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Use of Combination Therapy in Pneumonia

　　Richard G. Wunderink, MD,[12] of the University of Tennessee, Memphis, Tennessee, addressed the issue of the desirability of combination therapy compared with monotherapy. Combination therapy has several potential advantages. When used empirically in situations when the causative organism is unknown, the combination may expand the spectrum of activity of the regimen compared with a single agent. For treating a specific pathogen, the combination may be more potent than a single agent.
For bacteremic pneumococcal pneumonia, Dr. Wunderink studied the outcome of patients who, in retrospect, receive 1, 2, or 3 drugs that were active against the causative pneumococcus. The patients who received 3 drugs were sicker than the patients who received dual or monotherapy as assessed by acute physiology and chronic health evaluation (APACHE) score or by other scoring systems. In Dr. Wunderink's retrospective analysis, patients who received 2 drugs with activity had a better outcome than those who received 1 drug despite similar severity scores.[13] Specifically, patients who received a cephalosporin alone had a worse outcome than patients who received a cephalosporin plus a macrolide. This has been confirmed in other published and unpublished studies as well.
　　Why is dual therapy more effective than monotherapy for proven pneumococcal pneumonia? It is possible that some of the patients had dual infections with macrolide-sensitive, beta lactam-resistant organisms such as legionella or mycoplasma. There is no good evidence that cephalosporins and macrolides are synergistic for pneumococci, and there are no consistent data that vancomycin and cephalosporins are synergistic.
　　One interesting possible explanation is tolerance. That is, there are organisms that may be tolerant to beta lactams (ie, they appear to be sensitive, but the drug does not kill them). It is not clear what the clinical significance of this in vitro observation is.[14] A striking finding in work that is being confirmed, and is as yet unpublished, is that when polymerase chain reaction technique is used to look for the gene for beta lactam resistance, all pneumococci that test resistant have this gene. However, 20% of organisms that test sensitive also have this gene. Can this gene be derepressed, converting a sensitive pneumococcus to a resistance pneumococcus? This is an interesting hypothesis, although there are very few patients treated with beta lactam drugs for beta lactam susceptible organisms that have subsequently failed therapy with documented beta lactam-resistant pneumococci.
　　What about VAP? Is combination therapy useful for enhancing efficacy as well as expanding the spectrum of activity for the chosen antimicrobial regimen? According to Dr. Wunderink, the outcome of patients with VAP is clearly worse if the initial therapy is not prompt and microbiologically appropriate for the causative organisms. Thus, a clinically and geographically appropriate antibiotic regimen must be administered promptly. If the VAP occurs later (after 5 to 7 days of ventilator support), the Pseudomonas should be covered by combination therapy. Such a regimen would almost always involve combination therapy if it occurs after 5 to 7 days of ventilatory support, and if the patient is colonized with methicillin-resistant Staphylococcus aureus or Pseudomonas, or if these organisms are common in the hospital or community environment.
　　Dr. Wunderink then commented that the tradition of using combination therapy for Pseudomonas pneumonia might not be based on solid data. This tradition is based on a small number of cases in relatively ancient literature. Few of the patients received "modern" monotherapy (ie, ceftazidime or a carbapenem or a quinolone). Thus, we do not really have good evidence that combination therapy is better than monotherapy with a potent single agent.
　　In summary, Dr. Wunderink strongly recommended combination therapy for severe community-acquired pneumonia both in the setting of empiric therapy and in the setting of treating proven pneumococcal pneumonia. This is intriguing; however, this concept has not been embraced by all infectious disease and pulmonary authorities yet. For hospital-acquired pneumonia, Dr. Wunderink also strongly endorsed combination therapy to maximize the likelihood that therapy would be effective promptly. This is more universally endorsed.
Thus, this symposium pointed out the intensivists should consider using endotracheal tubes with suction ports to prevent endotracheal tube-associated pneumonia, and should have protocols assuring that the head of the bed is always elevated, and that the stomach is not overdistended. The symposium stressed the possible benefits of continuous infusions of beta lactam drugs, and the use of combination regimens in most settings, at least for initial therapy. Is your unit current regarding these issues?