Double-coverage of gram negatives with a fluoroquinolone?

Introduction

The benefit of empirically using two antibiotics to cover gram negative bacilli is a perpetual controversy. For patients in septic shock, failure to provide effective initial antimicrobial therapy correlates with increased mortality. Using two drugs may increase the likelihood of an including at least one antibiotic which covers the pathogen. This is a rapidly moving target due to ongoing increases in drug resistance.

Most research regarding double-coverage investigates combining a beta-lactam with an aminoglycoside. Aminoglycosides have a broad spectrum of efficacy against gram-negative organisms, but carry a risk of nephrotoxicity. Therefore, a common compromise to the question of double-coverage is to combine a beta-lactam with a fluoroquinolone instead. This gives us the reassurance of “double-coverage,” without concerns about nephrotoxicity. But what is the evidence behind this? This post will focus a bit on ventilator-associated pneumonia, as this is a common situation where this issue arises.

Resistance to fluoroquinolones is rapidly increasing

Fluoroquinolones have many excellent qualities including high oral bioavailability, broad spectrum coverage, and low toxicity. Unfortunately, these properties have caused them to be overutilized in the community. As the consumption of fluoroquinolones has increased, drug resistance has increased in parallel. Resistance is rising rapidly, and in some parts of the world >50% of enterobacteriaceae are resistant (Dalhoff 2012). This is important to bear in mind when interpreting studies, because the efficacy of ciprofloxacin 10 years ago is entirely different from the same drug today.

Rising rates of fluoroquinolone resistance (source: Asensio 2011)

Traditional antibiograms are misleading when designing combination therapy

Suppose in your hospital, gram-negative bacilli are on average 88% sensitive to piperacillin-tazobactam and 80% sensitive to ciprofloxacin. How much efficacy does ciprofloxacin add when combined to piperacillin-tazobactam? A common assumption is that the resistance to these two antibiotics is statistically independent. In that case, the likelihood of a pathogen resisting both antibiotics would be 2.4% (p=0.12 for resistance to piperacillin-tazobactam multiplied by p=0.20 for resistance to ciprofloxacin). This would suggest that by adding ciprofloxacin to piperacillin-tazobactam, the likelihood of covering a gram-negative rod increases from 88% to 98%. Unfortunately this is incorrect.

Combination antibiograms reveal that fluoroquinolones add little to beta-lactams

To actually determine how much fluoroquinolones add to a beta-lactam, a combination antibiogram is required. This is an antibiogram which lists the sensitivity of bacteria to single antibiotics as well as selected combinations of antibiotics (i.e., piperacillin-tazobactam plus ciprofloxacin). Although combination antibiograms remain under-utilized, some studies have used them to evaluate this question (table below). Based on these studies, if a gram-negative rod is resistant to a broad-spectrum beta-lactam, the likelihood of the bacteria being sensitive to ciprofloxacin is roughly 30% currently.

Data extracted from combination antibiograms reveal the incremental benefit of adding a second antibiotic. Dates refer to when data was collected, not when it was published.

* Indicates data extrapolated from combination antibiograms in which the sensitivity rates were rounded to the closest whole number. This may introduce some random error.

Lets return to our hypothetical scenario of combining piperacillin-tazobactam with ciprofloxacin. Ciprofloxacin will cover about 30% of the bacteria which are resistant to piperacillin-tazobactam, thus increasing the coverage from 88% to about 92% (rather than increasing coverage from 88% to 98%).

Potential harm of double coverage

In addition to inducing antibiotic resistance on a population level, this has also been observed at a patient level. Receiving a fluoroquinolone increases the risk of subsequently developing drug-resistant infections with organisms including clostridium difficile, MRSA, piperacillin-resistant Pseudomonas, and extended-spectrum beta-lactamase producing gram-negative bacilli (Charbonneau 2006, Niederman 2006). The ability of fluoroquinolones to select for multi-drug resistant organisms is notable. Years ago at Genius General Hospital, the first case of carbapenem-resistant enterobacteriaceae ever seen at our facility occurred in a previously healthy patient admitted from the community who received several antibiotics including levofloxacin, meropenem, and cefepime. This case was notable because it suggested that broad-spectrum antibiotics have the potential to generate novel multi-drug resistant organisms before our eyes in the ICU (1). Falagas 2007 found fluoroquinolone exposure to be the strongest independent risk factor for acquisition of carbapenem-resistant enterobacteriaceae.

