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Serious Bacterial (Pediatric)
Serious Bacterial Infections in Children with HIV
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Introduction
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Serious Bacterial Infections
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Clinical Syndromes
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transparent imagePneumonia
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transparent imageEpidemiology
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transparent imageDiagnosis
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transparent imageInitial Treatment
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transparent imageBacteremia
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transparent imageInitial Treatment
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transparent imageTreatment of Specific Pathogens
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transparent imageMeningitis
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transparent imageInitial Treatment
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transparent imageTreatment of Specific Pathogens
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transparent imageGastroenteritis
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transparent imageUrinary Tract Infection
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transparent imageSkin and Soft Tissue Infections
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transparent imageTypes of Skin and Soft Tissue Infections
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transparent imageBone and Joint Infections
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transparent imageSeptic Arthritis
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transparent imageOsteomyelitis
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Problems Due to Resistance of Bacterial Pathogens
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transparent imageAntibiotic Resistance Globally
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Summary
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References
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Introduction
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HIV-infected children have an exceptional vulnerability to invasive bacterial infections that is much greater than that seen in immunocompetent, HIV-uninfected children and HIV-infected adults. Because of this increased risk, the Centers for Disease Control and Prevention (CDC) added a new category of invasive bacterial infections to the list of pediatric AIDS-defining illnesses in 1987.(1)

Numerous defects in the immunologic system are responsible for the increased vulnerability of HIV-infected children to serious bacterial illness. These include defects in the cell-mediated (T-cell) and the humoral (B-cell) arms of the immune system; phagocytic abnormalities including decreases in neutrophil number, multiple defects in neutrophil function, and impairment in macrophage and monocyte function (2); functional asplenia (3); and defects in 3 components of complement.(3) These defects become more severe as the child's HIV disease progresses. Extrinsic factors in industrialized countries that increase susceptibility to infection in HIV-infected children include frequent use of broad-spectrum antibiotics, frequent hospitalizations, and the use of indwelling intravascular catheters that disrupt the integrity of skin. Major factors in developing countries include malnutrition, micronutrient deficiencies, and lack of adequate medical care. The results of these defects are increased susceptibility to infection with encapsulated bacteria beyond age 2 years,(4) increased nasopharyngeal colonization rates for Streptococcus pneumoniae and Haemophilus influenzae,(5) recurrent infections with the same bacterial species, increased susceptibility to infections with bacteria unusual in immunocompetent hosts, and increased morbidity and mortality.

Vaccines against bacterial agents or their toxins administered to HIV-infected children who do not receive treatment with effective antiretroviral therapy (ART) may not be protective because they often produce antibody titers that are lower and less persistent than those seen in HIV-uninfected children. These include H influenzae type B polysaccharide conjugate vaccine,(6) pneumococcal polysaccharide vaccine,(6) pneumococcal conjugate vaccine,(7,8) and pertussis vaccine (9) as well as diphtheria and tetanus toxoids.(10,11) A recent double-blind randomized trial examined the efficacy of a 9-valent pneumococcal vaccine in HIV-uninfected and HIV-infected children who were not treated with ART.(12) This vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to vaccine serotypes by 83 percent and 65 percent in HIV-uninfected and HIV-infected children, respectively. Although the vaccine reduced the incidence of a first episode of radiologically confirmed pneumonia in the HIV-uninfected children, it had little effect on pneumonia in HIV-infected children. Successful treatment of HIV-infected children with ART may result in improved antibody responses to measles, tetanus, and H influenzae type B vaccines following reimmunization.(13) However, the degree and persistence of these responses may be less robust than those in HIV-uninfected children.

The availability of effective ART in resource-rich nations has had a major impact on HIV-associated mortality in children. In the United States, prior to the widespread use of ART in children, the mortality rate of HIV-infected children 6 and 9 years of age was approximately 25% and 50%, respectively. The current use of combination ART, however, has slowed the progression of HIV disease in many children, resulting in fewer bacterial and other opportunistic infections and decreases in mortality.

Morbidity and mortality at unprecedented levels, however, currently are seen in HIV-infected children in many developing nations where there is malnutrition, difficulty in supplying adequate medical care, and an increased incidence of coinfection with organisms such as tuberculosis, cytomegalovirus, and syphilis.(14) The mortality rate in these nations is much greater than that seen in the United States, even before the availability of ART. The mortality rate of HIV-infected infants when compared with HIV-uninfected infants at 1 year of age in Rwanda was estimated to be 26% vs 2%, respectively.(15) Data from the clinical trial DITRAME ANRS 049a, conducted in Abidjan, Côte d'Ivoire, revealed a mortality rate by 1 year of age of approximately 50% and 5% for HIV-infected and HIV-uninfected infants, respectively.(15) Similar statistics were seen in Malawi and Uganda, where the median survival of HIV-infected children by 3 years of age in 2 pediatric cohorts was only 34%.(15) These deaths were due primarily to pulmonary infections, diarrhea, and malnutrition.

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Serious Bacterial Infections
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Serious bacterial infections occur more frequently in HIV-infected children than in HIV-uninfected children in resource-rich as well as resource-poor countries. In one large natural history study in which a cohort of 3,331 HIV-infected children was followed in the United States, the rate of serious bacterial infections in children between the ages of 0.1 and 20.9 years was 15.1 per 100 person-years.(16) The median age, CD4 count, and CD4 percentage for these children was 3.8 years, 420 cells/µL, and 17%, respectively, whereas those children who developed Pneumocystis jiroveci pneumonia (PCP) had a median age, CD4 count, and CD4 percentage of 3.9 years, 42 cells/µL, and 6%, respectively. These data indicate that serious bacterial infections may occur at CD4 counts and percentages that are much higher than those at which PCP occurs. The majority of these infections, however, occurred in children with CD4 percentages <15%, consistent with the findings of other studies in which bacterial illnesses occurred at a greater frequency in children with CD4 counts <200 cells/µL.(17,18) The most common clinical syndromes due to bacteria and their event rates were pneumonia (11.1 per 100 person-years), bacteremia (3.3 per 100 person-years), and urinary tract infection (1.6 per 100 person-years).(16) The clinical syndromes of osteomyelitis, meningitis, abscess, and septic arthritis had event rates of <0.2 per 100 person-years. In another large study that followed 2,167 perinatally HIV-infected children in the United States,(4) the most common serious bacterial infections were sepsis (56%) and pneumonia (25%). Less common infections were cellulitis (6.4%), meningitis (4.2%), sinusitis (3.1%), and adenitis (2.1%). Mastoiditis, internal organ abscess, osteomyelitis, and septic arthritis occurred at frequencies of <2%. In that study, serious bacterial infections occurred most frequently in children <1 year of age (21.5 episodes per 100 person-years), whereas, in children of 1 and 2 years of age, the rates decreased to 14.3 and 11.2 episodes per 100 person-years, respectively. The rate of these infections continued to decrease with increasing age so that, by 10 years of age, the estimated rate decreased to 3.3 episodes per 100 person-years.

