution of lymphadenopathy (as measured by ultrasound) with azithromycin. Management strategies for atypical disease are limited to retrospective reviews given that most patients are treated with antimicrobials before confirmation of the diagnosis. Macrolides, rifampin, doxycycline, gentamicin, trimethoprim-sulfamethoxazole and ciprofloxacin may be effective alone or in combination. Immunocompromised hosts with atypical disease clearly require prolonged antimicrobial therapy to reduce morbidity and mortality.
B. henselae bacteremia persists for weeks to months in kittens, despite the presence of specific antibodies. Most adult cats possess Bartonella antibodies but are not bacteremic. It is unknown when or how cats form protective immunity or whether vaccination induces immunity. Treatment of cats is impractical and routine culture or serologic testing of pets is not recommended.
PIDJ Volume 23(12)December 2004pp 1161-1162 Batts, S
Borrelia burgdorferi (spirochaete), spread by Ixodes tick. Nymphs (tiny) more likely to spread infection than adults (probably because not removed, rather than borrelia load) hence spring peak. A significant proportion will not remember tick bite. Causes Erythema Chronicum Migrans - usually about 5cm (smaller lesions may just be inflammatory), central clearing, can be multiple, not necessarily at site of bite), endocarditis, arthritis, neuropathy/radiculopathy (in US, not really seen in Europe), hepatitis, pneumonitis. Refer to CDC criteria for active disease. Diagnosis: if classic ECM then no need (although A. americanum produces similar lesion in US)! Serology (EIA) IgM at 2/52 but high false pos/neg, and early treatment may prevent seroconversion, so Western blot to confirm. Potentially co-infection with babesia and anaplasma (in US) - consider if unusually sick or bone marrow failure. ?LP for CSF EIA. Treatment failure of acute disease means misdiagnosis! Use Doxycycline if old enough, else high dose Amoxicillin for 14 days. Macrolides are less effective! If IV needed, then ceftriaxone most often used so treatment can be on outpatient basis (not more effective - use for heart block or neurological. Lesions take 1-2 weeks to heal; Jarisch Herxheimer like reaction can occur with increased erythema and systemic symptoms. Chronic fatigue common; retreatment, even parenteral, no better than placebo. Infectious Diseases Society of America guidelines.
Connecticut's attorney general has been supportive of patient groups in demanding access to long term or repeated courses of antibiotics for prolonged symptoms - despite study failing to show any benefit. Note that in early disease, serology may not yet be positive - so retest in convalescent phase. Doxycycline theoretically has good CSF penetration and appears to work well orally for neuro disease; less evidence for amoxicillin.
Borrelia are much more sophisticated organisms than other spirochaetes or bacteria - when inside cells exhibit camouflage proteins and have a resistant cyst form. Hence chronic disease can be very difficult to eradicate.
In a follow up study of 177 Swedish children with suspected neuroborreliosis, 11% had persistent facial nerve palsy. Otherwise there were no recurrent or persistent deficits. Headache and fatigue were no more common or disabling than in a control group. (PIDJ Nov 08)
Prophylactic doxycycline effective (NEJM) but attack rate without only 2.5% even in hyperendemic region: NNT=30. Incidence in New York State 10x higher than UK.
Can involve any organ or system of the body. Most cases in humans are caused by contact with infected animals (via skin or inhalation) or ingestions of animal products, such as unpasteurized milk and cheese. Four species are responsible for most human cases: B. abortus (found in cattle), B. melitensis (found in sheep and goats), B. suis (found in swine), and B. canis (foun in dogs). The clinical presentation can be acute or progressive, usually starting with nonspecific symptoms, such as fever, sweats (classically malodorous), weight loss, arthralgias, and myalgias. The most common findings on physical examination include:
Other systems:
It is a noncaseating granulomatous disease (differential: TB, coccidiomycosis, sarcoid, Hodgkins). Both cultures (esp in absence of preceding antibiotic treatment and incubation for at least four weeks) and serologic tests are useful for the diagnosis of brucellosis. Treat as for other intracellular organisms eg doxy and rifampicin (2 or more because high relapse rate) for 6 weeks, else aminoglycoside/quinolone.
New England Journal of Medicine. 352(22):2325-2336
A crippling problem in sub-Saharan Africa but also seen in South and South East Asia. Only malaria free zones in the tropics are cities (some) and communities at altitude. Malaria deaths continue to rise at a time when non-malarial deaths are falling - this is mainly due to waning efficacy of available medicines, despite the arrival of new agents. Resistance continues to be a major problem and a vaccine remains elusive. The prevalence of fake medicines in endemic countries is another major problem.
