Use of Gentamicin as Empiric Coverage for Ventilator-Associated Pneumonia: The “Con” Perspective

Argument #1: Monotherapy Is a Viable Tactic

Numerous studies have been published that have evaluated empiric monotherapy versus empiric combination therapy for VAP. Every single study that has evaluated gentamicin has done so as part of combination therapy. These studies demonstrate that monotherapy is as effective as combination therapy, which negates the need for empiric gentamicin.

Two meta-analyses have examined the effect of combination therapy versus monotherapy. Aarts et al. [1] identified 41 trials that included more than 7,000 patients. Their analysis included randomized trials evaluating empiric VAP regimens. The primary outcome was all-cause mortality. Overall mortality was 20% and no differences in survival were found between any of the treatment regimens. This meta-analysis included 29 unique treatment regimens. The overall risk of treatment failure was 37% and was similar between the groups, however, a subset analysis demonstrated an increased risk of treatment failure among the patients treated with ceftazidime-aminoglycoside compared with meropenem [2,3]. Paul et al. [4] performed a meta-analysis on trials examining β lactam monotherapy versus β lactam-aminoglycoside combination therapy for severe infections including VAP. This study examined 64 trials with more than 7,000 patients included and found that combination therapy with addition of an aminoglycoside did not affect mortality.

Argument #2: Very Few Patients Would Benefit

Utilizing gentamicin as part of an empiric regimen for VAP would expose a large number of patients to the side effects of gentamicin with little theoretical benefit. Clinical criteria for VAP include fever, purulent sputum, infiltrates on chest radiograph, worsening oxygenation, and leukocytosis [5]. These criteria are quite sensitive, however, the specificity is low. As such, these criteria capture the majority of VAP patients but they also capture many patients without VAP. A conservative estimate of specificity may be as low as 33% [6]. As such, out of a population of 300 patients with suspected VAP, only 100 ultimately will have a confirmed diagnosis by bronchoalveolar lavage (Fig. 1). Among these patients, perhaps only 50%–75% will have a gram-negative infection. Therefore, only 50–75 of these 100 patients even have the potential to benefit from gentamicin. Meropenem has a high coverage rate of gram-negative organisms, often as high as 90%. As a result, only seven of the remaining 75 patients would not have effective coverage with meropenem. Among these patients, it is likely that some would have gentamicin resistance, because gentamicin sensitivity to gram-negative organisms often varies between 70% and 95%. There is has been an increased rate of fluoroquinolone resistance in the past decade, but it is likely that some of the remaining organisms would be sensitive to ciprofloxacin, which could also be used for combination therapy. Even with effective in vitro coverage, there will still be some in vivo failures with gentamicin, and there are likely to be some patients who would recover on their own or who would not be harmed by antibiotic delay until culture results were available. Thus, among the original hypothetical population of 300 patients that had concern for VAP, it is likely that only one or two patients would benefit theoretically from gentamicin. All 300 patients would have to be exposed to gentamicin for little theoretical gain.

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FIG. 1.

Flow chart demonstrating that among an initial population of 300 patients, it is likely that only one or two patients would benefit from gentimicin.

Argument #3: Intellectual Consistency

It has been argued that inappropriate initial antimicrobial coverage leads to increased complications and mortality [7]. This philosophy argues that even a single case of inadequate empiric coverage is too much. However, this is not intellectually consistent with the way that VAP has been approached in the intensive care unit. It becomes a slippery slope when deciding which organisms should be covered. For instance, fungal pneumonia is rare but occurs on occasion. Stenotrophomonas maltophilia is a known, yet uncommon, pathogen in VAP. Attempts at universal appropriate empiric coverage would mandate extending empiric coverage to Stenotrophomonas infections and fungal infections, which is almost never done. This position would also argue for empiric coverage with three or four antibiotics directed at gram-negative infections in order to ensure that all of the empiric coverage is adequate. Intravenous colistin, a member of the polymyxin family, has nearly universal coverage against Pseudomonas aeruginosa and has even been advocated as an empiric agent for VAP [8,9]. This agent, however, is rarely utilized because of the risk profile. Most infectious disease and critical care physicians have felt that the risk profile of colistin does not justify its use as empiric therapy. Similarly, the risk profile of gentamicin should relegate its use to directed patient populations with known resistant organisms. In summary, the argument to add gentamicin to an empiric VAP regimen is intellectually inconsistent with a variety of approaches to infection treatment.

