Pneumonia, bacterial

Lisa A. Spacek, M.D., Ph.D.

PATHOGENS

CD4 >200: Streptococcus pneumoniae, Haemophilus influenzae, Legionella spp., M. tuberculosis, S. aureus, influenza
CD4 50-200: as above AND Pneumocystis jiroveci, Cryptococcus neoformans, Histoplasma capsulatum, Nocardia spp, Coccidioides immitis, Mycobacterium kansasii, Kaposi’s sarcoma
CD4 < 50: as above AND Pseudomonas aeruginosa, Aspergillus spp., Rhodococcus equi
S. pneumoniae most common bacterial pathogen

CLINICAL

Acute onset fever, chills, rigors, dyspnea, productive cough accompanied by egophony, fremitus, inspiratory crackles.
- Invasive pneumococcal, H. influenzae infections 100x more common in those with HIV vs. general population, and may mimic PCP.
In hospitalized, severe community-acquired pneumonia
- Risk of legionellosis may be 40x higher in those with HIV/AIDS vs. general population.
Cavitary disease
- Suspect P. aeruginosa when CD4 < 50, esp. if bronchiectasis, neutropenia, or steroid therapy. Radiographic findings may include consolidation, patchy interstitial infiltrates, and cavitation.
- Suspect S. aureus (and MRSA) if IDU, hemoptysis, concomitant influenza, prior history of MRSA colonization or infection in patient or close contact.
In those reporting weight loss, night sweats, hemoptysis
- Suspect TB with Sx >2 wks duration, past +PPD or IGRA, Hx of TB exposure or residence in endemic country, apical cavitary disease, hilar adenopathy, miliary or reticulonodular infiltrates. Empiric FQ therapy for community-acquired pneumonia 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.[7]
Tobacco use associated with increased risk.[8]

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, or within 12-18 hours, may establish probable etiology. Any isolation by sputum culture of Pneumocystis, M. tuberculosis, Legionella, Cryptococcus, or Histoplasma should be considered definitive Dx, and co-pathogen may be present.
Sputum and blood Cx are recommended.
- Blood Cx have higher yield in individuals with HIV; especially in setting of severe pneumonia, in those not on ART, and when CD4 < 350 cells/uL.
- MRSA rapid nasal testing recommended, if available.
- Diagnostic thoracentesis if pleural effusion or empyema as increased risk of invasive pneumococcal disease in those living with HIV leads to greater likelihood of extrapulmonary complications.
Multiplex PCR testing includes bacteria, atypical bacteria, viruses, and antibiotic resistance genes.[4]
Urinary antigen tests for L. pneumophilia and S. pneumoniae recommended in those hospitalized with severe CAP.[1]
Cryptococcal serum antigen in those with CD4 < 100 cells/uL.

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 if negative, BAL.
Recommendations for empiric treatment of bacterial pneumonia listed (alphabetical order).
- Combination therapy: amoxicillin/clavulanate 500 mg/125 mg PO three times daily or amoxicillin/clavulanate 875 mg/125 mg PO twice daily or cephalosporin (cefpodoxime 200 mg PO twice daily OR cefuroxime 500 mg PO twice daily) AND a macrolide (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) OR Doxycycline 100 mg PO twice daily x 7-10d.
  - Avoid macrolide if pt receiving macrolide prophylaxis or treatment for MAC.
- Monotherapy with respiratory fluoroquinolone: (gemifloxacin 320 mg or levofloxacin 750 mg or moxifloxacin 400 mg) PO once daily x 5-7d.
  - Avoid if Dx of TB being considered
Regimens recommended for patients with comorbidities include a β-lactam or cephalosporin in combination with either a macrolide or doxycycline. This provides coverage for macrolide- or doxycycline-resistant S. pneumoniae and β-lactamase-producing strains of H. influenzae, enteric GNB, most MSSA, M. pneumoniae, and C. pneumoniae.[1]

INPATIENT (EMPIRIC)

Give Abx within 4 hrs.
Preferred:
- Combination with β-lactam (ampicillin + sulbactam 1.5-3 g IV q6h or ceftriaxone 1-2 g IV once daily or cefotaxime 1-2 g IV q8h, or ceftaroline 600 mg IV q12h) PLUS either azithromycin 500 mg IV/PO once daily or clarithromycin 500 mg PO twice daily
- Fluoroquinolone: moxifloxacin 400 mg or levofloxacin 750 mg IV or PO once daily
Add coverage for MRSA or P. aeruginosa in those with prior respiratory pathogen isolation, also add coverage in those with severe inpatient pneumonia and recent hospitalization with exposure to IV ABX and locally validated risk factors for MRSA or P. aeruginosa. Obtain cultures and rapid nasal PCR, if available. Adjust coverage with continuation or deescalation based on results.[1]
- MRSA coverage: vancomycin 15 mg/kg IV q12h, adjust based on levels, or linezolid 600 mg q12h
- P. aeruginosa coverage: piperacillin-tazobactam 4.5 g IV q6h, cefepime 2 g IV q8h, ceftazidime 2 g q8h, imipenem 500 mg q6h, meropenem 1 g IV q8h, or aztreonam 2 g IV q8h
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.
Pseudomonas more likely in those with CD4 < 50 with bronchiectasis, neutropenia, or steroid therapy.
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	Preferred high-dose, oral drug of choice for pneumococcal infections once etiology established. Dosing up to 4g per day provides serum concentrations to inhibit isolates with MIC as high as 2. Lacks activity against atypical agents and nearly half of H. influenzae infections.
Amoxicillin + Clavulanate	Preferred high-dose, 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 MIC 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 therapy 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.
Ceftaroline	"Fifth generation cephalosporin" with broader spectrum activity including MRSA due to addition of the 1,3-thiazole ring moiety. FDA approved for community acquired pneumonia and skin and soft tissue infections.
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	Alternative treatment 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 is 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	Preferred treatment has activity against all major pathogens of bacterial pneumonia and advantages of once-daily dosing and high oral bioavailability. 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.[9] 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	Preferred treatment has activity against all major pathogens of bacterial pneumonia and has advantages of once daily dosing and high oral bioavailability. Avoid empiric use in pts recently treated with a FQ. Ciprofloxacin remains the FQ of choice for pseudomonal infections.
Omadacycline	Omadacycline is a semisynthetic aminomethylcycline with activity against MRSA, penicillin- and multidrug-resistant S. penumoniae, S. pyogenes, S. agalactiae, and VRE. It can overcome tetracycline resistance by circumventing ribosomal protection proteins and active efflux pumps.
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