Malaria has been with human beings for a long time in evolutionary terms, as seen in the numerous genetic mutations that occur for the express benefit of conferring partial immunity eg sickle cell trait, G6PD, hereditary spherocytosis. At the same time, the parasite has evolved multiple ways of avoiding the immune system, which is why developing a vaccine has proved so difficult. It is likely that our immune system has also evolved in response to pressure from the organism eg HLA_B53 confers 40% protection vs severe malaria.
The parasite sporozoite form is injected with salivary secretions into the human host. It circulates until it reaches hepatocytes, where it replicates and forms clusters called schizonts. These release trophozoites into the blood stream, where red cells are infected and further replication occurs. Disease only appears once widespread haemolysis has occurred, usually 3 weeks or more after initial infection. A proportion of trophozoites transform into gametocytes. When these are ingested along with human blood by another mosquito, they can then continue the life cycle in the mosquito. In P vivax and ovale, longlasting hypnozoites may persist in the liver, which can be responsible for late reactivation of disease. So suspect for a year after exposure (although Falciparum will present within 3 months).
In endemic areas, intermittent asymptomatic low level parasitaemia is seen commonly. Children are the most at risk of severe disease:
Even in adults with relative immunity, however, malaria causes recurrent, usually self-limiting, episodes of mild disease and is also responsible for chronic anaemia. In non-endemic disease, particularly travellers or people who have lost their immunity by long term lack of exposure after emigration, the infection is more likely to manifest with disease and the disease is more likely to be severe. Symptoms develop at least 3 months after exposure, but suspect the diagnosis in those at risk for up to 1 year after exposure (although falciparum usually presents within 3 months).
Usually affects young children, who present febrile in coma, +/- seizures. But often multisystem dysfunction. Meningitis is the main differential. Prognosis related to presence of recurrent seizures, raised intracranial pressure, metabolic derangement. There is a need to identify at risk cases not just severe because high mortality before quinine is started.
Respiratory distress usually due to acidosis rather than cardiac failure. Hence Kussmaul breathing predicts death.
Do not wait for the results of tests if symptoms/signs suggestive, since falciparum can be rapidly aggressive.
Malarial retinopathy found in severe malaria: patchy white spots similar to hard exudates, frosted branch appearance of vessels, and ring shaped haemorrhages (not pathognomic though, seen in infarction).
The blood smear is the classic test. Thin smears are best for identifying the particular type of malaria and the percentage parasitaemia (percentage of erythrocytes infected), but thick smears are more sensitive. Repeat testing is important - sensitivity is only 70% on a single smear, but rises to over 95% with 3 smears. Having >20% of periph forms with pigment (mature) reflects high burden of deep circulating parasites cf young ring forms, so a risk factor for poor outcome. >5% neutrophils containing ingested pigment is another risk indicator.
New molecular based antigen tests are expensive but are less reliant on operator experience.
HRP2 alone is probably most appropriate for high prevalence area where non-falciparum tends to be co-infection.
Blood cultures - accompanying bacterial sepsis common esp salmonella
Proposed UK Guidelines - BMJ in press. 80% of UK malaria now falciparum! Unclear exactly how imported disease differs from natural.
The non-falciparum malarias are still mostly sensitive to chloroquine - give orally for 3 days. G6PD deficiency should be excluded before chloroquine treatment is started in patients at risk. Treatment must also address eradication of liver stage hypnozooites - primaquine is effective.
In falciparum malaria:
7 days of quinine should then be followed a single dose of Fansidar (if likely to be sensitive), or by 5 days clindamycin or 7 days doxycycline.
WHO now recommends use of the newer artemisin derivatives (originally discovered in China) which have proved to be much more effective in terms of rate of clearance of parasitaemia (they are active against all stages of the parasite life cycle) and can be given intramuscularly, rectally as well as by other routes. In view of the problem of resistance, combination treatment is likely to be necessary for endemic areas. The rapid action of artemisin also makes the development of resistance less likely. No clear benefit for artemether for cerebral malaria in WHO multicentre trial. Rectal artesunate well absorbed, but no definite evidence of benefit.
Intermittent presumptive treatment beneficial in pregnant women, who are at risk of miscarriage. Cases of vertical transmission have been described, not in cases where Mums are chronically exposed however. Placenta appears to be a barrier of sorts.
Adjuncts:
A vaccine would be fantastic, but a potential candidate is yet to be found. There are several barriers:
Sporozoite vaccine in Mozambique reduces clinical malaria by 22% only, and only for 2-3 months. PfEMP1 is main antigen for natural antibody but high levels of variation. Probably best to go for T cell stimulating vaccine to knock out infected liver cells. Prime boost strategy = fowlpox vaccine first then modified viral vector eg adeno or smallpox. Current Kilifi trial. Combination probably more effective but likely to be too expensive for Africa.
