CLINICAL

  • Invasive pneumococcal, H. influenzae infections 100x more common in HIV+ pts vs. HIV-, and may mimic PCP.
  • Risk of legionellosis may be 40x higher in pts with AIDS vs. general population.
  • Suspect P. aeruginosa when CD4 < 50, esp. if bronchiectasis, neutropenia, or steroid therapy. Radiographic findings may include consolidation, patchy interstitial infiltrates, and cavitary disease.
  • Suspect S. aureus (and MRSA) if IDU, cavitary pneumonia, hemoptysis, concomitant influenza, prior history of MRSA colonization or infection in patient or close contact.
  • Suspect TB with Sx >2 wks duration, past +PPD or IGRA, Hx of TB exposure or residence in endemic country, hemoptysis, apical cavitary disease, hilar adenopathy, miliary or reticulonodular infiltrates. Empiric FQ therapy for CAP may delay appropriate Dx of TB and select for resistance to this important second-line drug class.
  • Increased mortality in HIV+ pts, esp in setting of: CD4 < 100, radiographic disease progression, and shock. [4]
  • Tobacco use associated with increased risk. [2]

DIAGNOSIS

  • Hx: cough, fever +/- sputum production, dyspnea, pleurisy
  • PE: fever, tachycardia, tachypnea, rales or signs of consolidation
  • CXR showing infiltrate, although CXR pattern not always predictive of etiology
  • Good quality sputum gram stain obtained before Abx may establish probable etiology. Any isolation of Pneumocystis, M. tuberculosis, Legionella, Cryptococcus, or Histoplasma should be considered definitive Dx, but a co-pathogen could also be present.
  • Blood Cx have higher yield in HIV+ pts with bacterial pneumonia; sputum and blood Cx recommended. Other rapid tests include Legionella and pneumococcal urinary antigens, cryptococcal serum antigen.

TREATMENT

OUTPATIENT (EMPIRIC)

  • Consider PCP if CD4 < 250, no prophylaxis, indolent course, dry cough, diffuse interstitial infiltrates, hypoxemia/desaturation with exercise out of proportion to CXR findings, thrush. Prolonged empiric PCP treatment without definitive Dx not recommended, pursue Dx with induced sputum, and BAL if negative.
  • Recommendations for empiric treatment of bacterial pneumonia listed (alphabetical order).
    • Azithromycin 500 mg PO x1, then 250-500 mg PO once daily x 5d or clarithromycin 500 mg PO twice daily or 1g (XL formulation) PO once daily x 7-10d.
      • Avoid macrolide if pt receiving macrolide prophylaxis or treatment for MAC.
    • Cephalosporin: (cefuroxime 500 mg, cefpodoxime 400 mg, cefprozil 500 mg, cefditoren 400 mg, cefdinir 300 mg) PO twice daily x 7-10d.
    • Doxycycline 100 mg PO twice daily x 7-10d.
    • Fluoroquinolone: (moxifloxacin 400 mg or levofloxacin 750 mg) PO once daily x 5-7d. (Avoid if TB being considered)

INPATIENT (EMPIRIC)

  • Give Abx within 4 hrs.
  • Preferred:
  • Aspiration pneumonia: clindamycin 600 mg IV q8h PLUS FQ as above.
  • Add PCP coverage (preferably TMP-SMX 5mg/kg IV/PO q8h +/- corticosteroids) if CD4 ≤250, no PCP prophylaxis, indolent course, dry cough, diffuse interstitial infiltrates, hypoxemia/desaturation with exercise out of proportion to CXR findings
  • If Pseudomonas suspected (CD4 < 50 with bronchiectasis, neutropenia, or steroid therapy): either ceftazidime 2 g IV q8h, cefepime 2 g IV q12h, or piperacillin/tazobactam 4.45 g IV q6h or 3.375 g IV q4h PLUS either ciprofloxacin 400 mg IV q12h or (gentamicin/tobramycin 5 mg/kg IV once daily + azithromycin 500 mg IV once daily)
  • Duration of therapy determined by etiology or suspected etiology and/or by clinical response. S. pneumoniae, H. influenzae: 7-10d; Enterobacteriaceae, Legionella: 14d; S. aureus, P. aeruginosa: 21d.

Selected Drug Comments

Drug

Recommendation

Amoxicillin

Probably oral drug of choice for pneumococcal infections once etiology established. Dosing up to 4g per day provides serum concentrations to inhibit isolates with MICs as high as 2. Lacks activity against atypical agents and nearly half of H. influenzae infections.

