Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Disease Specific Recommendations Bacterial Respiratory Disease Epidemiology       Bacterial pneumonia is a common cause of HIV-1 related morbidity . Incidence of approximately 100 cases per 1,000 HIV-1--infected persons per year have been reported, a rate much higher than in the noninfected population . In a study comparing rates among cohorts with similar other risk factors for bacterial pneumonia, those with HIV-1 infection were 7.8 times more likely to develop bacterial pneumonia than HIV-seronegative persons . For certain persons, bacterial pneumonia is a symptom of HIV-1 disease. Patients can develop serious pneumococcal infections with relatively preserved CD4+ T lymphocyte counts. The high rates of bacterial pneumonia and other pyogenic respiratory tract infections probably result from multiple factors including qualitative B-cell defects that impair the ability to produce pathogen-specific antibody, impaired neutrophil function or numbers or both, and non-HIV--related factors (e.g., cigarette smoking, use of crack cocaine, IDU, alcoholism, or liver disease). The most consistent predictor of bacterial infections is the CD4+ T lymphocyte count . The etiology of bacterial pneumonia among patients with HIV-1 infection has been reported . Consistent among these has been the relative prominence of Streptococcus pneumoniae, followed by Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. In the majority of studies, the pathogens of atypical pneumonia (Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia pneumoniae) are rarely encountered. On the basis of data derived from studies of pneumococcal bacteremia, infection with S. pneumoniae is 150--300 times more common among patients with HIV-1 infection than in age-matched HIV-uninfected populations . Recurrent pneumococcal pneumonia, either with the same or unrelated serotype, is also more common among HIV-1--infected patients, with a rate of 8%--25% within 6 months . Reinfection with a different strain is more common than relapse. In the majority of series, H. influenzae (usually nontypable) is generally the second most common cause of bacterial pneumonia . In patients with advanced immunosuppression, S. aureus and P. aeruginosa can cause particularly aggressive invasive pneumonias, sometimes associated with bacteremia and frequent relapses after cessation of therapy . As reported in pneumonia studies of non-HIV-1--infected patients, a high proportion (up to 33%) of patients with HIV-1 infection will have no specific microbiologic etiology defined. Many of these undefined cases are believed to be of possible bacterial etiology based on reviews of clinical and laboratory data, including response to antibacterial therapy. Clinical Manifestations HIV-1--infected patients with bacterial pneumonia generally present in a similar fashion to those without HIV-1 infection (i.e., acute illness characterized by chills, rigors, pleuritic chest pain, and purulent sputum). Physical findings consist of fever, tachypnea, tachycardia, rales or rhonchi, and other signs of consolidation. Lobar consolidation on chest radiograph is commonly observed and is a predictor of bacterial pneumonia, although atypical presentations with multilobar, nodular, or reticulonodular patterns are occasionally described . Patients ill over a period of weeks to months are more likely to have P. jiroveci pneumonia, TB disease, or an endemic chronic fungal infection . Diagnosis The pace of the respiratory disease, the underlying CD4+ T lymphocyte count, the circulating neutrophil count, and the appearance of the infiltrate should guide the diagnostic evaluation for bacterial pneumonia. At a minimum, a chest radiograph, blood cultures, a white blood cell count and, if available, a Gram's stain and culture of an adequate expectorated sputum sample, should be obtained before antibiotic administration. Because PCP is a common HIV-1--related respiratory infection and might co-exist with bacterial pneumonia, an induced sputum examination for P. jiroveci staining should be performed in the appropriate clinical settings. These would include known CD4+ T lymphocyte count <250 cells/µL, other signs of advanced immunodeficiency (e.g., thrush), a previous history of PCP or other AIDS-related condition, or diffuse infiltrates on chest radiograph. For both clinical and infection-control purposes, sputum samples (either expectorated or induced) for AFB staining and TB cultures should be obtained on all HIV-1--infected hospitalized patients with pulmonary infiltrates in the appropriate epidemiologic setting. A possible exception would be the patient who has an acute onset of an illness consistent with bacterial pneumonia, has no exposure to TB, has a previous negative TST, and who has not lived in or been exposed to high-prevalence areas for TB. In the absence of clinical improvement after initiation of antibiotic therapy and depending on the clinical history and radiographic findings, the following supplemental tests might be useful: urine antigen testing for L. pneumophila and histoplasmosis; IgM and IgG serology for M. pneumoniae and C. pneumoniae; serum cryptococcal antigen; CT scanning of the chest; and bronchoscopy with bronchoalveolar lavage and biopsy. Treatment Recommendations