Burkholderia pseudomallei - gram neg bacillus, causes CNS and liver/spleen abscesses, sepsis, pneumonia, parotitis (unique!). Looks like pseudomonas but sens to co-amox, resist to aminoglycoside. SE Asia but also S India, Taiwan so underrecognized (?Brazil). Rx Ceftaz standard, no advantage to adding Septrin. Meropenem probably better (case control data). High relapse rate so treat IV 6/52 then 6/12 oral septrin (Lancet review 2003).
Sandfly borne - reservoir can be human, dog or rodent. Microecology - ie seasonal, restricted range of environments. Can be epidemic. S Europe/Med, Ga ges, Nile, Amazon forest but patchy across to China and urban Brazil!
Skin (self limiting) or visceral depending on parasite. Pancytopenia, spleen > liver, cough, raised IgG/M. Not always fever. Black skin (kala azar). Assoc with immunodef - in HIV presentation can be mild and atypical, serology often neg but parasite numbers high.
Amastigotes (dots in macrophage) on microscopy (smear Buffy coat, spleen, marrow), serology, antigen dipstick. Antimony safe except pancreatitis in HIV - 30 jabs... Ambisome is drug of choice: 2-4mg/kg for at least 21mg/kg. Resistance in India. Paromomycin (IV) in phase 3, Miltefosine oral 28/7 compassionate use.
Cutaneous has different geography esp desert eg middle east, Sahara. Ulcer with nodular edge. Get tissue fluid from slit skin smear. Self resolving but braziliensis can spread to mucosa. Excise, freeze, burn. Infiltration with antimony. Azoles, rifampicin may be effective for certain species but studies difficult because self resolving.
Lots! New World Arenavirus in Central/South America, Rift Valley fever in Yemen/Saudi, even the Balkans have one. All are Arena viruses - incub 7-14 days. Lassa fever from rats (West Africa esp Sierra Leone), but human to human transmission esp blood. Most infections mild or subclinical (20% of fevers in endemic areas!). Myalgia, pharyngitis, d&v, retrosternal pain, proteinuria, deafness! Bleeding rare. Ribavirin effective.
Ebola has 92% case fatality, direct contact from symptomatic not aerosol. Reston subtype does not cause human disease but aerosol spread between apes. Monkeys are the usual source of infection esp bush meat but ?vector - no evidence for bats but caves etc risk. Incub 7-21, abrupt onset, mac-pap rash, d&v, ghostlike facies. Haemorrhage in second week.
Marburg (Germany) outbreak occurred in a lab, from African monkeys. Rare but current epidemic in Angola, >90pc case fatality, paed ward.
Don't do blood tests! Risk to lab. Specific elisa. Isolate, proph Ribavirin - there has never been a nosocomial case in the West.
Caused by Salmonella typhi but also paratyphi, though usually less severe. The advent of chloramphenicol almost disposed of it as a significant disease, but now there is resistance even to quinolones and third generation cephalosporins. Endemic in south and south-east Asia. If untreated, about 10% will continue to excrete for 3 months, 1-5% will excrete for a year or more (more likely if GI or GU disease). A quarter of chronic carriers will have no history of typhoid. Humans are the only host, transmission is associated with crops fertilised with sewage.
After ingestion, spread is via intestinal lymphatics into the blood stream. Incubation is 8-14 days, after which there is constant low level bacteraemia. Presentation can vary from mild fever to toxaemia with multisystem involvement. Usually there is a prolonged low level fever with headache and myalgia, a dry cough with creps/wheeze. Bradycardia is characteristic. There is often GI disturbance (constipation or diarrhoea, children more likely to have the latter), jaundice, hepatosplenomegaly +/or deranged LFTs. Rose spots appear on the back, arms and legs at the end of the first week in 25%. Fever then rises in stepwise fashion and if untreated can persist for 4 weeks. Malaise can persist for months in that case.
Differential diagnosis: TB, brucellosis, typhus, leptospirosis.
Most common complications are GI bleed, intestinal perforation (often preceded by fall in temperature), and encephalopathy. Other complications are legion, incl granulomas, abscesses, any organ.
Diagnosis is by blood culture (2-4ml required, sensitivity 30-90% depending) else bone marrow (80%+). Yield falls with duration of illness. Stool does not increase yield particularly and may only imply carriage. Widal test (O and H serology) usefulness depends on centre, due to varying cross reactivity with other local bacteria; become positive from day 10; 4 fold rise is diagnostic. Rapid antigen tests have only 80% sensitivity.
Quinolones (if organism sensitive - Nalidixic acid is a reasonable but not 100% reliable proxy) are 98% effective, leading to fever resolution in about 4 days, with chronic carriage rates of 2%. Better than chloramphenicol even if sensitive. Extensive experience with children, no evidence of bone/growth problems. Short (2-5 day) courses of ofloxacin are effective so good for epidemics. Azithromycin (7 days) or cefixime (oral)/cefotaxime (10-14 days) for nalidixic acid resistant strains - about 90% effective.