Amoxicillin + Clavulanate

Has all features of amoxicillin and reliable activity against H. influenzae, but more expensive. New XR formulation (1000/62.5 mg) allows increase in amoxicillin dose to 2000 twice daily to inhibit pneumococci with MICs as high as 2 mcg/mL without increasing the dose of clavulanate (125 mg twice daily), the diarrhea-causing component.

Ampicillin + Sulbactam

Good activity against S. pneumoniae and H. influenzae but lacks atypical activity and activity vs. P. aeruginosa. Third-generation cephalosporins are favored over parenteral beta-lactams for empiric threapy unless aspiration suspected.

Azithromycin

Has activity against all major pathogens causing CAP in immunocompetent pts, except P. aeruginosa, and has proven efficacy as monotherapy. Major advantages are convenience of once daily dosing and the tissue pharmacokinetics, which permit shorter duration of therapy. Up to 35% of pneumococci are resistant in vitro, but clinical significance of low-level resistance (MIC ≤ 8) is debated. Clarithromycin may have better PK profile, but may not be as well tolerated.

Cefaclor

Not recommended, given low potency against S. pneumoniae and lack of atypical activity.

Cefepime

Adds pseudomonal activity to spectrum of third-generation cephalosporins, so most useful when P. aeruginosa suspected or confirmed. Should be paired with macrolide when used empirically due to lack of activity against atypical pathogens.

Cefotaxime

With ceftriaxone, the parenteral beta-lactam of choice for empiric therapy unless aspiration or P. aeruginosa suspected. Should be combined with a macrolide or FQ in seriously ill pts.

Ceftazidime

Third-generation cephalosporin with enhanced activity against P. aeruginosa, but reduced activity against S. pneumoniae, H. influenzae compared to ceftriaxone, cefotaxime. Use should be limited to suspected or confirmed pseudomonal pneumonia.

Ceftriaxone

With cefotaxime, the parenteral beta-lactam of choice for empiric therapy unless aspiration or P. aeruginosa suspected. Should be combined with macrolide or FQ in seriously ill pts.

Cefuroxime axetil

With cefprozil, cefpodoxime and cefditoren, these are the oral cephalosporins of choice. Cefuroxime should generally not be used parenterally for empiric therapy of pneumonia due to poor pharmacodynamic target attainment against pneumococci relative to third-generation cephalosporins.

Clarithromycin

Like azithromycin has activity against all major pathogens in immunocompetent pts. XL formulations permit once daily oral dosing. Main disadvantage is lack of IV formulation. Up to 35% of pneumococci are resistant in vitro, but clinical significance of low-level resistance (MIC < 8) is debated. Has best PK profile of macrolides, but may not be as well tolerated as azithromycin.

Clindamycin

Treatment of choice for aspiration pneumonia, but may also be useful against multi-drug resistant pneumococci (resistance rates < 10%) and against MRSA. For the latter however, must rule out inducible clindamycin resistance with a D-test if isolate erythromycin-resistant.

Daptomycin

Do not use to treat pneumonia. Shown to be inferior to ceftriaxone in clinical trial of CAP treatment, presumably because it achieves low concentrations in broncho-alveolar lining fluid and may be bound to pulmonary surfactant.

Doxycycline

A rational choice for outpts due to activity against all major pathogens of CAP in immunocompetent pts. Resistance rates vary among pneumococci, but are generally less than 20%.

Levofloxacin

Has activity against all major pathogens of bacterial pneumonia and advantages of once-daily dosing and high oral bioavailability. Major concern is overuse of this class and promotion of resistance. Avoid empiric use in pts recently treated with a FQ. Although ciprofloxacin remains the FQ of choice for pseudomonal infections, the 750 mg daily dose of levofloxacin likely has similar activity.

Linezolid

Reliable activity against all Gram-positive bacteria and excellent oral bioavailability, but no activity against Gram-negative or atypical pathogens. Very expensive. RCT of linezolid versus vancomycin found greater clinical efficacy, but numbers were insufficient to evaluate isolates with vancomycin MICs >1mcg/mL. [10] Probably the preferred agent against strains with vancomycin MICs >1 mcg/ml. Use should generally be limited to MRSA pneumonia, especially when oral therapy is preferred and other drugs (TMP-SMX, clindamycin, FQ) are not options.

Moxifloxacin

Has activity against all major pathogens of bacterial pneumonia and has advantages of once daily dosing and high oral bioavailability. Major concern is overuse of this class and promotion of resistance. Avoid empiric use in pts recently treated with a FQ. Ciprofloxacin remains the FQ of choice for pseudomonal infections.

Piperacillin + Tazobactam

Broad-spectrum beta-lactam most useful when infection with P. aeruginosa suspected or confirmed. May be used without the tazobactam if susceptibility confirmed.