S pneumoniae is the most common pathogen causing invasive bacterial infections in HIV-infected children in the United States.(4) An incidence of 6.1 serious bacterial illnesses due to S pneumoniae per 100 person-years for children through age 7 years was seen,(19) and was similar to that seen in children with sickle cell disease through age 6 years. This rate was 100- to 300-fold the rates seen in immunocompetent, HIV-uninfected children in the United States and several other industrialized countries. Data presented at a 2003 World Health Organization (WHO) conference showed that pneumonia in HIV-infected children <5 years of age was the leading cause of hospital admission and the most frequent cause of death in the 6 participating African countries.(20) Although PCP was the most important cause of pneumonia rated "severe" or "very severe," bacteria were the most common cause of pneumonia overall.

Acute lower respiratory tract infection (LRTI), diarrhea, and bacteremia accounted for the majority of infections in 108 hospitalized HIV-infected children in Cape Town, South Africa.(21) In this study, none of the children received pneumococcal or H influenzae vaccines, intravenous gamma globulin, or ART. The children, whose median age was 61 months (1.5-214 months), had 136 episodes of serious bacterial infection; 85% of infections occurred in children <2 years of age and 40% of the children had 2 or more clinical syndromes. The most frequent syndromes were acute LRTI (44%), diarrhea (29%), septicemia (17%), and skin infections (5%). All other syndromes, including meningitis and urinary tract infection, accounted for <2% of infections. Bacterial cultures were positive in 24%, 18%, and 45% of children with acute LRTI, diarrhea, and septicemia, respectively. S pneumoniae, Campylobacter spp, and gram-negative bacilli accounted for the majority of the isolates in patients with acute LRTI, diarrhea, and septicemia, respectively. Of note, 33% of these episodes occurred in patients receiving cotrimoxazole (TMP/SMX) 3 times a week. In a recent surveillance study conducted in Malawi, the most frequently isolated bacteria in blood taken from 208 acutely ill HIV-infected children were nontyphoidal Salmonella spp and Escherichia coli; there were no isolates of S pneumoniae.(22) Of note, Salmonella spp are the most frequently isolated pathogen in HIV-infected children in areas of high malaria activity.(23)

HIV-infected children who are not severely immunocompromised and do not have neutropenia are most likely to respond to the age-appropriate antimicrobial regimens used in the treatment of many bacterial infections in HIV-uninfected children. The duration of therapy, however, often is greater and should be based in large part on the clinical course of the child. Lack of response to a regimen of appropriate duration and targeted to the pathogen(s) isolated should prompt a reevaluation of the child, as coinfection with several types of pathogens or infection with resistant bacteria may be present.

This chapter recommends diagnostic procedures and antibiotic treatment for serious infections in HIV-infected children based on current practices in health care institutions in resource-rich countries. In most cases, the severity of infection will require hospitalization of the child. The procedures and the antibiotics chosen should be used in accordance with the capabilities and limitations of the health care institutions providing treatment for these children. In addition, the type and prevalence of antibiotic resistance in each geographic region must be considered when choosing treatment.

The Child and Adolescent Health and Development (CAH) division of the WHO has developed the Integrated Management of Childhood Illness (IMCI) guidelines for the care and treatment of many diseases affecting children, including HIV-infected children, in many resource-poor countries.(24) The WHO also has published the Pocket Book of Hospital Care for Children: Guidelines for the Management of Common Illness with Limited Resources, which is updated frequently, accessible via the World Wide Web, and recommended highly to health care workers in resource-poor settings as an aid in selecting antibiotic regimens.(25)

Although this chapter provides a general overview of serious bacterial infections, it is important for the practitioner to have a low threshold for consulting experts in the care of immunosuppressed patients and for expanding the differential diagnosis, diagnostic work-up, and therapeutic coverage to include other pathogens likely to cause disease in HIV-infected children.

Guidelines for the use of TMP/SMX as prophylaxis for opportunistic infections in resource-poor nations have been established by the WHO and the Joint United Nations Programme on HIV/AIDS,(26) and are similar to previously developed U.S. guidelines.(27) It is highly recommended that these guidelines be followed. Recently, the combination of atovaquone and azithromycin was shown to be as effective as TMP/SMX for prophylaxis of opportunistic infections in children with HIV.(28)

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Clinical Syndromes
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Pneumonia
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Epidemiology
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Acute LRTI is a major cause of morbidity and mortality in HIV-infected children in resource-poor and resource-rich countries and may be due to a single pathogen or a combination of bacterial, viral, or fungal pathogens.(4,29) Children with lower CD4 T-cell counts generally have a higher incidence of bacterial pneumonia.(16) The spectrum of bacteria associated with pneumonia in HIV-infected children is wide. The pathogens most commonly seen include S pneumoniae, H influenzae type B, Staphylococcus aureus, and E coli. Other pathogens less commonly observed are Streptococcus viridans, Streptococcus pyogenes, Moraxella catarrhalis, Bordetella pertussis, Klebsiella pneumoniae, Salmonella spp, Pseudomonas aeruginosa, Legionella spp, and Nocardia spp.

Bronchiectasis may occur in HIV-infected children as a result of severe, unresolving, or recurrent pulmonary infections.(30) Of 164 HIV-infected children with "respiratory problems" in one study, 26 (15.8%) had bronchiectasis. Sixteen children had lymphoid interstitial pneumonia, 3 were found to have recurrent pneumonia, and 5 had unresolving pneumonia. Of the 12 children that had bronchoalveolar lavage, 7 had bacteria isolated and 6 of these 7 children had mixed infections of up to 4 organisms with various combinations of P aeruginosa, S aureus, Candida albicans, Mycobacterium avium complex, S viridans, B pertussis, chlamydia, multidrug-resistant Mycobacterium tuberculosis, and Corynebacterium spp.