5-10% relapse after 2-3 weeks, although the illness is rarely severe.
Chronic carriers can be treated with 28 day courses of Norfloxacin or ciprofloxacin.
Vi polysacc IM vaccine for 2yrs+, boost every 3 yrs. New Vi conjugate higly effective but not yet tested in infants or available. Ty21a is oral for 6yrs+, given in 3 doses 2 days apart, boost every 3-5 yrs.
Coxiella burnetti, responsible for 15% of endocarditis in Marseille! Also found in Spain, US, Australia - regional differences in clinical picture. Tick reservoir, associated with cattle, sheep and goats; usually inhalation esp dust. Acute infection often missed - pneumonia and hepatitis but often afebrile, without jaundice. Can be multisystem. Chronic infection leads to PUO, endocarditis, osteomyelitis, and chronic fatigue.
Serology only usually positive after 3-4 weeks; PCR not v sensitive except on heart valve specimens! Rx doxycycline with chloroquine (enhanced antibiotic effect), else Septrin.
Pox virus still occasionally crosses from animals including rodents causing small pox like disease.
Multisystem disease caused by Rickettsia infection. Different types, depending on insect vector. Mostly louse borne, associated with R. prowazeki and R. typhi, but can be (see below):
Persists in warzones and highland areas of social deprivation eg Ethiopia, Rwanda, Burundi, Andes. The Rickettsia survives in the midgut of the louse, where it can be passed to man by scratching of faeces into the skin, or by inhalation of the faeces, or by ingestion of the crushed louse itself. Not spread by actual bite of louse! Tends to be epidemic. Can recur 20 years or more later - Brill-Zinsser disease. Note that the louse can also transmit louse-borne relapsing fever.
There is no bite lesion, cf Lyme disease. After an incubation period of 1-2 weeks, there is a sudden onset of fever, headache, myalgia with rash (which can be purpuric). A vasculitic illness, which may be complicated by encephalitis, pneumonia, acute renal failure, skin gangrene. Mortality rates are 10-40%.
Diagnosis - Weil-Felix response (proteus cross-reactivity) has poor sensitivity or specificity. Serology is the gold standard.
Treatment is by Single dose doxycyline.
Tick typhus - Old World tick typhus is rather different from New World tick typhus! Rocky Mountain Spotted Fever (R rickettsii) is seen in the South Western and South Atlantic US states. Petechiae are a particular feature, hence the name. It is similar to louse borne typhus in that there is no bite lesion, and encephalitis is a common feature. High death rate, unless treated with tetracyclines or chloramphenicol. The African form (also seen in the Mediterranean, South Asia and Australia) has the same sort of non-specific fever, headache and myalgia but there tends to be a black ulcer (tache noir) at the bite site which then develops into a more generalized rash. A milder disease than louse borne typhus, unless complicated by other disease eg G6PD deficiency.
Murine typhus - Rickettsia typhi, same as louse borne typhus, but transmitted by fleas associated with rats. Infection occurs by scratching flea faeces into skin, or possibly by inhalation as dust. Widespread but sporadic, with occasional outbreaks (often associated with a particular infested building). Disease is clinically indistinguishable from louse borne typhus but tends to be milder with low mortality rates. Treatment is the same.
Scrub typhus - Rickettsia tsutsugamuchi,transmitted by mites. Found in Japan and the Far East, but also in Australia, India and Melanesia. Mites are found in well circumscribed ecologies called mite islands. In endemic areas, infection tends to present as unexplained, self-limiting fever. It can however produce a mild systemic illness with an eschar, similar to African tick typhus. In non-immune persons, multisystem disease can occur with a 10-20% mortality rate.
Viruses spread by an insect (arthropod) vector. At least 100 that infect humans. Some are global, whereas others have extremely limited geographical range (although they may be very important causes of encephalitis in those areas). The most important of the arthropod vectors are mosquitoes (eg Dengue fever, West Nile virus). Ticks can also carry a variety of arboviruses (eg Tick-borne encephalitis). Some of the arboviruses can be transmitted directly from human to human eg Congo Crimean fever, Rift Valley fever.
Most arboviruses are zoonoses ie their usual reservoir is animals esp birds and rodents. These animals may not manifest much in the way of disease. However, spill over into another species may be triggered by changes in the ecology eg a new vector. If this species does manifest disease, it can be a warning of an impending epidemic eg dead crows before West Nile Virus appeared in US. Dengue fever and Onyong Onyong are unique in having humans as their main reservoir.
There are 3 main patterns of disease:
Each arbovirus tends to present with only one of these patterns, but increasingly it appears that other presentations are possible.