Adults and adolescents with HIV who have never received any pneumococcal vaccine should receive a single dose of PCV13 regardless of CD4 count.[2]
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 PPV23. Another dose recommended in those ≥65, if ≥5 years since last PPV23. No more than 3 lifetime doses of PPV23.
Inactivated influenza vaccination for all during influenza season. Live-attentuated influenza vaccine contraindicated in HIV+ people. Influenza vaccination can reduce risk of bacterial pneumonia occurring as a complication of influenza.
Other prevention efforts include cessation of smoking, alcohol, and injection drug use.

Pathogen Specific Therapy

Pathogen	First-Line Agent	Second-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)

Basis for recommendation

Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. [PMID:31573350]
Comment: 2019 guidelines recommend sputum and blood culture in all patients treated empirically for MRSA and P. aeruginosa as well as those hospitalized with severe pneumonia. Increased yield for pathogens serves as the rationale for recommending Gram stain and culture after intubation. β-lactam/macrolide combination is preferred and supported by stronger evidence, whereas 2007 guidelines gave equal weight to β-lactam/macrolide and β-lactam/fluoroquinolone for standard empiric therapy for severe CAP. Guidelines do not recommend routine use of procalcitonin, steroids, or follow-up chest imaging.
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 3/14/2020.
Comment: Updated comment on bacterial pneumonia in HIV+ patients includes treatment recommendations.

References

Garcia Garrido HM, Mak AMR, Wit FWNM, et al. Incidence and Risk Factors for Invasive Pneumococcal Disease and Community-acquired Pneumonia in Human Immunodeficiency Virus-Infected Individuals in a High-income Setting. Clin Infect Dis. 2019. [PMID:31634398]
Comment: Dutch incidence rates of community-aquired pneumonia (CAP) and invasive pneumococcal disease (IPD) from 2008 to 2017 amounted to 111 and 1529 per 100,000 PY. Both occurred more often in those with CD4 < 500; however, incidence rates remained higher in those with CD4 > 500 when compared to general population (946 vs 188 per 100,000 PY). All cases of IPD were vaccine serotypes. Case fatality rate for IPD was 8% and for CAP was 4%. Authors recommend vaccination.
Rating: Important
Lee SH, Ruan SY, Pan SC, et al. Performance of a multiplex PCR pneumonia panel for the identification of respiratory pathogens and the main determinants of resistance from the lower respiratory tract specimens of adult patients in intensive care units. J Microbiol Immunol Infect. 2019;52(6):920-928. [PMID:31806539]
Comment: Results of a multiplex PCR pneumonia panel, which identifies 15 bacteria, 3 atypcial bacteria, 8 viruses, and 7 antimicrobial resistance genes within 1 hour, were compared to results of conventional cultures read at 18-24 hours, held for 2 days, and analyzed by a MALDI-TOF MS system. Other testing included: direct immunofluorescence staining for viruses and Chlamydia, serum IgM and IgG for M. pneumoniae, urine specimens for Legionella and pneumococcal antigen, and fluorescent immunoassay for influenza A and B. Authors attribute most discordance to antibiotic use prior to sampling and note that molecular diagnostics do not distinguish colonization from infection. Coinfections were documented in 42% of 59 specimens.
Collins LF, Havers FP, Tunali A, et al. Invasive Nontypeable Haemophilus influenzae Infection Among Adults With HIV in Metropolitan Atlanta, Georgia, 2008-2018. JAMA. 2019;322(24):2399-2410. [PMID:31860046]
Comment: A population-based surveillance study from 2008-2018, identified adults ≥18 years with invasive non-typeable H. influenzae. Of those with infections from 2017-2018 (n = 179), persons with HIV (n = 31) were more likely than those from 2008-2018 without HIV (n = 124) to be male (94% vs 49%), black (100% vs 53%), and have septic arthritis (35% vs 1%).
Attia EF, McGinnis KA, Feemster LC, et al. Association of COPD with risk for pulmonary infections requiring hospitalization in HIV-infected Veterans. J Acquir Immune Defic Syndr. 2015. [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
Kim JH, Psevdos G, Gonzalez E, 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. 2013;41(2):545-51. [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
De P, Farley A, Lindson N, et al. Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. BMC Med. 2013;11:15. [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
Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012;54(5):621-9. [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
Sogaard OS, Lohse N, Gerstoft J, et al. Hospitalization for pneumonia among individuals with and without HIV infection, 1995-2007: a Danish population-based, nationwide cohort study. Clin Infect Dis. 2008;47(10):1345-53. [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
Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-72. [PMID:17278083]
Comment: Recommendations for management of immunocompetent pts, information on laboratory testing, Abx selection and the role of specific pathogens.

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