Pneumonia due to Pseudomonas spp is infrequent but particularly problematic because it results in a necrotizing infection and may respond poorly to antibiotic treatment.(31) Pseudomonas pneumonia usually is acquired nosocomially, but it also can present as a community-acquired infection in HIV-infected patients, a mode of acquisition that is rare in HIV-uninfected individuals. Pseudomonas pneumonia may present as a fulminant infection with bacteremia, or may have a chronic or subacute course. Unlike pneumonia due to S pneumoniae, Pseudomonas infection usually is associated with a CD4 count <50 cells/µL. Multiple relapses are common and may occur despite an intravenous antibiotic course of 14 days.(32) Risk factors for Pseudomonas pneumonia include lung injury caused by prior opportunistic infections, bronchiectasis, chronic sinusitis, and repeated courses of broad-spectrum antibiotics that predispose patients to colonization.

Pneumonia is the predominant bacterial clinical syndrome in HIV-infected children in Africa. Because the etiologies of bacterial pneumonia in studies of HIV-infected children have been determined primarily by blood culture isolates from these patients, it is possible that the reported frequencies of bacterial pneumonia in developing countries represent underestimates. The pattern of respiratory infections in HIV-infected children in Africa is similar to that seen in resource-rich nations prior to the use of ART, with the exception of tuberculosis, which is uncommon in resource-rich nations.(29) Common nonbacterial pathogens are P jiroveci, Mycobacterium tuberculosis, and cytomegalovirus (CMV).(20) The difficulty in differentiating the various etiologies of pneumonia is a major obstacle to appropriate therapy.(20)

In Soweto, South Africa, HIV-infected and HIV-uninfected children hospitalized with LRTI were studied. LRTI was found to be the most common cause of hospitalization and mortality in all children aged 2-60 months, regardless of HIV status.(33) However, HIV-infected children had a significant increase in bacteremic LRTI relative to uninfected children and a higher case-mortality rate. Frequently encountered pathogens were S pneumoniae, H influenzae type B, S aureus, and Salmonella spp. LRTI due to E coli was significantly more common in HIV-infected children than in HIV-uninfected children. In HIV-infected and HIV-uninfected children aged 2-24 months, S pneumoniae was the most frequently isolated pathogen. The relative risk of pneumonia due to S pneumoniae was 43 for these younger HIV-infected children compared with HIV-uninfected children. In this same age group, HIV-infected children had relative risks of 21, 98, 49, and 13 for pneumonia due to H influenzae type B, E coli, S aureus, and Salmonella spp, respectively, compared with HIV-uninfected children. In children aged >24 months, S pneumoniae was found in 37% of those infected with HIV but in only 20% of HIV-uninfected children with LRTI.

In Cape Town, South Africa, LRTI accounted for 44% of 136 episodes of severe infection in HIV-infected children who required hospitalization or were hospitalized concurrently.(21) Blood cultures were positive in 24% of these cases and the predominant bacterial isolates, in order of frequency, were S pneumoniae, S aureus, H influenzae, and E coli. Notably, 31% of the S pneumoniae isolates were penicillin resistant, and 33% of LRTI occurred in children receiving TMP/SMX 3 times weekly.(21)

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Diagnosis
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The differential diagnosis of fever, tachypnea, and hypoxia in an HIV-infected child is extensive and includes bacterial, viral, and fungal pneumonias. The ability to determine the cause of pneumonia often is limited because infected material cannot be obtained for culture without performing an invasive procedure. Chest X rays, blood cultures, and sputum Gram stains and cultures are essential components of the diagnostic workup and will help determine the etiology. However, the absence or presence of alveolar consolidation on chest X ray may not help in distinguishing pneumonia due to bacteria from that due to viral pathogens or P jiroveci.(33) For example, radiographic patterns with PCP may have the appearance of a bacterial pneumonia. Chest X rays of children with H influenzae (type B and nontypeable) pneumonia will show consolidated areas in some cases, but diffuse bilateral infiltrates may be seen in others.(34) The appearance of Pseudomonas pneumonia on chest X ray may be that of a lobar infiltrate, or, less commonly, diffuse interstitial disease and cavitary lesions.(34) The most sensitive diagnostic techniques are bronchoscopy with bronchoalveolar lavage and/or lung biopsy. However, if these procedures cannot be done, induced sputum may yield clues to the etiology. If empyema is present, a specimen should be obtained for microbiologic evaluation.

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Initial Treatment
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Initial treatment should target the most likely pathogens based on the age of the child and the level of immunosuppression. S pneumoniae is the most common cause of bacterial pneumonia after the neonatal period. Therefore, initial treatment for children >1 month of age should provide coverage for this organism unless there is compelling evidence that the infection is not caused by S pneumoniae. Because of the high prevalence of penicillin resistance in pneumococcus and many other respiratory pathogens in resource-rich nations, the initial antibiotic regimen for an HIV-infected child should consist of a second-generation cephalosporin (eg, cefuroxime) or a third-generation cephalosporin (eg, cefotaxime or ceftriaxone). Neutropenic patients also should be treated with an antipseudomonal drug such as ceftazidime to provide activity against Pseudomonas spp. If S aureus is suspected and there is a prevalence of community-acquired methicillin-resistant S aureus (CA-MRSA) >10%, vancomycin should be added to the antibiotic regimen.

The type of bacteria isolated and the antibiotic susceptibility pattern should then guide changes in the antibiotic regimen. Because slower responses to antibiotic treatment or relapses may occur in HIV-infected children,(34) careful monitoring is required. Prolonged antibiotic therapy may be necessary in many cases.