Major Arbovirus Disease
In general, effective killing at 4-5x Minimum inhibitory concentration (MIC) - but of course tissue concentration will not be the same as plasma concentration. Broad spectrum antibiotics tend to have higher MICs.
People generally like antibiotic guidelines, but there are opposing expectations. Senior medical staff see it as being a guide, to be used flexibly; residents want it to be more comprehensive, more detailed (thus more prescriptive) - in fact, if not prescriptive, tend not to get followed! Surgeons want it to be easy to apply, priority being to process patients efficiently. Medics are not keen on multi-discip support eg clinical pharmacist, but this is probably fear of the unfamiliar; popularity rises after introduction. Concordance between guidelines and actual practice by supervisors is important to preserve credibility (PMID 18397925)
See Basics for antibiotic resistance.
ie penicillins and related antibiotics, viz cephalosporins, monobactams, sharing a ring structure. Bind to Penicillin Binding Proteins on the bug during replication and so block cell wall cross linking. Active against gram positive organisms. Resistance to penicillin has never been described in Streptococcus pyogenes, for some mysterious reason. Amoxicillin is supposed to be broader spectrum than phenoxy/benzylpenicillin but is of limited use against H influenzae, and most moraxellas are resistant. Fluclox needed vs Staphylococcus aureus but then you have MRSA. Resistance in Pneumococcus is emerging.
Resistance is usually due to Beta lactamase enzymes released by resistant bugs that will deactivate beta-lactam antibiotics. Alternatively, defective Penicillin Binding Proteins may be produced. The former mechanism can be circumvented by co-administration of a beta-lactamase inhibitor eg clavulanate as found in co-amoxiclav. The latter is the mechanism of resistance in Pneumococci, so beta lactamase inhibitors do not help.
Even if an organism is sensitive to a penicillin, other antibiotics may work better, due to Eagle effect - penicillin only acts during cell division, so for three quarters of cell cycle it has no effect. Antibiotics that work through a different mechanism eg against protein synthesis may be used preferred (eg Clindamycin, Linezolid) or else combined with a penicillin to act synergistically eg an aminoglycosides.
Renally excreted. Do not penetrate meninges well unless they are inflamed ie work in meningitis at high dose, no good against cerebral abscess. Clavulanate does not penetrate well either.
Penicillin allergy is probably rarer than reported. Sensitivity is usually to the basic structure so true allergy to one beta-lactam mostly predicts sensitivity to all. If there is a history of immediate anaphylaxis, urticaria or confluent, pruritic rash, then all beta lactams should be avoided; the risk of cross sensitization to monobactams is less, so these might be considered if clinically indicated.
If the history of penicillin allergy is more vague eg non-confluent, non-pruritic rash over a small area or rash developing after 72 hours of exposure, then it is usually reasonable to avoid beta lactams unless serious illness develops, in which case use of a cephalosporin should be considered. BNFc
Other Adverse Reactions include encephalopathy (related to high doses, or high levels in renal impairment), Sodium/potassium overload.
Cephalosporins have a broader activity, esp 3rd generation cephalosporins eg cefotaxime, ceftriaxone which are effective against most gram positives and gram negatives. Good for meningitis (penetrate inflamed meninges at high dose) but not effective against pseudomonas, enterococcus, listeria, MRSA, and not that great against normal staphs so beware if possible line infection or neonatal meningitis. Some pneumococci can be resistant. Ceftriaxone is drug of choice for Lyme with complications; it is not recommended for immediate treatment of meningococcal disease as any subsequent calcium containing infusions will reduce its plasma levels.
Against Pseudomonas, use Ceftazidime (same drawbacks as ceftriaxone otherwise), +/- an anti-pseudomonal aminoglycoside to act synnergistically. Extended-infusion dosing (4 hr infusion every 8 h) for Pseudomonas disease improved survival cf historical cohort in adults (Clin Infect Dis. 2007 Feb 1;44(3):357-63.)
The carboxypenicillin Tazocin (Piperacillin plus beta-lactamase inhibitor Tazobactam) is generally reserved for serious infections of the immunocompromised and for CF patients, as it is anti-pseudomonal (+/- synnergistic aminoglycoside eg tobramycin).
The Monobactams are related beta-lactams - Aztreonam. They have anti-pseudomonal activity. There is less risk of penicillin cross sensitivty compared with cephalosporins.
Meropenem similar to imipenem (with Cilastin=Primaxin), broad spectrum, but can be used vs CNS infection. Good anaerobic cover, will treat all but the most resistant pneumococci.
These related beta-lactams do not seem to encourage the development of ESBLs as much as cephalosporins.
Act on folate metabolism. Trimethoprim effective for UTI, LRTI, Shigella/Salmonella. Side effects (Stevens-Johnson syndrome and blood dyscrasias) less severe and less common than for Septrin.
