Nosocomial Pneumonia Forum: The Second Annual Debate on the Critical Role of Empiric Therapy

At an industry-sponsored symposium held in conjunction with CHEST 2002, the annual meeting of the American College of Chest Physicians, five leaders in critical care medicine addressed controversies in empiric therapy for nosocomial infection. There were two debates centering on the impact of quantitative cultures on outcomes in nosocomial pneumonia and unrestricted access to antibiotics as a means of controlling antibiotic resistance.

This program was supported by an unrestricted educational grant from Elan Pharmaceuticals..

The Importance of Appropriate Antibiotic Therapy for the Treatment of Nosocomial Pneumonia

Antimicrobial resistance is a concern in patients with ventilator-associated pneumonia (VAP) or nosocomial pneumonia (NP).

“Looking at the data you see that regardless of the drug/bug combination, resistance rates have been increasing over the last ten years,” said Marin H. Kollef, MD, FCCP, Washington University School of Medicine in St. Louis. “Resistance is an escalating problem.”

Strategies for combating or avoiding antibiotic resistance may become more important in the near future. The lack of major new drugs in the pipeline means careful stewardship of current medications will be needed for at least ten years.

The risk factors for inadequate antibiotic therapy largely mimic those for resistance: prior antibiotic exposure and the presence of invasive devices. It is clear that the most important factor clinicians have control of is antibiotic agents (Ibrahim EH, et al. Chest 2000;118:146).

Ambrose and colleagues treated patients with either cefepime or ceftazidimine, two different generation cephalosporins with different mechanisms of resistance. When clinically successful eradication or the need for additional drugs were the endpoints, it appeared to be favorable for the more advanced fourth-generation medication (Owens RC Jr, et al. Conn Med 1997; 61:225).

“This is part of the reasoning behind antibiotic cycling or heterogeneity,” said Dr. Kollef. “By removing an antibiotic that is more likely to cause resistance, you see changes in the antibiotic profile over time.”

Shorter durations of therapy are another intervention.

An article by Singh, et al. used the Clinical Pulmonary Infection Score (CPIS) based on fever, white blood cell count, tracheal aspirant quality, chest x-ray and gas exchange. The total score is 12 and a score >6 is associated with pneumonia (Singh N, et al. Am J Respir Crit Care Med. 2000;162: 505).

Patients were randomized to 3 days, versus 10 to 21 days of antibiotic therapy. After 72 hours, if their score was still >6, antibiotic therapy was stopped. Those getting the shorter course had fewer superinfections with resistant organisms.

“They improved the environment of the ICU, inducing less resistance with this truncated course of empiric therapy when objective criteria indicated patients were at lower risk for infection,” said Dr. Kollef.

Ibrahim and colleagues developed an algorithm using a combination of medicines covering 90 % of isolates associated with VAP in their unit. The regimen was modified within 48-hours and the patients could not have more than 7 days of drug therapy unless they met predetermined endpoints for fever and white blood cell count (Ibrahim EH, et al. Crit Care Med 2001;29:1109).

The number of patients getting an adequate initial antibiotic increased from 50 % to nearly 90 %. Roughly 6 days were removed from the average duration of antibiotic treatment. Finally, about 74 % of the patients were on only one antibiotic at 48 hours.

“These findings emphasize that antibiotics alone are not the answer,” stressed Dr. Kollef. “We need to treat with effective regimens, but we also need to think about prevention.”

The CDC suggests the 12 steps to prevent resistance outlined in Table 1.

Debate #1: Quantitative Cultures are Needed to Improve Outcomes in Nosocomial Pneumonia

Despite the fact that research has been going on for years, there is no widely accepted gold standard for comparing diagnostic tests. There is a lack of definition of what is a true negative.

“There are some things constantly seen in the literature,” said Richard Wunderink, MD, FCCP, from the University of Tennessee, Memphis. “Clinical criteria consistently overdiagnose pneumonia, culturing endotracheal aspirates consistently have more microorganisms than invasive cultures and mimics of pneumonia can be found when looked for.”

A group from Canada asked clinicians before diagnosis what they thought the probability was that a person had pneumonia. Most of the time, they found the clinician thought the probability was in a “gray” 50%-60% range.

After bronchoscopy there was a much better discrimination value and a very good ability to exclude pneumonia. There were also changes in antibiotic management with only about one in five seeing no change in therapy (Heyland DK. Chest 1999;115:1076).