Telithromycin

New ketolide that is active against virtually all S. pneumoniae, including macrolide-resistant isolates. Unusual side effect is impaired visual accommodation. Avoid in pts on PIs, as it may interact adversely. Concern for risk of fulminant hepatic failure prompted FDA to remove indication for acute sinusitis and AECB.

Trimethoprim + Sulfamethoxazole

Unreliable activity vs. S. pneumoniae and H. influenzae make this a poor empiric choice for CAP, but it remains treatment of choice for PCP and should be added when PCP suspected. Has also become an option for MRSA infections.

Vancomycin

Predictable activity against virtually all S. pneumoniae and S. aureus strains, but limited activity against other common CAP pathogens. Little rationale for use in empiric treatment of pneumonia unless MRSA suspected. Emerging evidence suggests vancomycin has poor activity against MRSA strains with MICs >1 mcg/ml. Consider use of linezolid for pneumonia caused by such strains.

Tigecycline

Broad-spectrum tetracycline derivative active against resistant MRSA, drug-resistant pneumococcus, ESBL+ bacilli, some multidrug-resistant Acinetobacter, anaerobes, and atypicals. Not active against P. aeruginosa. Non-inferior to levofloxacin in immunocompetent patients with CAP, however given its extremely broad-spectrum and lack of oral formulation, its use should be restricted to pathogen-directed therapy for resistant organisms in hospitalized patients when other options are not available.

FOLLOW UP

  • IV to PO switch when clinically improved, T < 100, RR < 24, PO2 >90, tolerating PO.
  • For pts not responding to empiric therapy for routine bacterial pathogens, consider MRSA, P. aeruginosa, PCP, TB and other mycobacterial infections, cryptococcosis and other fungal infections, KS, lymphoid interstitial pneumonitis.

OTHER INFORMATION

Prevention by Vaccination

  • Pneumococcal vaccine indicated in all HIV-infected persons regardless of CD4 count.
  • Preferred vaccination, one dose PCV13, followed by PPV23 at least 8 wks later. If CD4 < 200, may wait longer than 8 wks to administer PPV23 until CD4 >200.
  • Alternative vaccination, one dose of PPV23, followed by PCV13 at least 1 year after last PPV23. PPV23 recommended in those 19-64, if ≥5 years since last PPV. Another dose recommended in those ≥65, if ≥5 years since last PPV.
  • Inactivated influenza vaccination for all during influenza season. Live-attentuated influenza vaccine contraindicated in HIV+ people.

Pathogen Specific Therapy

Pathogen

1st Line Agent

2nd Line Agent

Streptococcus pneumoniae

Amoxicillin, penicillin

Cephalosporin (ceftriaxone, cefotaxime, cefpodoxime, cefprozil, cefditoren, cefuroxime axetil, cefdinir), macrolide (azithro, clarithromycin), FQ (moxifloxacin, levofloxacin, gemifloxacin), clindamycin, doxycycline, telithromycin

Haemophilus influenzae

Amoxicillin/clavulanate, cephalosporin (ceftriaxone, cefotaxime, cefpodoxime, cefprozil, cefditoren, cefuroxime axetil, cefdinir)

FQ (moxifloxacin, levofloxacin, gemifloxacin), macrolide (azithro, clarithromycin), TMP/SMX

Legionella spp.

Macrolide (azithromycin, erythromycin), FQ (moxifloxacin, levofloxacin)

Clarithromycin (no IV form), doxycycline, ciprofloxacin

Staphylococcus aureus-methicillin suspect.

Oxacillin, nafcillin, cefazolin

Clindamycin, TMP/SMX, vancomycin,

Staphylococcus aureus-methicillin resist.

Vancomycin, linezolid

Clindamycin, TMP/SMX, minocycline, doxycycline or tigecycline, quinupristin/dalfopristin. AVOID DAPTOMYCIN

Pseudomonas aeruginosa

Beta-lactam (ceftazidime, cefepime, piperacillin +/- tazobactam, ticarcillin +/- clavulanate, carbapenem, aztreonam) PLUS tobramycin

Beta-lactam plus gentamicin, Beta-lactam plus ciprofloxacin or levofloxacin 750mg

Anaerobes (aspiration)

Clindamycin, beta-lactam/beta-lactamase inhibitor

PCN plus metronidazole, carbapenem, moxifloxacin

Mycoplasma pneumoniae

Macrolide (azithromycin, clarithromycin, erythromycin), doxycycline

FQ (gatifloxacin, moxifloxacin, levofloxacin, gemifloxacin)

Chlamydia pneumoniae

Macrolide (azithromycin, clarithromycin, erythromycin), doxycycline

FQ (gatifloxacin, moxifloxacin, levofloxacin, gemifloxacin)

Nocardia spp.