Trimethoprim plus sulfamethoxazole (co-trimoxazole, Septrin) is drug of choice for Pneumocystis pneumonia; toxoplasmosis; nocardiasis. Susceptibility to TMP (bactericidal) is usually more critical to efficacy than susceptibility to SMX (bacteriostatic).
Staph aureus incl some MRSA (but only gets used for MRSA UTI), but not group A streptococcus susceptible. Acinetobacter, Enterobacter, E. coli, Klebsiella, Proteus, Salmonella, and Shigella are variably susceptible. No activity against anaerobes. Good penetration esp middle ear, CSF.
The first member of the oxazolidinones class, inhibits protein synthesis by binding to the 50S ribosomal subunit (same as chloramphenicol, macrolides). It is approved for use for serious infections caused by
Also has activity against rapidly growing mycobacterial species including Mycobacterium fortuitum, Mycobacterium chelonae (MIC90 8-16 g/mL), multiple Nocardia spp. (MIC90 = 4 g/mL) and Mycobacterium tuberculosis!
Although linezolid is generally bacteriostatic, it has been used successfully to treat resistant, deep seated infections incl VRE endocarditis, bone infections. Resistance has developed on prolonged courses, however. As it acts on protein synthesis (like clindamycin), potentially useful against toxin producing clones.
Recommended linezolid dosing is 10 mg/kg every 12 h for children >=12 years (maximum dose, 600 mg every 12 h) and 10 mg/kg every 8 h for children <12 years of age. Based on limited pharmacokinetic data in neonates, linezolid clearance appears to be relatively decreased in premature infants and <7 days of age; these patients should receive 10 mg/kg every 12 h increasing to 10 mg/kg every 8 h in all neonates beyond the first week of life, regardless of gestational age.
Good for bones and joints, reasonable CSF penetration. No dose modifications for hepatic/renal impairment unless severe.
SEs - reversible thrombocytopenia and other haem abnormalities (less common in children), optic atrophy (esp prolonged courses), is a monoamine oxidase inhibitor (MAOI) hence some important interactions incl foods.
Pediatric Infectious Disease Journal. 23(10):955-956, October 2004.
eg Gentamicin. Inhibit protein synthesis. Effective against gram negatives, some gram positives including Staph aureus but not vs Pneumococcus or Strep. Poor CNS penetration. Tobramycin effective against Pseudomonas but less effective vs some other gram negatives. Need drug free period to penetrate bacteria - allows adaptive resistance to fall - so aim for low trough (less than 0.5 in 4 hours before dose). Gentamicin 6 mg/kg OD but differs between centres. Hartford nomogram gives interval for adults. No peak required if once daily! (Alison Thomson). Low volume of distribution so if obese tends to get toxic.
Aminoglycoside ototoxicity is associated with a genetic susceptibility in a third to a half of all cases. Most commonly mitochondrial shows bacterial origin. Should we screen patients likely to need repeated courses eg CFs, chemotherapy patients, preterm neonates? Consider costs of deafness, cochlear implant etc.
Glycopeptide, blocks attachment of new cell wall units (similar to penicillin). Active against gram positives including MRSA, but resistant Enterococci described and some MRSA have reduced sensitivity. Good for bone; does not penetrate meninges well (even worse than penicillin) but can be used for meningitis where penicillin resistant pneumococci are prevalent.
Time dependent rather than concentration dependent killing so aim for trough 10-15 (15-20 used for MRSA with reduced sensitivity). 10mg/kg 6hrly (continuous infusion probably ideal, but hardly practical!). Renal excretion so caution with renal impairment. Not as fast at killing as fluclox. Consider combination with aminoglycoside for synergy.
Review recently showed that toxicity is not particularly concentration dependent. Not much evidence that it can cause ototoxicity. Troughs of over 10 are associated with quicker defervescence and arrest in white cell response, no toxicity reported at troughs under 20. Red man syndrome is a flushing reaction esp upper body - not true allergy, so may be managed by slowing infusion (also seen with other antibiotics).
Teicoplanin very similar, but long duration of action so once daily dosing. Can be given IM! Levels not usually done as no clear relationship between levels and toxicity, but may be good for high risk patients or severe infection (aim for trough of about 25 mg/dl - at least 15, max 60 - or 50x MIC of bug). Still renally excreted. Cross-sensitivity with vancomycin can occur, but is not a contra-indication. Red man syndrome can occur.
Block protein synthesis, but reversibly hence bacteriostatic cf aminoglycosides. Effective against a range of Gram-positive cocci so used as an alternative to penicillin in allergic patients. Variable resistance seen; sometimes effective against penicillin resistant staphylococci including some MRSA, but poor activity against Haemophilus. Variable resistance seen in streptococcus, pneumococcus. They are also effective against a range of intracellular pathogens, particularly Chlamydia, Bordetella pertussis, Mycoplasma pneumoniae, and Legionella pneumophila. Also active against Corynebacterium diphtheriae, Treponema pallidum and Campylobacter species.