Fagon, et al. completed a randomized control trial with clinical suspicion of VAP as entry criteria. The two groups were treated based on tracheal aspirant cultures (TAC) versus bronchoscopic protected specimen brush (PSB) or bronchoalveolar lavage (BAL).

The TACs were positive in almost twice as many cases as the BAL gram stain with a small number in each group having a negative gram stain with subsequent positive culture. This showed, according to Dr. Wunderink, that gram staining is effective in excluding patients having a positive culture (Fagon JY, et al. Ann Intern Med. 2000;132:621).

In the protected specimen or invasive group, 85% of those with negative cultures did not get any antibiotics at that time while 60% of the clinical patients still were medicated. The mortality rates were similar.

“Patients with invasive cultures had a lower percentage of polymicrobials compared to TACs where almost half were polymicrobial,” said Dr. Wunderink. “There may be selection bias against tracheal aspirates because having more microorganisms makes it likely you are going to miss one and have inappropriate therapy.”

There were fewer prescriptions and, in every category except carbapenems, antibiotic use was down. There was a significant difference in the percentage of antibiotic-free days and those never-prescribed antibiotics.

“Quantitative cultures do lead to changes in management,” said Dr. Wunderink. “Inappropriate use of antibiotic choices in VAP is consistently associated with increased mortality. The only way around that is using quantitative cultures, resulting in fewer antibiotics and possibly decreasing inappropriate use.”

“While I agree we have to have adequate therapy for patients with VAP, we also have to avoid the failure to treat,” said Michael S. Niederman, MD, FCCP, from Winthrop-University Hospital in Mineola, NY. “I think it’s a given that if we rely on invasive quantitative cultures to make treatment decisions, this means some patients with pneumonia are untreated.”

He said the debate on the use of bronchoscopy and quantitative cultures is “silly”. Once a clinician gets the data needed, they should narrow therapies as soon as possible and stop medications when no longer indicated. Bronchoscopy is not required to meet those goals.

“I think empiric therapy is an acronym for Excellent Management, Prepared in Rational Thought, Ideal For The Critically Ill,” he said. “On the other hand bronchoscopy is a strategy that is Barely Realistic, and Otherwise Not Clinically Helpful.”

The focus has to be on appropriate antibiotic therapy yielding, as Luna and others pointed out, a lower mortality rate. However, it also matters when you give it. Significant reductions in mortality were found when patients got appropriate therapy immediately. Dr. Niederman suggests that it may be too late if you wait for the bronchoscopy results (Luna CM, et al. Chest. 1997; 111:676). (Figure 1)

Clinical diagnosis in these patients can be accurate. Pugin and colleagues looked at CPIS results in 28 patients who had undergone BAL with bacterial index (BI). If the CPIS was >six, 93% of those had a BI >5. If the CPIS was <6, all BI scores were <5. A CPIS >6 had a sensitivity of 93% and specificity of 100% (Pugin J, et al. ARRD. 1991;143:1121).

“Clinicians work like the CPIS,” said Dr. Niederman. “They use clinical judgment, sum all the data together and arrive at a decision. This study shows when you put all the clinical data together, it is possible to have a very accurate basis for diagnosing VAP.”

Bronchoscopy may not be needed to achieve less antibiotic use. In the study from Singh et al., patients were managed without bronchoscopy using the CPIS. Even without the invasive tests, there was, in Dr. Niederman’s words, a “dramatic” reduction in medication use (Singh N. Am J Resp Crit Care Med. 2000;162:505).

The problem of false negatives is another major concern. Histological studies show different stages of the disease are seen in different parts of the lung. Results become contingent on sampling the area where the pneumonia is located.

“How could you allow your clinical management to be dictated by a technique which is subject to a variety of methodological and reproducibility issues?” asked Dr. Niederman. “A false negative means the patient has pneumonia and you are not going to be using antibiotics, a very bad event.”

Another clear limitation is previous use of antibiotics. Souweine’s study noted that those patients recently started on antibiotics are not likely to get a positive result from bronchoscopy even if they have pneumonia (Souweine B, et al. Crit Care Med. 1998;26:236).

Marquette’s study compared bronchoscopy results with autopsy findings. For protected brush, BAL and quantitative endotracheal aspirates, there was only 60% sensitivity. Again, this shows that many needing antibiotic therapy may be missed if medication decisions are based on quantitative cultures (Marquette C, et al. Am J Respir Crit Care Med.1995;151:1878).