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Bacteremia
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HIV-infected children, especially those <2 years of age, have an increased risk of bacteremia relative to uninfected, immunocompetent children. In the CDC Pediatric Spectrum of Disease project, sepsis was diagnosed in 401 of 714 HIV-infected children with bacterial infections in the United States,(4) whereas the incidence of bacteremia in study participants of the Pediatric AIDS Clinical Trials Group was 3.3 per 100 person-years.(16) In South Africa, the relative risk of bacteremia secondary to S pneumoniae pneumonia in HIV-infected children <2 years of age was 50 times that of uninfected children.(35) An odds ratio of 2.68 for bacteremia in HIV-infected children relative to uninfected children was seen in Zimbabwe.(36) The incidence of bacteremia also increases as the CD4 count decreases.(37) Bacteremia often occurs secondary to infection of the lung, gastrointestinal tract, vascular catheters, and skin and soft tissue (38) as well as other sites, including the ear, sinuses, and urinary tract. Bacteremia without an identifiable focus may occur, especially with S pneumoniae. In a study of pneumococcal bacteremia in the United States, a focus of infection could not be found in 10 of 54 bacteremic children.(39)

Many of the bacterial pathogens that infect HIV-infected children are those that also infect HIV-uninfected, immunocompetent children. S pneumoniae is most frequently isolated, but in children with advanced HIV disease, bacteremia may be caused by other bacterial species less commonly seen in immunocompetent children. These include nontyphoidal Salmonella spp, Pseudomonas spp, E coli, Campylobacter jejuni, Listeria monocytogenes, Citrobacter spp, Enterobacter spp, Klebsiella spp, Rhodococcus equii, and Actinomyces israelii.(40-42) Prior to 1990, H influenzae bacteremia accounted for 12.5% of gram-negative bacteremia in HIV-infected children in the United States but was not seen after that time.(42) This decrease may be related to the widespread use of the H influenzae type B conjugate vaccine. In Zimbabwe, gram-positive pathogens isolated from blood cultures of children with HIV, in order of frequency, were coagulase-negative staphylococci, S pneumoniae, S aureus, R equii, and A israelii.(36) Gram-negative pathogens isolated in this study were S enteriditis, E coli, and K pneumoniae.(36)

A retrospective study that analyzed the impact of central venous catheters (CVC) on bacterial infection in HIV-infected children showed that HIV-infected children <6 years of age had an increased frequency of CVC-related bacterial infections relative to older HIV-infected children.(37) Bacteria associated with CVC infections included S aureus, S epidermidis, Enterococcus spp, Pseudomonas spp, Acinetobacter spp, and other gram-negative rods,(37) as well as Bacillus cereus.(43)

Recurrent bacteremia and polymicrobial bacteremia are not uncommon infections in HIV-infected children. Complications of bacteremia include septic shock, disseminated intravascular coagulation, and seeding of the pathogens to multiple organs. Bacteremia due to Salmonella spp has very high rates of relapse following completion of a short course of antibiotic treatment.(2,38,44,45) Metastatic complications may occur and result in osteomyelitis, meningitis, pneumonia, endocarditis, and pyelonephritis.(38) S aureus bacteremia frequently results in dissemination of infection to multiple sites.

The mortality rate from bacteremia is dependent on multiple factors including the type of pathogen, presence of metastatic lesions, immune status, age, nutrition, and availability of medical care. In the United States, of 54 HIV-infected children who presented with S pneumoniae bacteremia, death occurred in only 2 children who had associated meningitis.(39) However, in Zimbabwe, death occurred in 20 of 67 HIV-infected bacteremic children who were infected with a variety of pathogens. The highest mortality occurred in children <18 months of age.(36) Gram-negative bacteremia generally carries a higher mortality than does bacteremia due to most gram-positive bacteria. In HIV-infected children the United States, the case-fatality rate for Klebsiella spp, E coli, and P aeruginosa was 57.1%, 54.5%, and 52.6%, respectively.(42) Mortality due to S aureus infections without endocarditis varies from 2.6% to 19%, with a significantly higher mortality if S aureus endocarditis is present.

Predisposing, but not essential, conditions that favor Pseudomonas bacteremia are a low CD4 count, neutropenia, and the presence of a CVC. Pseudomonas may be community acquired or nosocomially acquired, with the urinary tract, upper and lower respiratory tracts, and CVCs serving as the primary sources. Bacteremia with Pseudomonas may be associated with several different types of skin lesions that include tender, red papular lesions and ecthyma grangrenosum. Hypotension and other signs of sepsis often accompany Pseudomonas bacteremia. Because bacteremia due to Pseudomonas spp, predominantly P aeruginosa,(46) has a high mortality, especially in the presence of CD4 count <100 cells/µL and neutropenia,(47) aggressive and prolonged treatment is needed.

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Initial Treatment
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Initial treatment should provide antibacterial coverage for the most likely pathogens. Ill-appearing children with S pneumoniae bacteremia in regions with significant rates of penicillin-resistant pneumococcus should be treated initially with a third-generation cephalosporin plus vancomycin until the susceptibility of the isolate is known. Vancomycin should be discontinued once the isolate is shown to be susceptible to penicillin or a cephalosporin. Vancomycin may be used in cases of hypersensitivity to beta-lactam antibiotics. Treatment with appropriate antibiotics for 10-14 days generally is sufficient. The child who clears bacteremia within a day and appears well may be able to complete antibiotic therapy as an outpatient.

Where penicillin-resistant, gram-positive bacteria are not suspected, a child who has a CD4 count >200 cells/µL and an absolute neutrophil count (ANC) >500 cells/µL, and who does not have a CVC, can be treated initially with ceftriaxone or cefotaxime until culture results are available. Following isolation of an organism, antibiotic therapy should be modified appropriately. Broad-spectrum antibiotics should be considered with severely immunosuppressed children until culture results are available. For children with an ANC <500 cells/µL, treatment with ceftazidime to provide coverage for Pseudomonas spp should be considered until culture results are available. Vancomycin should be part of an antibacterial regimen if S aureus is suspected and there is a 10% or greater prevalence of methicillin-resistant S aureus (MRSA) in the community.(48)

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Treatment of Specific Pathogens
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Catheter-related bacteremia can be treated with ceftazidime and vancomycin to cover Pseudomonas and MRSA, respectively. Once the bacterial pathogen(s) are identified, a decision can be made regarding catheter removal. For certain species of bacteria (eg, S epidermidis), catheter-associated bacteremia often can be treated with antibiotics alone without catheter removal, if the patient is stable and the blood cultures rapidly become sterile.(37) Treatment involves approximately 14 days of appropriate antibiotics, followed by observation for recurrence. Certain bacteria, such as Bacillus spp, cannot be eradicated without catheter removal.(43) In these cases, a shorter course of approximately 7 days of antibiotics may be given following catheter removal.