Newer macrolides are active against non-Tuberculous Mycobacteria, Helicobacter pylori and Bartonella.
All have gastrointestinal side effects. Newer macrolides tend to achieve better plasma levels and have less side effects.
Pneumococci that are resistant to erythromycin (approximately 5 to 20% of strains currently) also are resistant to the new macrolides. Azithromycin is more active than either erythromycin or clarithromycin against Haemophilus influenzae, but the three macrolides have similar in vitro activity against other common respiratory pathogens.
NB lots of drug interactions!
Resistant mycoplasma are rare but do exist - try cipro, else tetracycline.
Block DNA synthesis by bacteria (uniquely among antibiotics).
Good against gram negatives, including Salmonella, Shigella, Neisseria, Pseudomonas (one of the few oral antipseudomonals). Good intracellular penetration so active against organisms such as Chlamydia, Mycoplasma, Legionella and some Mycobacteria. But no anti-anaerobic activity, and not very good against common gram positives eg Pneumococcus, Enterococcus, Staphylococcus (in fact, use is associated with MRSA). The newer types (Gatifloxacin, Moxifloxacin, Levofloxacin) have better gram positive activity but would still not be your first line choice, and have less antipseudomonal activity.
Good tissue penetration including central nervous system. 80% of orally administered drug is bioavailable so the IV route is only used when absorption impaired.
Adverse Effects:
Block protein synthesis (but different ribosome subunit to macrolides, etc). A lot of resistance so tend to get used only for intracellular organisms eg Chlamydia, Rickettsia (eg Q fever), Brucella (in combination with rifampicin), Borrelia (esp Lyme). Traditionally used for oral infections eg periodontitis, aphthous ulcers vs anaerobes but increasing resistance. Can be used for MRSA skin infections. Minocycline has broader activity and is an option for meningococcal prophylaxis.
Use only in children over 12yrs to avoid staining teeth. Doxycycline is just once daily. Absorption affected by calcium/magnesium/iron salts incl antacids.
Related to macrolides, blocks protein synthesis. Shown in animal models to better than penicillin at killing group A strep, even where bug is sensitive (due to Eagle effect, see above). It should also theoretically reduce toxin production, so might be relevant for toxic shock etc. Good anaerobic activity. Occasional strep resistant so always combine with penicillin.
Oral form available but tastes foul; opening capsules and mixing with food is an alternative to the suspension.
Associated with pseudomembranous colitis, so was out of favour for a long time.
Quinopristin + dalfopristin - blocks protein synthesis. Active vs VRE, needs central line. SE - long QT.
Effective therapy vs brain abscess (but use with other agent(s)); Typhoid (and other invasive salmonellosis), but resistant strains in some areas, quinolones and third-generation cephalosporins are as effective. Not used for carrier state. Consider for meningitis (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) esp penicillin-allergic patients or penicillin resistant. In Africa high levels of resistance (80% for Hib in Kenya, 17% for Pneumo in Malawi). Consider vs intracellular infections incl Rickettsiae (preferred for parenteral therapy, pregnancy, young children), Typhus (murine), Q fever, Meliodosis (with tetracycline).
Blocks RNA synthesis (unique). Choice for prophylaxis vs invasive Haemophilus influenzae or Neisseria meningitidis, TB, atypical mycobacterial infections. Consider as adjunctive treatment for staph infection esp endocarditis, shunt infection. Reduces MRSA carriage. Acts vs intracellular organisms so good for chronic granulomatous disease.
Ribavirin reduces viral load in Adenovirus. Cidofovir for EBV (needs Probenecid as kidney protection - important to maintain hydration).
CMV immune globulin available - no data. Foscarnet if concern about ganciclovir exposure/resistance.
Zanamivir and Oseltamivir but not Amantadine (targets M2 protein, only effective against type A influenza, rapid resistance and side effects common) recommended for influenza in children with risk factors (chronic lung/cardiac/renal disease, immunodeficiency) within 48 hrs of onset. Zanamivir used for adolescents 12 years and older - taken twice daily for 5 days by diskhaler (age less important than ability to use device)! No resistance, very low rate of side effects (wheeze!) Significant reduction in time to alleviation of symptoms. Oseltamivir is oral, diarrhoea and vomiting are the only significant side effects - the earlier it is started the better: starting within 12 hours reduced duration of illness by 3 days, start within 48 hours and only 1 day benefit. 5% of childhood infections will become resistant whereas this is unusual in adults, probably due to higher viral loads in primary infection. (NICE guidelines). 2 adolescents in Japan have committed suicide while on it, plus there have been a number of other neuropsychiatric reports.