“My summary approach is to define the presence of pneumonia clinically and start therapy immediately with a combination therapy based on local microbiologic data,” said Dr. Niederman. “Modifications can be made based on tracheal aspirate, the clinical response and microbiological data. I think we can achieve these goals without quantitative cultures.”

Debate #2: Unrestricted Access to Antibiotics Will Control Antibiotic Resistance

“It is important to recognize that there are many factors which propagate resistance,” says Joseph P. Lynch, III, MD, FCCP, of the University of Michigan Medical Center in Ann Arbor. “It is also important to know that not all antibiotics are alike in their affinity to be associated with resistance.”

One factor in curtailing resistance is to have heterogeneity of drug use. If done inappropriately, formulary restrictions can lead to homogeneity by overusing a specific class of antibiotics.

There is good information from many sources, according to Dr. Lynch, that clones of antimicrobial resistance genes are amplified in a given area by selection pressure from antibiotic use.

For example in penicillin resistance among pneumococci, three major clones account for over half of all resistance. The question becomes is it possible to get rid of the clones by changing prescribing practices?

A study from Alaska looked at penicillin resistant Strep. pneumoniae following an educational program that dropped antibiotic usage up to 35 %. Despite this, there was no change in resistance. Looking at factors for predicting resistant clones, specific serotypes were most important. Antibiotic use accounted for seven percent of the resistance (Hennessy TW, et al. Clin Infec Dis. 2002;34:1543).

“Once you have resistance clones in place, it is difficult to eradicate them,” said Dr. Lynch. “We have more and more circumstances where once the mutation has occurred, you begin to see it increase over time.”

He sees similar findings with extended spectrum beta lactamases (ESBL), methicillin resistant Staph. aureus (MRSA) and vancomycin resistance. There seems to be multiple genetic mutations driving resistance.

“Numerous studies show that monotherapy with a single class of antibiotic can lead to unacceptably high rates of resistance,” said Dr. Lynch. “Theoretically, using a limited number of antibiotics, leading to relatively homogenous use, may drive resistance.”

He calls for the addition of non-antibiotic-based strategies to help limit resistance. Among these is aggressive decontamination of possible infection sites in every ICU.

“Of all pneumonias in hospitals in the CDC database, 86% were in patients on mechanical ventilation,” he noted. “Using less mechanical ventilation is probably going to have a greater impact on reducing overall infections and resistance than restricting antibiotics.”

The antibiotic history is important. In a study by Kollef, the most common was cephalosporin resistance. Of the 23 patients with gram negative bacteria resistant to cephalosporins, 91% had been exposed to a cephalosporin during the same hospitalization (Kollef MH, et al. Chest 1998;113:412).

Findings from a French series of VAP patients also found that recent history of antibiotic use was an important factor. Of those who had received antibiotics for any reason in the two weeks prior to the pneumonia diagnosis, 65 % were infected by P. aeruginosa or Acinetobacter. By contrast, only 19 % of antibiotic-naïve patients had pneumonias caused by these two organisms (Fagon J-Y, et al. Am Rev Resp Dis. 89;139:877).

Although agreeing with much of what Dr. Lynch said in his presentation, John E. McGowan, Jr., MD, Emory University School of Medicine in Atlanta, did have a fundamental disagreement with the proposed solution.

“The question for tonight is whether unrestricted access to antibiotics control resistance and my answer is ‘no’,” said Dr. McGowan. “Extensive use of single classes of antimicrobials has lead to marked increases in resistance, so efforts to encourage heterogeneity may better stabilize antibiotic resistance.”

He noted that heterogeneity is not the same as unrestricted access. The key is establishing formularies and practice guidelines that give doctors more than a single choice.

White’s group looked at the effects of prior authorization for prescribing certain antimicrobials. Total expenditures for antibiotics decreased by 32% with dramatically increased susceptibilities in the ICU. There was no change in overall survival and median time from positive blood culture to discharge (White AC, et al. Clin Infect Dis. 1997; 25:230).

Clinical data indicate to Dr. McGowan that programs influencing practitioner choice have value. D. Gruson studied a supervised rotation and restricted use of ceftazidimine and ciprofloxacin. Episodes of VAP decreased from 231 to 161, gram-negative pathogens decreased and their susceptibilities “increased significantly” (Gruson D, et al. AJRCCM. 2000;162:837).

“I suggest that unrestricted access is actually the ultimate cop-out,” said Dr. McGowan. “There are other reasons for resistance beside antibiotic selective pressure. We have clinical data showing the value of other ways to influence choice.”