Clinical evidence for double-coverage in ventilator-associated pneumonia?

There are few prospective randomized controlled trials evaluating double-coverage with a fluoroquinolone. In 2008, Heyland published a randomized controlled trial of meropenem with or without ciprofloxacin for the treatment of 739 patients with ventilator-associated pneumonia. Combination therapy did not have any effect on mortality or duration of mechanical ventilation. The generalizability of this study may be limited because the sensitivity of gram-negative organisms to meropenem was unusually high by current standards. However, this study certainly argues against any potential synergistic benefit of a beta-lactam combined with a fluoroquinolone.

What do the guidelines say?

The Infectious Disease Society of America (IDSA) guidelinesfor ventilator-associated pneumonia recommend using the combination of a beta-lactam plus either a fluoroquinolone or aminoglycoside for patients with risk factors for drug-resistant organisms. However, the guidelines also emphasize the use of current, local antibiograms to guide therapy. These guidelines were published in 2005, and the recommendation to consider combination therapy with ciprofloxacin is based on Ibrahim 2001, which in turn was based on data collected from 1999-2000. The relevance of 15-year-old antibiotic sensitivity data is unclear today. Canadian and British guidelines published in 2008 were less enthusiastic about combination therapy. The IDSA guidelines are currently under revision, with a new version planned for next summer.

Conclusions

With resistance to fluoroquinolones increasing before our eyes, the benefit of double-coverage is rapidly decreasing. Combination antibiograms show that pathogens resistant to beta-lactams are unlikely to be sensitive to fluoroquinolones, and thus the benefit of adding a fluoroquinolone is marginal. Unless the local combination antibiogram suggests otherwise, fluoroquinolone double-coverage should probably be abandoned (Zadikian 2012, Johnson 2011). Adding a fluoroquinolone makes us feel better, but this is a false sense of security.

If we are concerned about the efficacy of the beta-lactam, one approach is to use a more effective beta-lactam. For example, consider treating a ventilator-associated pneumonia where the sensitivity of gram negative bacilli to piperacillin-tazobactam is 88% and the sensitivity to cefepime is 92%. Combining piperacillin-tazobactam and ciprofloxacin may seem more powerful than cefepime monotherapy. However, as discussed above, adding ciprofloxacin to piperacillin-tazobactam probably only increases its coverage from 88% to 92%. Therefore, cefepime alone is probably as effective as the combination of piperacillin-tazobactam plus ciprofloxacin, while avoiding the additive toxicities of two different drugs. Other investigators have similarly noted at their institution that imipenem was superior to the popular combination of piperacillin-tazobactam and ciprofloxacin (95% vs. 91%; Fox 2008). A local combination antibiogram will facilitate informed decisions.

Ultimately the only way to substantially improve coverage over a beta-lactam may be to add an aminoglycoside (preferably tobramycin or amikacin). The fluoroquinolone compromise fails, and we are led back to the age-old question of beta-lactam monotherapy versus double-coverage with an aminoglycoside. And that’s a question for another day.

Notes:

(1) The patient was isolated with Ebola-like intensity and ultimately made a complete recovery. Carbapenem-resistant enterobacteriaceae were not seen in the ICU for some years after the patient's departure.

Image credits: http://www.freeimages.com/photo/synergy-1564658

Source data for table:

Ann Arbor 2007-2008: Pogue 2011
MD Anderson 2012: Smith et al.
Texas 2008-2012: Thurman 2014
U. Chicago 1999-2005: Christoff 2010
U. Nebraska 2008-2011
U. Penn 1999: Mizuta 2006
U. Wisconsin 2004-2006: Fox 2008
Wake Forest 2004: Beardsley 2006
Wash U. St Louis 2002-2006: Micek 2010