By: Dr. Geoffrey Modest
A Dutch study looked at 2283 patients with community-acquired pneumonia (CAP) admitted to the hospital but not the ICU during three 4-month periods in 2011-2013, with different antibiotics as the preferred empirical treatment for each period, and with the order of these treatments randomized separately for the different hospitals (N Engl J Med 2015;372:1312-23).
–Case definition: at least 2 of the clinical criteria (below)
–Clinical criteria: cough, purulent sputum or change in sputum character, temp >38C or <36.1C, lung exam with rales and/or consolidation, WBC >10K or >15% bands, CRP >3x upper limit of normal, dyspnea/tachypnea/hypoxemia, new or increased infiltrate on xray
–Median age of patients 70. 2.5% had received PPSV23 vaccine and about 2% PCV13. 20% had cardiovascular disease, 40% COPD or asthma, 10% other pulmonary diseases, 16% cancer, 18% diabetes. 77% had radiologically confirmed CAP
–Intervention strategies:
–β-lactam: amoxicillin (in 31%), amoxacillin plus clavulanate (in 43%), or 3rd generation cephalosporin (ceftriaxone in 17%)
–β-lactam/macrolide: penicillin, amoxacillin, amoxacillin plus clavulanate, or 3rd generation cephalosporin, in combination with azithromycin, erythromycin or clarithromycin
–fluoroquinolone: moxifloxacin or levofloxacin
–Primary outcome: all-cause mortality within 90 days of admission; secondary outcomes: time to starting oral treatment, length of hospital stay, minor or major complications in the hospital
–Results:
–microbiology: 15.9% s pneumonia, 6.8% h influenza, 2.1% atypicals (mycoplasma pneumoniae, chlamydia pneumoniae, and legionella species), 2.5% viruses, 65% no pathogen identified.
–most frequent reason for deviation from the β-lactam strategy was perceived need to cover atypicals (8.1%)
–Comparing the strategies of β-lactam, β-lactam-macrolide combo, fluorquinolone, respectively, crude 90-day mortality was 9.0% (59 patients) vs 11.1% (82 patients) vs 8.8% (78 patients) – nonsignificant differences. Also nonsignificant when adjusted for pneumonia severity or if limited to group with xray-confirmed CAP.
–These results suggest noninferiority of the β-lactam strategy, even after controlling for providers’ deviating from the antibiotic strategy by clinical considerations.
–median length of stay 6 days for all strategies
–median time to starting oral therapy in the hospital was 3 days for fluoroquinolones and 4 days for others
— they did do urinary antigen testing for strep pneumoniae and legionella pneumophila. Those with legionella were preferentially given ciprofloxacin or other appropriate antibiotics
–The pathogens found were similar among the strategy groups, but there was more bacterial resistance in the group on the β-lactam strategy. This was not associated with worse clinical outcomes.
Current US guidelines:
–US guidelines (IDSA/ATS –infect disease soc of America/amer thorac soc, 2007): for outpatient treatment
–previously healthy and no use of antimicrobials in past 3 months: macrolide (azithro, clarithro, erythro) OR doxycycline (prefer macrolide)
–presence of comorbidities (chronic heart, lung, liver, renal disease; diabetes; alcoholism; malignancy; asplenia; immunosuppression; or use of antimicrobials in the past 3 months): fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [750mg] OR β-lactam (first line: high-dose amoxicillin, amoxicillin-clarulanate; alternatives: ceftriaxone, cefpodoxime, or cefuroxime) PLUS a macrolide.
–in regions with high rate (>25%) of infection with high-level (MIC>=16) macrolide-resistant s. pneumoniae, consider one of the alternative agents and don’t use a macrolide by itself. [note: the US overall had a resistance rate of 41.15% in 2009 (the UK by contrast, has 4.20%)
Overall, pretty low incidence of atypical CAP infections during this study. Although this was a hospital-based study, it seems that an outpatient strategy, with likely less sick patients, would yield similar results. A major concern in this study is the remarkably low rate of vaccination (<5% had either of the pneumococcal vaccines). The vast majority of these patients, by age or comorbidities, would qualify for both PPSV23 and PCV13 vaccines, and this is especially important because of the worldwide spread of antibiotic-resistant s. pneumoniae. For example, a 2002 article found that 14-16% of pneumococci were multi-drug resistant (at least 3 classes, including β-lactam, macrolides, tetracyclines, sulfonamides, and chloramphenicol). In terms of atypicals), there was a meta-analysis comparing β-lactam antibiotics vs those active against atypical pathogens, finding that in 18 trial with 6749 patients with non-severe community acquired pneumonia, there was no advantage in using specific antibiotics against atypicals other than those with Legionella (in subgroup analysis), where there was a significantly lower failure rate in those on an antibiotic active against Legionella (RR 0.40, 0.19-0.85), a rare cause of pneumonia in this meta-analysis (only 75 patients in whole sample, or about 1%). In this meta-analysis, there was no difference in cure rates between antibiotics, including those considered ineffective for mycoplasma or chlamydia pneumoniae. (see BMJ. 2005;330(7489):456).
So, what makes sense? First, i think we should be aggressive in vaccinating people against pneumococcal pneumonia, the most common of the bacterial pneumonias. Second, it is impressive that both mycoplasma and chlamydia seem to do okay with β-lactam antibiotics, in both this study and the BMJ meta-analysis. I continue to be very concerned about increasing bacterial resistance. Articles in the past have promoted levofloxacin as the go-to antibiotic for pneumonia. But, of course, that might well lead to unintended consequences. Specifically bacterial resistance both with lung pathogens and others (eg, the increasing resistance of H pylori to antibiotics, exacerbated by the fact that single agents are unable to cure the infection but quite good at causing resistance). Perhaps the safest strategy is to use a macrolide, when resistance levels are low, or doxycycline, as suggested by IDSA/ATS, or to use a β-lactam but make sure the CAP was not from legionella (a very unusual cause), which does do better with a fluorquinolone or macrolide. Based on the above studies, I do find the last strategy appealing, though would be great to have a prospective trial confirming it.