Therapy for HIV-1--related bacterial pneumonia should target the most commonly identified pathogens, particularly S. pneumoniae and H. influenzae. Treatment guidelines appropriate for HIV-1--uninfected patients are applicable to those with HIV-1 infection . Specific recommended regimens include either an extended spectrum cephalosporin (e.g., cefotaxime or ceftriaxone) or a fluoroquinolone with activity against S. pneumoniae (e.g., levofloxacin, moxifloxacin, or gatifloxacin) (AIII). Combination therapy with a macrolide or quinolone plus a cephalosporin should be considered for those with severe illness (AIII). For high-level penicillin-resistant isolates (MIC >4.0 mg/mL), therapy should be guided by susceptibility results. Determining whether meningitis is present is important because the recommended fluoroquinolones do not reliably attain adequate cerebrospinal fluid (CSF) levels for treating pneumococcal meningitis. Among patients with severe immunodeficiency (CD4+ T lymphocyte counts <100/mL), a known history of previous Pseudomonas infection, bronchiectasis, or relative or absolute neutropenia, broadening empiric coverage to include P. aeruginosa and other gram-negative bacilli should be considered. Possible options for therapy include ceftazidime, cefepime, piperacillin-tazobactam, a carbapenem, or high dose ciprofloxacin or levofloxacin. For ceftazidime and ciprofloxacin, other antimicrobial agents would be needed to provide optimal coverage for gram-positive infections. Monitoring and Adverse Events A clinical response (i.e., a reduction in fever and improvement in laboratory studies, physical findings, and respiratory symptoms) are generally observed 48--72 hours after initiation of appropriate therapy. Radiographic improvement might require additional time for demonstrable improvement. Management of Treatment Failure HIV-1--infected patients who fail to respond to appropriate antimicrobial therapy, as determined by a lack of reduction in fever, failure of the total WBC to return toward normal, persistent or worsening pulmonary signs, symptoms or radiographic abnormalities, progressive hypoxemia or other evidence of progressive disease, should undergo further evaluation, especially bronchoalveolar lavage or transbronchial biopsy, to search for other infectious and noninfectious causes of pulmonary dysfunction. Broader spectrum antimicrobial therapy might be required while additional diagnostic testing is pursued. Management in consultation with an infectious disease specialist is recommended. Prevention of Recurrence The strategy most effective in preventing bacterial pneumonia in HIV-1--infected patients is to optimize ART (AII). No well-documented benefit has been determined for secondary prophylaxis (chronic maintenance therapy) after successful completion of antibiotic treatment for bacterial respiratory tract infections. Adults and adolescents who have a CD4+ T lymphocyte count of >200 cells/µL should be administered a single dose of 23-valent polysaccharide pneumococcal vaccine if they have not received it during the preceding 5 years (BII). Annual administration of influenza vaccine might be useful in preventing pneumococcal superinfection of influenza respiratory tract infections (BII). Administration of antibiotic chemoprophylaxis to HIV-1--infected patients who have frequent recurrences of serious bacterial respiratory infections should be considered (CIII). TMP-SMX, administered for PCP prophylaxis and clarithromycin or azithromycin, administered for MAC prophylaxis, are appropriate for drug-sensitive organisms. However, caution is required when using antibiotics solely for preventing the recurrence of serious bacterial respiratory infections because of the potential for development of drug-resistant microorganisms and drug toxicity. Special Considerations During Pregnancy The diagnosis of bacterial respiratory tract infections among pregnant women is the same as for nonpregnant adults, with appropriate shielding of the abdomen during radiographic procedures. Bacterial respiratory tracts infections should be managed as in the nonpregnant adult, with certain exceptions. Clarithromycin should be avoided because of the occurrence of birth defects associated with its use among mice and rats (DIII). Because arthropathy has been observed among immature animals with the use of quinolones during pregnancy, quinolones are generally not recommended in pregnancy and among children aged <18 years. However, >200 cases of ciprofloxacin use in pregnancy have been reported to various pregnancy registries, and its use has not been associated with arthropathy or birth defects after in utero exposure in humans. Therefore, quinolones can be used in pregnancy for drug-resistant disease when other alternatives are not available (CIII). Pneumococcal and influenza vaccine can be administered during pregnancy, and influenza vaccine is recommended for all women who will be in the second or third trimester of pregnancy during the peak of influenza season (AIII). Because administration of vaccines might be associated with a transient rise in plasma HIV-1 RNA levels, vaccination of pregnant women is best done after ART has been initiated to minimize increases in plasma HIV-1 RNA levels that might increase the risk for perinatal HIV-1 transmission.