Treatment of nontyphoidal Salmonella with ampicillin, TMP/SMX, ceftriaxone, cefotaxime, or chloramphenicol should be instituted until susceptibility is known.(27) Treatment duration of 4-6 weeks is necessary to prevent relapse.

Methicillin or oxacillin should be used for susceptible strains of S aureus. In regions with a high incidence of CA-MRSA, alternative therapy such as clindamycin or vancomycin should be considered. Vancomycin or linezolid should be considered for nosocomially acquired S aureus, as these organisms are likely to be methicillin resistant. Length of treatment in the absence of metastatic foci is approximately 21 days. If the patient remains bacteremic for more than 3 days after beginning adequate therapy, a thorough evaluation for sites of dissemination, such as lungs, heart valves, bones, and central nervous system (CNS), should be considered.

Treatment of bacteremia due to Pseudomonas spp includes intensive clinical support and a combination of 2 antipseudomonal agents (47) such as ceftazidime or imipenem plus an aminoglycoside or a quinolone (quinolones are not recommended for children <18 years of age), for a minimum of 2 weeks. Antibiotic therapy should be adjusted based on the results of susceptibility tests. The sources and metastatic foci of infection (lungs, skin infection, urinary tract infection, sinuses, CVC) must be determined and treated surgically when appropriate. If a CVC is infected, it may be possible to eradicate the infection without catheter removal in approximately 65% of cases.(31) If infection persists or recurs, catheter removal will be necessary.

If Campylobacter jejuni is suspected, both blood and stool cultures should be obtained. No studies have established the optimal treatment of Campylobacter bacteremia. Two weeks of intravenous therapy with cefotaxime, imipenem, gentamicin, chloramphenicol, or erythromycin most likely will provide adequate treatment.

Invasive, nonmeningeal Listeria infection may be treated with ampicillin plus an aminoglycoside, or with intravenous TMP/SMX alone, if penicillin allergic, for 10-14 days.(49) The treatment course for Listeria meningitis should be no shorter than 14-21 days.

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Meningitis
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Although S pneumoniae is the most common cause of acute bacterial meningitis in HIV-infected children, many other bacterial pathogens, including Neisseria meningitidis, H influenzae, Salmonella spp, and L monocytogenes, must be included in the differential diagnosis. The diagnostic workup should include a lumbar puncture (LP). Appropriate studies, including stains and cultures for bacteria, fungi, and acid-fast bacilli, and rapid antigen tests for bacteria and cryptococcus should be performed on the cerebrospinal fluid (CSF).

For children >1 month of age, initial treatment should include a third-generation cephalosporin and vancomycin if purulent CSF is obtained upon LP or if an etiologic agent cannot be identified. In the absence of specific recommendations for HIV-infected children <1 month of age, initial treatment with standard empiric treatment for meningitis (consisting of ampicillin and cefotaxime) is reasonable.

Dexamethasone may be used to reduce the effects of CNS inflammation, although concomitant administration of dexamethasone decreased the penetration of vancomycin into the CSF in animal studies.(50) For the child with a CSF shunt and meningitis, initial therapy should include vancomycin and ceftazidime. Following isolation of an organism, treatment should be modified depending on the bacteria identified and its resistance pattern. Repeat LP may need to be performed in some children if the treatment response is not satisfactory, if the etiologic agent is penicillin-resistant S pneumoniae and results from cefotaxime and ceftriaxone resistance testing are not yet available, if dexamethasone was administered,(49) or if gram-negative organisms are isolated. Therapy may need to be prolonged, depending on the response and the resistance pattern of the bacterial isolates.

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Initial Treatment
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Initial treatment of suspected bacterial meningitis beyond the neonatal period always should include coverage for S pneumoniae unless specific information suggesting a different pathogen is available, such as the findings on Gram stain of the CSF. A combination regimen of vancomycin and either cefotaxime or ceftriaxone should be used in children beyond the neonatal period until a pathogen and antibiotic susceptibilities are known.

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Treatment of Specific Pathogens
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Meningitis due to penicillin-susceptible pneumococcus should be treated with meningitis-level doses of penicillin, ampicillin, cefotaxime, or ceftriaxone. The combination of vancomycin and rifampin may be used for children with hypersensitivity to penicillins and cephalosporins.

The high prevalence of antibiotic-resistance in S pneumoniae has made the treatment of pneumococcal meningitis complex. Treatment of penicillin-nonsusceptible and cephalosporin-nonsusceptible pneumococcus is problematic mainly because concentrations of penicillins and cephalosporins in the CSF usually are not high enough to achieve prompt eradication of some intermediately resistant and most highly resistant pneumococcal strains. Therefore, meningitis due to strains of pneumococci with intermediate-level or high-level resistance to only penicillins can be treated with either ceftriaxone or cefotaxime alone. However, meningitis due to strains of pneumococci that are nonsusceptible to both penicillins and cephalosporins should be treated with a combination of vancomycin plus either ceftriaxone or cefotaxime. The combination of vancomycin plus either ceftriaxone or cefotaxime is recommended because clinical experience to support the use of vancomycin alone for the treatment of pneumococcal meningitis is insufficient.(49) Rifampin should be added to this regimen after 24-48 hours if the isolate is susceptible to rifampin and the patient has clinical deterioration, if repeat LP fails to show eradication of the bacteria, or if the isolate has high-level resistance (minimal inhibitory concentration [MIC] >=4 µg/mL) to ceftriaxone or cefotaxime.(49)

Meropenem, a carbapenem-class antibiotic approved for children >3 months of age with meningitis, was shown to have very good activity against penicillin-susceptible pneumococcus and was a very promising agent for the treatment of meningitis due to penicillin-resistant pneumococcus. However, because a recent study revealed that 49% of 59 isolates with either intermediate-level or high-level resistance to penicillin also had meropenem resistance, meropenem is not recommended for the treatment of meningitis caused by intermediately or highly resistant pneumococcus.(49)

Meningitis due to Salmonella spp should be treated with ceftriaxone or cefotaxime for no less than 4 weeks.(49) H influenzae meningitis can be treated with ceftriaxone or cefotaxime or the combination of ampicillin and chloramphenicol (49) for at least 10 days. Listeria meningitis may be treated with ampicillin plus an aminoglycoside for a minimum of 14-21 days.(49)

