Saturday, September 02, 2006

Double coverage and pseudomonas, part II

Having spent some time looking into this matter and benefited from some ID tutelage, I can affirm that there are two general justifications for double covering pseudomonas and/or other gram negatives. The first is to ensure appropriate coverage; with the high incidence of multi-drug resistance bacteria in our hospitals currently, we want to make sure that our monotherapy doesn’t consist of a drug to which the bacteria is resistant. The second justification, as the pharmacist suggested, is indeed to prevent the emergence of further antibiotic resistance. Let’s evaluate each of these rationales.

But first, let’s familiarize ourselves with the profile of the enemy. Using pseudomonas as our poster child, antibiotic resistance patterns measured in the DC VA in 2004 were as follows:

Anitbiotic Percent susceptible
Piperacillin 78
Ceftazidime 79
Gentamicin 83
Tobramycin 88
Aztreonam 64
Ciprofloxacin 63
Levofloxacin 68
Meropenem 89

Improving outcomes
So, does double covering severe gram negative infections reduce mortality or lead to better patient outcomes? You would think so, considering that for the single antibiotics we would use there’s a 10-20 percent chance that the bug is going to be resistant. The evidence, though, is less than impressive.

The main support for double covering pseudomonas seems to come from a meta-analysis by Safdar et al. published in the Lancet in 2004. Their meta-analysis included 17 studies looking at monotherapy versus combination therapy for patients with gram negative bacteremia. Most of the studies used beta-lactams and aminoglycosides in single and combination therapy. While overall there were no differences in mortality, analysis of the Pseudomonas bacteremias showed a quite substantial mortality benefit (OR 0.50, 95% CI 0.30-0.79) with combination therapy. The authors concluded that combination antimicrobial therapy was indicated when there was a strong suspicion for Pseudomonas, but not otherwise.

Contradicting Safdar’s findings, Paul et al. conducted a large meta-analysis of 64 trials including 7586 patients comparing beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for sepsis. They found that double coverage conferred no advantage over single coverage in sepsis, even when gram negative and Pseudomonas infections were analyzed separately. They did find more nephrotoxicity in the double coverage group, and they concluded that aminoglycosides should not be added to beta-lactam therapy in sepsis.

They also did not find that double coverage affected the development of resistance.

Other studies:
De Pauw et al.: Ceftazidine was safer and as effective as the combination of piperacillin and tobramycin for empirically treating febrile neutropenic patients.

Eggimann and Revelly: ventilator associated pneumonia should not be treated with antibiotic combination therapy, which may promote the emergence of drug resistant bacteria. Cunha and Damas et al. draw similar conclusions.

From this, I would say that double covering for pseudomonas makes sense for patients with unspeciated bacteremia where pseudomonas is thought likely, but not in other circumstances.

Preventing Resistance
As far as preventing antibiotic resistance, there seems to be little evidence. The Infectious Diseases Society of America guidelines lists the following factors that can contribute to antibiotic resistance:

Greater severity of illness of hospitalized patients
More severely immunocompromised patients
Newer devices and procedures in use
Increased introduction of resistant organisms from the community
Ineffective infection control and isolation practices and compliance
Increased use of antimicrobial prophylaxis
Increased empiric polymicrobial antimicrobial therapyHigh antimicrobial usage per geographic area per unit time

They make the following comment:

The last strategy suggested in table 6, use of combination antimicrobial therapy to reduce emergence of resistance, is theoretically attractive and is the basis for current treatment of tuberculosis with multiple antimicrobials. It has not been adequately tested clinically to determine if overall institutional resistance can be reduced by the use of combination therapy for individual patients [47]. In one study of Enterobacter, no benefit in reducing emerging resistance was observed when combined third-generation cephalosporin and aminoglycoside therapy was used [48]. The risks include increased antimicrobial costs and the potential for increasing resistance by raising the number of antimicrobials and antimicrobial courses administered. The use of combination therapy is, however, already widespread for the treatment of seriously ill patients, so controlled trials to determine the effect on resistance prevention are reasonable.

It seems to me that the additional risk of toxicity from these powerful antibiotics probably outweighs the potential benefit of delaying the development of drug resistance, when there’s also a chance that the additional antibiotic exposure could actually speed up the development of drug resistance. I have a hard time justifying this one. Anybody with a different take?