Reexamining quinolone use in the intensive care unit: use them right or lose the fight against resistant bacteria.

Numerous studies have shown that in the therapy of infections in the critically ill, antibiotic-resistant organisms are becoming increasingly common and threatening the ability to provide accurate empirical therapy (1–3). Many factors have driven this problem, including the indiscriminate use of antibiotics when infections are unlikely and prolonged use of therapy for documented infections, long after the patient has had a good clinical response. In addition, for a variety of pathogens, usage-driven resistance has been documented, but often this information is not considered in the selection of antimicrobial therapy (4, 5). For example, a history of recent therapy with a specific agent might preclude its repeated use for subsequent infections, because this behavior might lead to a loss of efficacy of that agent. In the current issue of Critical Care Medicine, this issue is explored, but with a new twist, namely that the prior usage of quinolones in the intensive care unit (ICU) not only can drive resistance to this class of antibiotics but can also promote the emergence of multidrug-resistant Gram-positive and Gram-negative bacteria, making other classes of antimicrobials also ineffective (6). In a prospective observational study conducted over 15 months, Nseir and colleagues (6) evaluated 239 patients admitted to an ICU with no history of antibiotic therapy before admission, who had routine screening cultures for multidrugresistant bacteria (MRB). These cultures were collected on admission and then weekly and included nasal, anal, and axillary swabs, tracheal aspirates in intubated patients, and clinical cultures as dictated by need. Overall, 56% received fluoroquinolone (FQ) therapy, and a total of 77 patients acquired 108 MRB while in the ICU. The MRB included methicillinresistant Staphylococcus aureus as well as ceftazidimeor imipenem-resistant Pseudomonas aeruginosa, extended spectrum -lactamase producing Gramnegatives, Acinetobacter baumanii, and Stenotrophomonas maltophilia. Among these 77 patients, 62 had received an FQ and these patients had 98% of the isolated Gram-negatives resistant to FQs, compared with 23% FQ resistance in those without such prior therapy. In addition, the FQ-treated patients had a high rate of infection with all of the other MRB that were studied. In a univariate analysis comparing those who acquired MRB with those who did not, risk factors included longer duration of antibiotic therapy, FQ use (80% vs. 45%), and duration of FQ therapy. The mean duration of FQ use before MRB emergence was 7.4 days, with the majority of patients having a 10-day exposure to FQs. Interestingly, there were no differences between the patients who acquired MRB and those who did not with regard to the use of other antibiotics including extended-spectrum penicillins, carbapenems, aminoglycosides, and cephalosporins. The consequences of infection with MRB included acquisition of more ICU infections with these organisms, a longer duration of ventilation, a longer length of ICU stay, and a higher mortality rate. Many of these findings were also corroborated in a case-control analysis matching 72 patients with FQ therapy to 72 patients without this therapy, controlling for other demographic factors. In this analysis, patients with FQ therapy had a longer length of ICU stay, used more antibiotics per patient, but used less aminoglycoside therapy (implying that quinolones were being used in many as an aminoglycoside substitute). Patients with FQ therapy had a significantly greater number of ICU-acquired MRB. The data in this study raise a number of important issues. First, it is clear that FQ use can drive resistance not only to quinolones but also to other classes of antibiotics. Although this study did not examine mechanisms, other data have demonstrated that FQ use can induce bacterial efflux pumps that expel not only quinolones but also a variety of -lactams (including meropenem, but maybe less so imipenem) (7). If indeed quinolone use drives the emergence of MRB in the ICU, then we have to give careful thought to how to use these drugs. Often these agents are used as part of a combination regimen, with a -lactam, and in place of an aminoglycoside. As mentioned, this appeared to be part of the rationale for their use in the study by Dr. Nseir and colleagues. However, such behavior may mean that if the patient develops another infection later in the hospital stay, the therapeutic options may be limited because both FQs and -lactams may be less effective as a consequence of the earlier use of FQs. This realization emphasizes that maybe we do not routinely need prolonged combination therapy, once we have identified the etiological pathogen and can treat it with a single effective agent, based on culture and sensitivity data (8, 9). We also need to better define how long to treat patients, since many critically ill patients with severe infections, including ventilator-associated pneumonia, can have a maximal clinical response and good clinical outcome with as few as 8 days of therapy (10, 11). In addition, the data may imply that we have to be very cautious about viewing quinolones as first-line therapy in the ICU. On the other hand, if we use them for a second episode of infection, they will have preserved activity, whereas if they are used empirically for all initial episodes of ICU infection, the therapy of subsequent infections could be compromised. Another issue raised by this study is whether it matters which quinolone is used. In the study by Dr. Nseir and col*See also p. 283.