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Gastroenteritis
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Bacteria associated with gastroenteritis in HIV-infected patients include Salmonella spp, Shigella spp, Campylobacter spp, Aeromonas hydrophilia, Vibrio spp, Clostridium difficile, and enterotoxigenic, enterohemorrhagic, enteropathogenic, or enteroinvasive E coli. Salmonella spp, Shigella spp, and Campylobacter spp may disseminate and cause widespread serious infection. The presence of white blood cells, blood, parasites, and C difficile toxin in stool samples should be determined, and bacterial culture should be performed. Special tests must be performed to determine the presence of disease-causing E coli. If the infection is due to Salmonella spp or Shigella spp, treatment with ampicillin, TMP/SMX, cefotaxime, or ceftriaxone should be initiated. Treatment for Campylobacter spp infection includes erythromycin or azithromycin. Bacterial isolates should be tested for antibiotic susceptibility and the antibiotic regimen should be adjusted accordingly.

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Urinary Tract Infection
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HIV-infected children have an increased incidence of urinary tract infection.(37,44,51) The most common bacterial isolate is E coli.(51,52) Klebsiella spp, Enterobacter spp, Enterococcus spp, Pseudomonas spp, Proteus spp, and Morganella spp or mixtures of organisms also can cause urinary tract infection. A urine specimen obtained by sterile technique should be examined for white cells and bacteria, and cultured. Blood cultures and appropriate renal studies should be obtained on patients with fever and evidence of pyelonephritis. Because of the elevated relative risk of bacteremia associated with urinary tract infection in this population, aggressive intravenous antibiotic treatment is required in patients with suspected pyelonephritis or constitutional symptoms such as fever. Antibiotic treatment should be guided by the susceptibilities of the bacterial isolates. Although cystitis often can be treated with a relatively short course of therapy, pyelonephritis usually requires a minimum of 2 weeks of therapy.

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Skin and Soft Tissue Infections
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Bacterial skin and soft tissue infections (SSTIs) are seen frequently in HIV-infected children. Skin infections are associated more commonly with S aureus than with other bacteria, partly due to the increased nasal carriage of both methicillin-sensitive and methicillin-resistant S aureus in HIV-infected patients.(53,54) A variety of other organisms including Pseudomonas spp also can cause SSTIs in certain clinical situations.

CA-MRSA is causing SSTIs with increasing frequency.(55) The appearance of these isolates is concerning because oxacillin and cephalosporins are not active against them. CA-MRSA usually causes minor SSTIs but in other cases can progress rapidly to serious and life-threatening infections, including necrotizing fasciitis, pneumonia, osteomyelitis, and bacteremia in children as well as adults.(56,57)

As in all infections, identification of the organism, antibiotic susceptibility results, and careful monitoring of clinical response should guide further treatment. Blood cultures and Gram stain and culture of infected material should be performed, especially if CA-MRSA is prevalent in the community or if an unusual pathogen is suspected. If lesions are thought to be due to disseminated infection, a thorough workup for metastatic foci of infection should be performed. An aspirate or biopsy of an infected lymph node may be necessary, especially for those not responsive to antibiotics that are active against methicillin-susceptible S aureus and group A streptococci, in order to rule out MRSA, cat-scratch disease, mycobacterial infection, and malignancy. Rectal exam usually is sufficient to detect a perianal abscess, although computed tomography (CT) imaging may be needed in systemically ill children who are thought to have deep abscesses. Infected material obtained at the time of perianal abscess drainage should be sent for microbiologic evaluation.

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Types of Skin and Soft Tissue Infections
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Cellulitis

Cellulitis may be caused by S aureus, group A streptococci, H influenzae type B, group B streptococci, and P aeruginosa. For facial cellulitis, if the patient is ill, or if the cellulitic area has a purplish hue, ceftriaxone or cefotaxime should be used to provide coverage for H influenzae type B. For severely immunocompromised or gravely ill patients, antibiotic coverage should be extended to include gram-negative enteric bacteria and P aeruginosa. Leading-edge cultures from cellulitic areas may help in making the microbiologic diagnosis. Following isolation of an organism, therapy should be tailored accordingly.

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Catheter-Related Soft Tissue Infections

Two types of central catheter-related soft tissue infections occur: exit site infections and tunnel infections. Exit site infections are superficial infections around the catheter site with erythema and tenderness, and, occasionally, discharge. A tunnel infection is an infection that extends along the tunnel through which the CVC has been inserted. Erythema is present at the exit site and tenderness on palpation can be found over the entire catheter tunnel. Discharge often can be expressed from the exit site. Although the most common bacteria causing these 2 types of infections are S aureus and S epidermidis, a wide variety of gram-positive cocci and gram-negative bacilli also can cause these infections. Exit site infections often may be treated with antibiotic therapy alone. Initial treatment with vancomycin will provide coverage for S aureus and S epidermidis. If S aureus or S epidermidis is isolated and shown to be susceptible to oxacillin (or nafcillin), vancomycin should be stopped and oxacillin (or nafcillin) therapy instituted. Antibiotics should be tailored to bacteria isolated from the exit site. Often, 7-14 days of antibiotic treatment is necessary for bacterial eradication. Catheter removal, however, is necessary for bacterial eradication in cases of catheter tunnel infections. Initial antibiotic therapy should include vancomycin and then be directed toward the bacteria isolated from the infected site and catheter tip. Because the infection is deep-seated, antibiotic treatment often must be continued for at least 7 days following catheter removal.

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Skin Lesions of P aeruginosa Infection

Skin lesions caused by P aeruginosa infection are more common in advanced stages of HIV infection and include ecthyma gangrenosum, erythematous macular or maculopapular lesions, and violaceous nodules.(46) P aeruginosa can be cultured from these lesions and, often, from the blood. Ecthyma gangrenosum is a painless, round, indurated, ulcerated lesion containing a central black eschar. It usually occurs during P aeruginosa bacteremia, but may occur following infection of hair follicles. The erythematous and macular, maculopapular, or nodular lesions occur following disseminated P aeruginosa infection.(46) Treatment with 2 antipseudomonal antibiotics for at least 2 weeks should be instituted.