Argument #4: There Are Other Options for Double Coverage

If double coverage of gram-negative organisms is believed to be necessary, there are options available other than gentamicin. The use of fluoroquinolones has received some criticism because of increased resistance, however, ciprofloxacin is a viable alternative to gentamicin as a second gram-negative agent [10]. Ciprofloxacin has a better pharmacokinetic profile, because it has good pulmonary penetration and has far less toxicity. Additionally, in many institutions, there is still a good sensitivity of P. aeruginos to ciprofloxacin (76% at one of our institutions).

Argument #5: Broad Guidelines Do Not Apply at the Local Level and Ignore Risk Stratification

Resistance profiles are quite variable between institutions. In certain transplant and tertiary/quaternary referral centers, resistance patterns would be expected to be much greater than in community hospitals with a less critical patient population. The antibiogram at a major university demonstrated the following sensitivity profile to Pseudomonas species: meropenem, 90%; piperacillin-tazobactam, 90%; and gentamicin, 82%. The antibiogram at St. Catherine's Hospital in Garden City, Kansas, reported a 98% sensitivity of Pseudomonas species to meropenem. Given these sensitivity profiles, there are clearly local differences in intensive care units that argue against broad guidelines that recommend gentamicin as a second agent for empiric VAP coverage. Even multi-drug–resistant pathogens vary between intensive care units within individual hospitals [11]. This argues that antibiotic decisions should be made based upon unit-specific antibiograms rather than national guidelines.

Argument #6: Gentamicin Is a Suboptimal Antibiotic

The final nail in the coffin of double coverage with gentamicin resides within its pharmacokinetics and risk profile. The in vitro coverage of gram-negative organisms may be broad, however, there are substantial drawbacks to its in vivo use. There are a variety of studies that have reported that inadequate empiric antibiotic coverage may increase mortality [7]. However, these studies do not necessarily mean that all antibiotics with in vitro sensitivity will reduce that increased risk of mortality. It is possible that gentamicin will not reduce that risk of mortality even if it provides in vitro coverage of the offending organism. The pharmacokinetic profile of gentamicin is suboptimal, in that it penetrates pulmonary tissue poorly [12]. Panidis et al. [12] evaluated the distribution of gentamicin in critically ill patients with VAP and found that there was only a 32% penetration into the alveolar fluid. Such poor tissue penetration cannot be overcome by increased dosing because of toxicity concerns. It is very likely that this level of tissue penetration is not adequate to treat many cases of VAP and may explain treatment failures. Not only may the in vitro sensitivity reflect inaccurately in vivo efficacy, but the cytotoxicity of the drug is substantial. Significant nephrotoxicity can occur in up to 20% of those treated with gentamicin [13]. A meta-analysis of β-lactam monotherapy versus β-lactam/aminoglycoside combination therapy demonstrated a threefold risk of nephrotoxicity in the combination arm [4]. Long-term hemodialysis treatment would be a detrimental complication in the setting of little added benefit of double empiric coverage with gentamicin. Ototoxicity is also a well-known complication of gentamicin that can affect one's quality of life.

Summary

No advantage has been demonstrated for combination therapy in empiric treatment of VAP. The addition of gentamicin would likely only benefit less than 1% of all patients initially suspected of having VAP. Because of the problematic nature of the pharmacokinetic profile of gentamicin, the benefit of this agent may be even smaller than 0.3%. This miniscule benefit comes at the cost of significant complications such as severe nephrotoxicity and ototoxicity. Recommending gentamicin as empiric therapy across all patient populations is not appropriate based on variations in local resistance patterns. In summary, there is no definitive evidence to suggest that the benefits of gentamicin outweigh the costs of its utilization in the empiric treatment of VAP.