HCAP guideline adherence associated with increased mortality?

Apparently according to recent findings. A Tweet from DB, a hard-nosed guideline skeptic, alerted me to this paper in Lancet Infectious Diseases:

Background 

The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes...

Findings

303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group...

Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness...

Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy.

According to this commentary in Medscape the main difference between the adherent and the non-adherent regimens was the use of double gram-negative coverage in the former. This often involved the use of an aminoglycoside as the secondary gram negative drug. Since the study findings showed little difference in pathogen coverage between the two groups, the difference in outcomes must have been driven by adverse effects of treatment. Aminoglycoside toxicity is well known and may have been a driving factor.


Why do the IDSA HCAP guidelines advocate double gram-negative coverage for patients deemed to be at high risk for drug resistant pathogens? In looking at the primary sources cited in the guidelines it appears that it was based on these two papers. They were not comparative antibiotic trials, so this is not high level evidence. Both papers involved VAP patients at large academic medical centers---the sickest of the sick. What the guideline authors drew from these studies were antimicrobial sensitivity patterns, from which it was determined that double gram-negative coverage was needed to cover the spectrum. In one study it was a carbapenem plus a quinolone; in the other it was a carbapenem plus amikacin. It would appear that the rationale was spectrum coverage rather than synergy or concerns about emerging resistance. The spectrum may not need to be so broad in patients with HCAP in community hospitals. To the guideline authors' credit, they emphasize that antibiotic selection must be guided by local antibiograms.


So are the guidelines flawed? It's possible that the evidence they draw on is not generalizable, as it comes from a sicker population of patients than those encountered in many community hospitals. The HCAP guidelines are around 6 years old. An update is due to be published about a year from now. What should clinicians do in the meantime? First I think we have to acknowledge, based on multiple lines of evidence, that the underlying principle behind the guidelines is valid: the initial therapy needs to be sufficiently broad to cover the likely spectrum. In other words get it right, with sufficiently broad spectrum antibiotics, from the get go (ie, in the ER). That said, clinical judgment and knowledge of the local antibiogram may alter the treatment regimen. How so? I wouldn't venture to make a definitive statement but in some cases a regimen of single agent gram-negative coverage alongside single agent MRSA coverage might be considered. At the very least the clinician should ask, given the local resistance pattern, what if anything a quinolone or and aminoglycoside would add to the spectrum already covered by a carbapenem.


Are there lessons here concerning guidelines in general? Yes and no. This study is a reminder that guidelines are not mandates, nor are they a measuring stick for EBM. Moreover, although guidelines aim to adhere to the EBM principle of “best evidence”, that evidence is often of low quality as has recently been demonstrated for the IDSA guidelines. On the other hand this study is an anomaly, going against the overwhelming body of other evidence showing that guideline adherence leads to improved outcomes. Maybe the HCAP guideline is an exception. For example, regarding the guidelines for community acquired pneumonia (CAP) every study I know of links adherence to better outcomes [1] [2] [3] [4] [5] [6] [7].