Invited Commentary: Drs. Donald Craven & Michael Niederman

We're discussing Kett et al, "Implementation of guidelines for management of possible multi-drug resistant pneumonia in intensive care: an obervational, multicentre cohort study," published March 2011 in Lancet Infectious Diseases. As part of a performance improvement initiative, the IMPACT-HAP team prospectively observed 303 patients at risk for MDR pneumonia at four academic hospitals. Surprisingly, more of those who got appropriate antibiotics died (34%) than those treated off-ATS/IDSA guidelines (20%), with Kaplan-Meier-modeled 28-day survival of 65% vs. 79%, p=0.0044. The authors conclude by recommending that due to safety concerns, "a randomised trial be done before further implementation of [the ATS/IDSA MDR pneumonia guidelines]."   Read the article / abstract

Pulmonary Central: Dr. Craven and Dr. Niederman, you were the co-chairs of the committee that produced the 2005 ATS/IDSA guidelines on healthcare-associated, hospital-acquired and ventilator-associated pneumonias. What is your reaction to the article by Kett et al?

Drs. Craven and Niederman: After looking closely at the Kett article with the guideline co-authors, we were bothered by the flaws in study design, and we felt that their conclusions that the guidelines were misleading and that adherence to the guidelines increased mortality,  were overstated and misleading.   We have submitted a letter from committee members to the editor of Lancet Infectious Diseases voicing our concerns.

There are several key structural problems with this study that undermine its validity, the main one is that it was observational and non-randomized, and subject to bias. The patients receiving “compliant” therapy were demonstrably sicker than those getting “non-compliant” therapy (more severe sepsis, higher APACHE II scores, and more patients with Pseudomonas aeruginosa pneumonia) all of which could have explained their higher mortality. Secondly, no information on time-to-dosing of antibiotics was provided, nor the specific drug and dosing regimens used and similar numbers of patients in the “compliant” and “non-compliant” groups received appropriate antibiotic therapy.  In severely ill patients with sepsis, time to prescribing antibiotics is known to influence mortality, and antibiotics for all patients must be chosen with knowledge and consideration of local patterns of antibiotic resistance (i.e., hospital-specific data on resistant pathogens and antibiograms).  Thirdly, de-escalation and stopping of antibiotics are a critical part of the guideline recommendations that were not followed in many of the patients in the “compliant group” after culture data were available. It’s not clear if these patients contributed to the excess mortality in the compliant group, or by how much.

 Our formal response in Lancet Infectious Diseases will elaborate on these and other serious concerns about this article. An update of the 2005 guidelines is clearly overdue, which should happen next year. For now, though, we strongly believe the data of Kett et al should not lead physicians to change practice or abandon the 2005 guidelines.

Pulmonary Central: How do you respond to people like Victor Yu, who argues that the guidelines are fueling a vicious cycle of escalating antibiotic resistance -- that we over-diagnose pneumonias and use “excessive force” in MDR coverage in the ICU, ironically creating and perpetuating the problem of MDR infections by trying to control them?

Drs. Craven and Niederman: Victor Yu is correct that the diagnosis of pneumonia is often difficult.  However, there are good data suggesting that in severely ill patients, including those at risk for pneumonia caused by multidrug-resistant pathogens (MDR), or sepsis, that appropriate antibiotics improve reduce mortality and improve outcomes. Therefore, you can’t afford to guess the pathogen and be wrong. The use of inappropriate antibiotics may not be easily fixed 48 hours later, and can increase the risk of mortality or complications. 

Having said that, we do need to practice good antibiotic stewardship and avoid overuse of antibiotics. There are two good ways to do accomplish this, both of which are emphasized in the 2005 guidelines. First, de-escalation is recommended when culture data are available. Physicians are very good at starting antibiotics, but may not be as good at stopping them when culture data become available. This is one of the reasons we were so critical of the Kett study, since de-escalation of antibiotics was generally poor.  We believe this should also have been considered “non-compliant” since de-escalation is a key principle of the guidelines.  Thanks to some excellent data by Jean Chastre, MD, we also emphasized in the 2005 guidelines that the duration of therapy in most patients with uncomplicated pneumonia can be limited to 7-8 days versus 14-15 days which was often the practice before the 2005 guidelines. Finally, the use of local antibiotic susceptibility data in a hospital antibiogram may allow more targeted therapy and thereby alter the initial selection of antibiotics. For example, if you have an outbreak of Stenotrophomonas maltophilia, or a highly resistant strain of P. aeruginosa or Acinetobacter species, you may need to alter the initial, empiric antibiotic choices as suggested in the 2005 guidelines. Also, in hospitals without MDR pathogens or if there are diagnostics clues suggesting the likely pathogen in a stable patient, one or two drugs may be used as empiric therapy, with careful monitoring of the clinical response.   

PC: What would you change about the guidelines? I should say, what will you change, since you’re updating them next year, correct?

Drs. Craven and Niederman:  The guidelines are not the Holy Grail, they’re a rational framework to guide decision-making in each hospital ICU.  The guideline principles and recommendations should be for big and small ICUs in community and academic hospitals. Clearly, practices vary widely, and a lot has changed in six years.

We believe that the revised 2011 guideline needs to incorporate several new areas that have emerged including over the past five years, including:

       Better understanding of the heterogeneity of HCAP;

       Need for proper dosing in an era of increasing antimicrobial resistance

      The importance of pharmacokinetic and pharmacodynamic information

       New Drug development, which unfortunately has been limited (e.g., tigecycline and doripenem);

       New concerns about MDR pathogens

      “KPC/CPE”-producing gram-negatives, and the “ESKAPE “organisms

      Rising minimum inhibitory concentrations (MICs) in MRSA

 This is always going to be a dynamic process. The bugs are smart, resistance is continually emerging, and studies provide a stream of new information. We would like to see the guidelines updated as often as every two years, if possible, taking into consideration all of these factors:

       New studies informing us on principles such as:

      Guideline validation

      De-escalation methods

      Better antibiotic trials

      Use of aerosolized antibiotics

      Prevention: Selective digestive decontaimination  (SDD),  the best prevention strategies for VAP

       New diseases: such as ventilator-associated tracheobronchitis (VAT)

       FDA Guidance for HAP/VAP trials

       Find methods to update the guidelines more frequently when new data are available.

It’s important to remember, guidelines are just that: guidelines. They can’t ever be a rubber stamp or a one-size-fits-all formula. The principles in the guidelines are based on the data available and graded. We feel strongly they still provide the best available framework to treating patients at risk for MDR pneumonia. Applying the guidelines in each individual patient is part of the art of medicine.

Michael S. Niederman, M.D.
Chairman, Department of Medicine
Winthrop-University Hospital
Professor of Medicine

Vice-Chairman, Department of Medicine

SUNY at Stony Brook

Donald E. Craven, M.D. 

Chairman, Center for Infectious Diseases & Prevention

Lahey Clinic Medical Center

Professor of Medicine

Tufts University School of Medicine
Burlington, MA

Michael S Niederman, MD is the American Thoracic Society co-chair of the committee that produced the 2005 HAP/HCAP/VAP guidelines; Donald E. Craven, MD is the Infectious Disease Society of America co-chair of the committee.

(Posted April 1, 2011)