TMP/SMX, sulfonamide

Minocycline (non-severe), carbapenem + amikacin (severe)

References

  1. Attia EF et al: Association of COPD with risk for pulmonary infections requiring hospitalization in HIV-infected Veterans. J Acquir Immune Defic Syndr Jul 11  [PMID:26181820]

    Comment: The Veterans Aging Cohort Study studied nearly 42,000 HIV+ veterans followed from 1996-2009 and found an association between COPD and community-acquired pneumonia (IRR, 1.9; 95%CI, 1.6-2.3).
    Rating: ImportantImportantImportantImportantImportantImportantImportant

  2. De P et al: Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. BMC Med 11:, 2013  [PMID:23339513]

    Comment: Meta-analysis of 8 pooled cohort studies found current smokers versus current non-smokers at higher risk for bacterial pneumonia (RR, 1.7, 95%CI, 1.4-2.1) and concluded that smoking cessation may mitigate this risk.
    Rating: Important

  3. Drummond MB et al: Factors associated with abnormal spirometry among HIV-infected individuals. AIDS 29:1691, 2015  [PMID:26372280]

    Comment: Cross-sectional anaylsis of multi-center data on 908 HIV+ individuals (78% men and 68% current smokers) showed abnormal spirometry in 37% suggesting role of screening spirometry.

  4. Kim JH et al: All-cause mortality in hospitalized HIV-infected patients at an acute tertiary care hospital with a comprehensive outpatient HIV care program in New York City in the era of highly active antiretroviral therapy (HAART). Infection 41:545, 2013  [PMID:23264096]

    Comment: Retrospective study of 9,101 HIV+ individuals admitted to urban, teritary St. Luke’s-Roosevelt Hospital Center, identified 237 deaths from 2004 to 2008. In chart review of 208 cases, mortality due to AIDS-related illnesses was associated with younger age (44 vs 50 yrs, p = 0.001), women (45 vs 25 %, p = 0.013), and lower CD4+ T cell counts (10 vs 66, p = 0.001). Cause of death was categorized as sepsis (35%), bacterial pneumonia (20%), cardiac disease (6%), liver disease (4%), and non-AIDS-related malignancy (4%).
    Rating: ImportantImportantImportant

  5. Mandell LA et al: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44 Suppl 2:S27, 2007  [PMID:17278083]

    Comment: Recommendations for management of immunocompetent pts, information on laboratory testing, Abx selection and the role of specific pathogens.

  6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/327/bacterial-respiratory. Accessed October 1, 2015.

    Comment: Updated comment on bacterial pneumonia in HIV+ patients includes treatment recommendations.

  7. Malinis M et al: Clinical outcomes of HIV-infected patients hospitalized with bacterial community-acquired pneumonia. Int J Infect Dis 14:e22, 2010  [PMID:19586789]

    Comment: Prospective study of 118 HIV+ pts and 2790 HIV- pts hospitalized for bacterial CAP found no difference in length of stay or time to clinical stability. More liver disease and alcohol/drug use seen in HIV+ pts. Majority of HIV+ pts had CD4>200.

  8. Zolopa A et al: Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 4:, 2009  [PMID:19440326]

    Comment: Prospective study of 141 early ART (within 14d of starting OI tx) vs 141 deferred ART (after OI tx completed). OIs included serious bacterial infections 12%, not limited to pneumonia. Early ART had fewer AIDS progression/deaths (OR, 0.5; 95% CI = 0.3-0.9).

  9. Sogaard OS et al: Hospitalization for pneumonia among individuals with and without HIV infection, 1995-2007: a Danish population-based, nationwide cohort study. Clin Infect Dis 47:1345, 2008  [PMID:18834317]

    Comment: Danish nationwide population-based cohort study of first-time hospitalization to treat pneumonia (excluding AIDS-defining PCP) included 3,516 HIV+ and 328,738 HIV- individuals followed from 1995-2007 documented decline in incidence rate ratios for those HIV+ from 35 (95%CI, 28-42) in 1995-1996 to 6 (95%CI, 5-8) in 2005-2007. Risk factors for increased risk of pneumonia were IV drug use, low CD4, nadir CD4, older age, and absence of ART.
    Rating: Important

  10. Wunderink RG et al: Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 54:621, 2012  [PMID:22247123]

    Comment: RCT of 348 hospitalized patients with MRSA nosocomial pneumonia treated with linezolid (N=172) versus vancomycin (N=176) in per protocol analysis 58% versus 47% achieved "clinical success" at end of study (p=0.042), 60-day mortality was 16% versus 17%, respectively.
    Rating: Important

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Last updated: December 9, 2015