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Lymphadenitis

Adenitis may be caused by typical bacterial pathogens, such as S aureus and group A streptococci, but also may involve bacteria such as S viridans, Enterobacter spp, and S epidermidis.(51) The etiologic agent of cat-scratch disease, Bartonella henselae, also should be considered in the diagnosis. Initial treatment should be directed against S aureus and group A streptococci and then changed if necessary to antibiotics that are active against the isolated bacteria.

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Perirectal Abscess

Perirectal abscesses are seen more frequently in immunosuppressed patients, especially those with neutropenia.(58) The most frequently isolated bacteria include Bacteroides spp, P melaninogenicus, Peptostreptococcus spp, E coli, K pneumoniae, and S aureus. In addition, Enterococcus spp and Acinetobacter spp have been reported in HIV-infected children.(51) A combination of clindamycin or metronidazole plus an aminoglycoside, ceftriaxone, or cefotaxime will be active against most of the bacteria associated with these infections. The nonneutropenic child should have prompt surgical drainage or aspiration of the abscess, even if local fluctuance is not palpable.(58,59) Material obtained from drainage or aspiration of the abscess should be sent for Gram stain and aerobic and anaerobic culture. Antibiotics should be tailored to the bacterial isolates obtained from the infected material. In an HIV-infected child with severe neutropenia, drainage often is not attempted because of the lack of pus formation. In these cases, intravenous antibiotics are given for 2-3 weeks. Surgical drainage or aspiration then can be performed if there is disease progression with abscess formation.

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Bone and Joint Infections
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Septic Arthritis
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Hematogenous septic arthritis is thought to occur following bleeding into a joint with secondary seeding by bacteria from another site.(60) A number of cases of septic arthritis have been reported in patients with hemophilia and HIV infection.(60) Development of hematogenous septic arthritis was associated with lower CD4 counts. Although fever, increased white blood cell count, and elevated erythrocyte sedimentation rate often were present, the classic signs of joint swelling, pain, redness, and warmth usually were modified. Joint aspiration with appropriate chemistries, cell counts, and microbiologic studies should be performed. The predominant bacteria isolated from infected joints are S pneumoniae, S aureus, S viridans, S pyogenes, H influenzae, Salmonella spp, and Klebsiella spp.(17) Treatment consists of intravenous antibiotics targeted against the isolated bacteria for at least 3 weeks. Arthrotomy, arthroscopic lavage, or repeated aspiration may be needed as adjunctive therapy to decrease joint cartilage destruction by proteolytic enzymes that accumulate in the infected joint.

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Osteomyelitis
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Although osteomyelitis occurs in HIV-infected children,(17,37) it is seen less frequently than other types of serious bacterial infection in HIV-infected patients. A variety of organisms have been reported in HIV-infected patients, including S aureus, S pyogenes, nontyphoidal Salmonella spp, H influenzae, and M catarrhalis. Occasionally, mixed infection may be seen. Diagnosis involves appropriate radiographic studies and culture of blood and material obtained from infected bone by needle aspirate or biopsy. Treatment requires prolonged intravenous therapy with antibiotics that achieve high bone penetration and are directed against the identified or presumed causative bacteria. In some instances, blood and/or bone cultures may not identify an organism. In such cases, patients are treated with antibiotics empirically chosen in consultation with a specialist.

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Problems Due to Resistance of Bacterial Pathogens
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Resistance of numerous bacterial pathogens to many antibacterial agents continues to increase globally. Frequencies, patterns, and distributions of resistant bacteria vary significantly with geographic regions and often reflect the usage patterns of antibiotics. Factors that increase antibiotic resistance in resource-poor and resource-rich nations include total antibiotic consumption as well as underuse through lack of access, inadequate dosing, poor adherence, and substandard antimicrobial usage.(18)

These increases in bacterial resistance create barriers to treatment of severe and recurrent infections in HIV-infected children and adults, especially in resource-poor countries, because of increased treatment complexity and the need for expensive and often unavailable antibiotics for appropriate treatment.

The treatment of infection due to S pneumoniae has been problematic because of increasing resistance to many available antibiotics. The CDC's Active Bacterial Core Surveillance Report for 2004 showed that, in the United States, 8.4% of S pneumoniae isolates had high-level resistance to penicillin (MIC >=2 µg/mL) and 13.0% had intermediate-level resistance (MIC >=0.12 µg/mL).(61) In addition, erythromycin, TMP/SMX, and tetracycline resistance were found in 17.4%, 15.0%, and 7.2%, respectively.

Further complicating the treatment of S pneumoniae is the fact that penicillin-resistant strains often have some degree of cross-resistance among penicillins, cephalosporins, and carbapenems. In addition, vancomycin tolerance (the ability of S pneumoniae to escape lysis and killing by vancomycin) was found in 3% of 116 clinical isolates of pneumococci in a study in the United States. Such resistance may result in treatment failure, particularly in cases of meningitis in which bactericidal activity is critical for eradication.(62)

Mortality rates due to infection with penicillin-resistant pneumococcus may be increased among HIV-infected persons. In San Francisco, the mortality rate of HIV-infected adults infected with high-level penicillin-resistant pneumococcus was 7.8 times higher than that of the same population infected with susceptible or intermediate-level resistant pneumococcus.(63) Although comparative studies have not been done for HIV-infected children, in HIV-unininfected children non-CNS-invasive infections due to S pneumoniae with intermediate resistance to penicillin resulted in a significant increase in length of hospitalization and in time to defervescence (but not in a higher mortality rate) compared with infections due to penicillin-sensitive S pneumoniae.(64)

Surveillance studies of antimicrobial resistance have shown that bacterial resistance also has been increasing in many nosocomial pathogens in the United States.(65) The prevalence of resistance in many bacterial isolates from sites participating in the CDC's National Nosocomial Infections Surveillance increased from 1998 to 2002. Vancomycin-resistant enterococci increased in prevalence to 28.5% of reported clinical enterococcal isolates, whereas MRSA had increased to 59.5% of S aureus isolates. Resistance of K pneumoniae and Enterobacter spp to third-generation cephalosporins increased to 20.6% and 31.1%, respectively. Resistance of P aeruginosa to imipenem, quinolones, and third-generation cephalosporins increased to 21.1%, 29.5%, and 31.9%, respectively.