NICE recommends prophylactic oseltamavir when flu incidence reaches a critical level. Licensed for prophylactic use in children aged one year and above. Duration of post-exposure prophylaxis is 10 days (previously 7).
Antifungal drugs mostly act on cell walls via ergosterol synthesis (amphotericin and nystatin disrupt end product rather than synthesis). In general, allow 7 days before deciding whether there has been any treatment response.
NB - it may be necessary to reverse immunodeficiencies, operate to remove fungal balls, or transfuse granulocytes to achieve cure. Aspergillus lesions may increase in size with return of neutrophils.
Fluconazole is fungistatic vs yeasts (ie Candida), but has no activity on moulds (ie Aspergillus). It is more reliably absorbed than itra and less toxic than keto. Use for superficial candidal infections and in deep tissue infections with susceptible Candida species. Has been important as prophylaxis against fungal colonization and superficial fungal infections in the immunocompromised patient, but C krusei is resistant and C glabrata has reduced susceptibility, so itraconazole probably a better choice (but danger of fostering resistance). Good CNS penetration so approved for the treatment of cryptococcal meningitis.
Flucon needs 12mg/kg for severe infection (except in neonates). Beware long QT and enzyme induction with all azoles.
Itraconazole has greater activity against aspergillosis, sporotrichosis, cryptococcosis, and other fungi in oral form. Needs an acidic environment for optimal absorption, associated with liver damage - monitoring drug levels is recommended (IV dose is same as PO dose. Levels 6+ hrs post dose, trough should be 0.5).
Posaconazole for prophylaxis in neutropenia appears superior to flucon/itra, but more GI side effects. Posoconazole even active vs zygomyces.
Voriconazole is a new second generation drug with broader spectrum including aspergillus, Fusarium, Scedosporium, coccidioides, histoplasma. Better than fluconazole vs candida, incl C. krusei, glabrata. Penetrates brain (CNS fungal disease has 95%+ mortality), lung, kidney. Wide interpatient variation in dosing esp CYP mutations. Linear dosing in kids cf zero order in adults, so levels useful. IV, give loading dose 6mg/kg bd for 1 day, then 4-5mg/kg bd (infants: 8 then 6). Oral bioavailability 96%! Over 40kg, give 400mg bd for 1 day then 200-300; under 40kg 200 then 100-150. SE Visual disturbance but usually mild & only 30 mins, no long term. Rash & photosensitivity (with chronic use sunblock not very effective, unfortunately). Transient rise in transaminases. Cheaper than ambisome esp Oral form. Superior to ambisome in adults ( N Engl J Med 2002; 347:40815), probably synergistic with caspofungin Clin Infect Dis 2004; 39:797802).
Caspo Pharmacokinetics suggest loading at 70 mg/m2/d followed by dosing at 50 mg/m2/d (neonates 1 mg/kg/d for 2 days then 2mg/kg). SEs fever, headache, rash, anaemia, LFTs, GI symptoms.
Caspofungin (Cancidas, an echinocandin) vs candida (including azole-resistant spp), aspergillus (fungistatic) - cell wall lysis, synergistic with amphotericin. However, not much use for anything else: Cryptococcus neoformans, zygomycetes, Fusarium, Scedosporium and Trichosporon are relatively resistant. Licensed for unresponsive aspergillus or patients who cannot tolerate amphotericin or itraconazole, but lack of data on safety and efficacy. Only IV form, does not penetrate uninflamed meninges well. Micafungin has more aspergillus activity.
Amphotericin causes hypokalaemia and renal impairment. Its activity is dose dependent. 3 lipid formulations, lower complications and easier administration but no direct comparisons between them, and no clear difference in side effects. Liposomes conflict with granulocyte infusions, leave 10 hours gap before and after. Mix amphotericin with intralipid (1:5) to emulate lipid forumlation!
So for invasive candidiasis, any will do! Fluconazole is probably as good as ambisome, with less side effects. Use Voriconazole if resistant candida eg krusei; certainly not inferior to amphotericin in non-neutropenic (Lancet. 2005 Oct 22-28;366(9495):1435-42). Caspofungin similarly is at least as good as amphotericin, with less side effects; the trial with Anidulafungin had the lowest reported mortality of any of the trials. If struggling, flucytosine (bone marrow toxicity), fluconazole and caspofungin are all synergistic with amphotericin Clinical Infectious Diseases 2006;42:1289-1296.
Theoretical antagonism between amphotericin/nystatin (both cell wall disruptors) and keto/itraconazole (cell wall synthesis disruptors) but not in vitro.
Cryptococcus responds to amphotericin or fluconazole. Fluconazole prophylaxis is effective.
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