From The Ohio State University, Columbus, OH.
Correspondence to: Julie E. Mangino, MD, Department of Internal Medicine, Division of Infectious Diseases, The Ohio State University, N-1150 Doan Hall, 410 West 10th Ave, Columbus, OH 43210. E-mail: firstname.lastname@example.org.
The author has no funding or conflicts of interest to disclose.
In this month’s issue, Zainah et al share a retrospective review, performed at a 900-bed teaching hospital in Detroit, Mich, on 115 patients with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia; the primary outcome was mortality at 28 days. Most specimens were sputum (∼70%); importantly, the Minimum Inhibitory Concentration (MIC) to vancomycin was 1 or less, both in 64.5% of those who died and 70.9% of those who survived, and was not significant in univariable analysis. The majority (>55%) of patients had health care–associated pneumonia (HCAP), followed by ventilator-associated bacterial pneumonia (∼20%) and hospital-acquired bacterial pneumonia (HABP), and less than 10% had community-associated pneumonia. Pneumonias were multilobar in more than one third of the patients, and ∼87% were admitted to the intensive care unit with mean (SD) Acute Physiology and Chronic Health Evaluation II scores of 18.72 (SD, 7.72), which was higher in nonsurvivors.
The mean (SD) treatment duration was 13.1 (SD, 7.1) days, and overall mortality was 27.8% among 32 patients. For the 83 survivors, 9 (10.8%) were treated for less than 8 days, 33 (39.8%) were treated for 8 to 13 days, 26 (31.3%) were treated for 14 to 20 days, and 15 (18.1%) were treated for more than 20 days. For the 32 nonsurvivors, 11 were treated for less than 8 days, 14 for 8 to 13 days, 6 for 14–20 days, and 1 for more than 20 days. The duration of therapy for survivors was statistically significant (P < 0.001), with longer durations of therapy predicting survival at 28 days. Most patients (n = 70) were treated with vancomycin alone with similar survival results (P < 0.001), but nonsignificance in those who were switched between the 2 drugs (n = 32) or who were treated with linezolid alone (n = 12). Importantly, diabetes mellitus was also a predictor for death.
The organisms causing HABP (>48 h of in-hospital incubation), ventilator-associated bacterial pneumonia, and HCAP, denoting significant preadmission health care exposure, are addressed in the guidelines for the management of pneumonia in adults in 2005.1 Recommendations include empirical coverage with optimized dosing, for both MRSA and multidrug-resistant Gram-negatives, for patients with known multidrug-resistant risk factors, late-onset disease, and all disease severities.1 In a review by Jones2 of the SENTRY Antimicrobial Surveillance Program (1997-2008) assessing all regions (United States, Europe, and Latin America), S. aureus caused 28% of the episodes of HABP and VABP, “B” specifically denoting bacterial causes. Noteworthy over time, however, S. aureus susceptibility to oxacillin (ie, MSSA) increased from 42% to 46%, with MRSA at 54% in 2008.3
The treatment duration for MRSA pneumonia was not clearly defined in the 2005 guidelines. Regarding length of treatment, “efforts should be made to shorten the duration from the traditional 14 to 21 days to periods as short as 7 days, provided the pathogen is not P. aeruginosa, and the patient has a good clinical response with resolution of clinical features of infection.”1 In more recent guidelines for treatment of MRSA infections, vancomycin or linezolid twice daily or clindamycin (if the strain is susceptible) is recommended for 7 to 21 days for health care– or community-associated MRSA pneumonia, depending on the extent of the infection.3 This does not apply if bacteremia or empyema is present, and longer treatment and surgical debridement are recommended. In comparative therapeutic pneumonia trials, agents are usually administered for 7 to 14 days, if MRSA bacteremia is not documented.
The mean duration of therapy, in the most recent randomized, double-blind, multicenter trial that compared linezolid to vancomycin, was 10 days (range, 2–22 days) for both agents.4 Although the investigators found significantly better clinical and microbiologic cures with linezolid (58%) compared with vancomycin (47%), there was no difference in mortality between the 2 arms at 60 days. Notably, in this comparative trial, more patients were on mechanical ventilation, had MRSA bacteremia and also kidney disease in the vancomycin arm.5
Today, a primary goal of infectious diseases clinicians is to do everything feasible to avoid the development of resistance; this goal must be concomitantly offset by recommending appropriately dosed agents for adequate durations to optimize patient outcomes. De-escalation and pathogen-directed therapy are crucial to attain both objectives. From the available evidence, we do not have a “final answer” for which MRSA pneumonia therapy prevents death or how long to treat MRSA pneumonia. When vancomycin MICs are more than 1, which was not predominant in the current study of Zainah et al, linezolid seems a thoughtful choice compared with vancomycin, based on dosing required to reach desired trough levels for efficacy. Was the mortality benefit of the longer duration of therapy needed to avoid death, negated with switching between the agents or linezolid only therapy?
The current study has inherent limitations: it is single-center and retrospective, and, most importantly, those who died early on with MRSA pneumonia (ie, due to severity of illness) never had the chance to experience the longer treatment duration for clinical cure. Nonetheless, this succinct study provides valuable defense that shortening therapy to less than 7 days is surely undesirable for most patients with MRSA pneumonia. The optimal treatment duration for MRSA pneumonia appears to be closer to 10 days as a minimum; treating for 14 days or more seems prudent, as it is pathogen directed, and decisions to switch to a susceptible oral agent can be addressed based on clinical response. Clearly, additional study is needed to answer MRSA treatment duration definitively, but a longer duration seemed to have improved survival in this diverse cohort. This knowledge is very helpful to those asked to make such a recommendation each day.
1. Guidelines for the management of adults with hospital-acquired, ventilator–associated and healthcare–associated pneumonia. Am J Respir Crit Care Med
. 2005; 171: 388–416.
2. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator associated bacterial pneumonia. Clinical Infectious Diseases
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3. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin resistant Staphylococcus aureus
infections in adults and children. Clin Infect Dis
. 2011; 52 (3): 285–292.
4. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus
nosocomial pneumonia: a randomized controlled study. Clin Infect Dis
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nosocomial pneumonia: implications of the ZEPHyR trial. Ann Pharmacother
. 2012; 46 (10): 1432–1435.