Resistance of the bacterial pathogens associated with diarrhea (Shigella spp, nontyphoidal Salmonella spp, and Campylobacter spp) to numerous antibiotics has been increasing in the United States. In 2002, 92% of Shigella isolates were resistant to 1 or more antibiotics and 58% were multidrug resistant. The most common antibiotics to which resistance was found and the associated frequencies of resistance were: ampicillin (77%), streptomycin (54%), TMP/SMX (37%), sulfamethoxazole (32%), and tetracycline (31%).(66) Twenty-one percent of nontyphoidal Salmonella isolates were resistant to 1 or more antibiotics, 16% were resistant to 2 or more antibiotics, and 9% were resistant to 5 or more antibiotics. The highest prevalence of resistance in nontyphoidal Salmonella was to tetracycline (15%), streptomycin (13%), ampicillin (13%), and sulfamethoxazole (13%). Resistance of Campylobacter spp to at least 2 different antibiotics was found in 51% of isolates. The highest frequencies of resistance were to tetracycline (40%), nalidixic acid (21%), and ciprofloxacin (20%).

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Antibiotic Resistance Globally
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Antibiotic resistance of S pneumoniae to several antibiotics is increasing globally.(67) Rates of penicillin resistance range from 2.4% in Germany to 50.1% in South Africa.(67) Antibiotic-resistant S pneumoniae has been seen with increasing frequency in HIV-infected patients in South Africa, Kenya, and Zimbabwe and may be due, in part, to increased use of antibiotics.(68-70) Rates of macrolide resistance range from 14.7% in Canada to 88.3% in Vietnam.(67) In private health care settings in South Africa where macrolides are available, an increase in resistance of S pneumoniae to macrolides has been documented.(69) Macrolide resistance increased from 1% to 21% in S pneumoniae isolates 2 months after initiation of a mass azithromycin prophylaxis campaign to eradicate trachoma in an aboriginal village in Australia.(71) Resistance of S pneumoniae to fluoroquinolones also is increasing, with local frequencies ranging from 1% to 18%.(67)

Resistance to several antibiotics also is being seen in H influenzae (B and non-B serotypes) globally.(67) Data from the LIBRA TARGETed surveillance program show that ampicillin resistance ranged from 6.4% in South Africa to 43% in France.(72) Although clarithromycin resistance ranged from 9% to 19%, most isolates were susceptible to azithromycin, amoxicillin-clavulanate, and quinolones.

The prevalence of resistance in S aureus also is increasing globally.(73) A survey of MRSA isolates from 8 large hospitals (>500 beds) in Africa and Malta from 1996 to 1997 showed that 15% of the 1,440 isolates of S aureus tested were methicillin resistant.(74) The prevalence of MRSA ranged from 21% to 30% in Nigeria, Kenya, and Cameroon and <10% in Tunisia, Malta, and Algeria. All MRSA isolates were susceptible to vancomycin, with MICs <=4 mg/L. The majority (>60%) of MRSA strains were multidrug resistant. The SENTRY Antimicrobial Surveillance Program has shown that South Africa also has a high prevalence of MRSA (41.5% methicillin resistance in a sample of 94 clinical isolates from 1998 to 1999).(75) Of special note is that MRSA was found to be more common in HIV-infected children than in uninfected children in South Africa.(76) Knowledge of the incidence of MRSA in the community should be a factor in deciding whether oxacillin or a cephalosporin can be used to treat a staphylococcal infection. It is recommended that in areas where CA-MRSA causes >10% of S aureus infections, antibiotics such as TMP/SMX, doxycycline, clindamycin, linezolid, and vancomycin should be considered as initial therapy, depending on the availability of the antibiotic and the severity of infection; an oral antibiotic should not be used to treat severe infections.

High levels of resistance to multiple antibiotics were found in many areas of the developing world in the major bacterial pathogens associated with diarrhea (Shigella spp, Campylobacter spp, nontyphoidal Salmonella, and V cholerae).(77) In Kenya, 90% of such primary isolates tested had resistance to 1 or more antibiotics, and 74% had resistance to 3 or more antibiotics. All isolates of Shigella dysenteriae type 1 tested were resistant to at least 6 antibiotics.(78)

Resistance of bacterial pathogens to TMP/SMX is increasing and is of particular concern because cotrimoxazole is the least expensive and one of the most frequently used antimicrobial agents. TMP/SMX resistance may be linked to the widespread use of TMP/SMX for prophylaxis of PCP and treatment of bacterial infections, and to the use of sulfadoxine-pyrimethamine to treat patients with chloroquine-resistant malaria.(79) That selection pressure on bacteria results from prolonged use of TMP/SMX for the prophylaxis of PCP has been demonstrated by the increase of TMP/SMX resistance in E coli isolated from HIV-infected adults in HIV units at San Francisco General Hospital (from 24% of isolates in 1988 to 74% in 1995).(80) Significant TMP/SMX resistance in clinically important bacteria also has been reported in South Africa,(81) Malawi,(79) and Zimbabwe.(68) Bacterial resistance leading to decreased effectiveness of TMP/SMX was demonstrated by a study in which women with either cystitis or uncomplicated pyelonephritis were treated with TMP/SMX. Those women who had infections due to TMP/SMX-resistant E coli had poorer bacteriological and clinical outcomes than those who had TMP/SMX-susceptible E coli.(82) Of concern is that increasing resistance to TMP/SMX may not only develop in bacterial pathogens but may also lead to decreased efficacy in prophylaxis and treatment of PCP, and in the use of sulfadoxine-pyrimethamine against P falciparum.

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Summary
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HIV-infected children are at increased risk for infection with a wide variety of bacteria that also infect immunocompetent children, as well as with unusual bacteria predominantly seen in immunocompromised hosts. Many of the serious bacterial illnesses occur at a much higher CD4 T-cell count and percentage than do other opportunistic infections. Although many of the typical bacterial infections have common presentations, recurrent infections become more frequent with increasing immunosuppression. Careful monitoring and early and prolonged antibiotic treatment often are necessary to achieve successful resolution of the illness. Treatment of many bacterial infections has become complex and expensive because of increasing bacterial resistance globally. Infection and malnutrition contribute to the markedly increased mortality rate of HIV-infected children in developing nations relative to that seen in industrialized nations.

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