{beta}-Lactam and Fluoroquinolone Combination Antibiotic Therapy for Bacteremia Caused by Gram-Negative Bacilli

The role of combination antibiotic therapy with a beta-lactamand a fluoroquinolone for bacteremia caused by gram-negativebacilli, to our knowledge, has not been previously described.Much of the previous study of combination therapy has includedbeta-lactams and aminoglycosides. We conducted a large retrospectivecohort study to evaluate 28-day all-cause mortality in patientswith monomicrobial bacteremia due to aerobic gram-negative bacilliwho received either a combination of beta-lactams and fluoroquinolonesor beta-lactam monotherapy. We enrolled adult patients admittedto Mayo Clinic hospitals from 1 January 2001 to 31 October 2006in the study. After stratification of patients by Pitt bacteremiascores, we used Cox regression models to estimate the hazardratios (HR) for 28-day all-cause mortality after adjusting forthe propensity to receive combination therapy. We identified398 and 304 unique patients with bacteremia caused by gram-negativebacilli who received single and combination antibiotic therapy,respectively. In less severely ill patients with Pitt bacteremiascores of <4, combination therapy was associated with lower28-day mortality than single therapy (4.2% [9 of 214] versus8.8% [28 of 319]; adjusted HR, 0.44; 95% confidence interval[CI], 0.20 to 0.98; P = 0.044). In critically ill patients withPitt bacteremia scores of $≥$ 4, there was no difference in 28-daymortality between combination and single therapy (25.6% [23of 90] versus 27.8% [22 of 79]; adjusted HR, 0.87; 95% CI, 0.47to 1.62; P = 0.660). These findings were consistent for 14-dayall-cause mortality. In this large cohort, we found for thefirst time that combination therapy with beta-lactams and fluoroquinoloneswas associated with a reduction in 28-day all-cause mortalityamong less severely ill patients with bacteremia caused by gram-negativebacilli.

INTRODUCTION

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INTRODUCTION

The efficacy of combination antimicrobial therapy in patientswith bacteremia caused by gram-negative bacilli has been previouslyexamined. The majority of studies have included beta-lactamand aminoglycoside antibiotic combinations. Overall, there wasno significant reduction in mortality with beta-lactam and aminoglycosidecombinations compared to beta-lactam monotherapy in patientswith bacteremia caused by gram-negative bacilli (16, 18, 25).However, decreased mortality was demonstrated in subgroups ofpatients with Pseudomonas aeruginosa bacteremia (4, 14, 25)and critically ill patients with Klebsiella species bacteremia(17). A clinical benefit with combination therapy was also seenin neutropenic patients with bacteremia caused by gram-negativebacilli (10, 18). As a result, beta-lactam and aminoglycosidecombination therapy has been frequently used in patients withP. aeruginosa bacteremia, but not in patients with bacteremiadue to other gram-negative bacilli (6). This approach is particularlyuseful in patients with risk factors for P. aeruginosa bacteremiafor whom combination therapy is started empirically; otherwise,there is little benefit if the decision to start combinationtherapy is delayed until a gram-negative organism in blood culturesis identified (4, 14, 15). In addition, due to the potentialdrug-related adverse events associated with aminoglycosidesin critically ill patients, particularly nephrotoxicity, empiricaluse of these drugs has been limited (21, 26).

With the increase in antibiotic resistance among gram-negativebacilli, use of combination antibiotic therapy for bacteremiacaused by gram-negative bacilli has reemerged. Studies haveshown that inappropriate antimicrobial treatment can be reducedwith empirical administration of combination therapy (19). Despitethe increasing use of fluoroquinolones due to their relativelybroad spectrum of antimicrobial activity and an acceptable safetyprofile, the inclusion of fluoroquinolones in combination antimicrobialregimens for bacteremia caused by gram-negative bacilli, toour knowledge, has not been exclusively studied. A meta-analysisshowed comparable mortality, favorable clinical outcomes, andless nephrotoxicity with ciprofloxacin and beta-lactam combinationsthan with aminoglycoside and beta-lactam combinations in patientswith febrile neutropenia (3). Recent studies also showed thatthe combination of a fluoroquinolone with a beta-lactam hadin vitro and in vivo synergy against extended-spectrum beta-lactamase-producingEscherichia coli and P. aeruginosa isolates, respectively (8,22). This combination contributed less frequently than did monotherapyto in vitro selection for resistance in three different gram-negativebacilli (8, 9).

We hypothesized that the empirical use of fluoroquinolones incombination with beta-lactam antibiotics, prior to identificationof the gram-negative bacilli and availability of susceptibilityresults, decreases mortality in patients with bacteremia causedby gram-negative bacilli compared to single-beta-lactam treatment.The primary aim of this cohort study was to compare the 28-dayall-cause mortality in adult patients with bacteremia causedby gram-negative bacilli who received a combination of beta-lactamand fluoroquinolone antibiotics to that in patients who receivedsingle-beta-lactam treatment after stratification by acute severityof illness.

(A poster of this study was presented at the 108th General Meetingof the American Society for Microbiology, 4 June 2008, Boston,MA.)

MATERIALS AND METHODS

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MATERIALS AND METHODS

Setting. The study was conducted at two Mayo Clinic hospitals: SaintMary's Hospital and Rochester Methodist Hospital, located inRochester, MN. Both are large tertiary-care hospitals that havea combined total of over 1,950 licensed beds and provide carefor local residents, as well as referral patients, in a widevariety of medical and surgical subspecialties. The study wasapproved by the institutional review board at the Mayo Clinic,Rochester, MN.

Case definition. Bacteremia caused by gram-negative bacilli in this study wasdefined as the growth of any aerobic gram-negative bacillusin a blood culture. Monomicrobial bacteremia caused by gram-negativebacilli was defined as the growth of only one gram-negativebacillus in a blood culture, and polymicrobial bacteremia wasdefined as the growth of more than one organism in a blood culture,excluding coagulase-negative staphylococci, Corynebacteriumspp., and Propionibacterium spp. Cases were classified accordingto the site of acquisition into nosocomial, health care associated,and community acquired (11). The primary source of bacteremiawas defined using the Centers for Disease Control and Preventioncriteria (12).

We defined single-antibiotic therapy as the administration ofonly beta-lactam antibiotics with activity against gram-negativebacilli within 24 h of obtaining blood cultures that was continuedfor a minimum duration of 48 h. Combination antibiotic therapywas defined as the use of two antibiotics, with one being abeta-lactam with activity against gram-negative bacilli andthe other a fluoroquinolone, with both started within 24 h ofobtaining blood cultures and given for a minimum duration of48 h. Beta-lactam antibiotics with activity against gram-negativebacilli in this study included piperacillin-tazobactam, ticarcillin-clavulanate,aztreonam, imipenem-cilastin, meropenem, ertapenem, cefepime,ceftazidime, ceftriaxone, cefotaxime, cefixime, and cefoxitin.Fluoroquinolone antibiotics included ciprofloxacin, levofloxacin,gatifloxacin, and moxifloxacin.

Critically ill patients were defined as those who had Pitt bacteremiascores of $≥$ 4, and less severely ill patients were defined asthose with Pitt bacteremia scores of <4 (20).

Case ascertainment. A cohort of 2,362 consecutive episodes of monomicrobial bacteremiacaused by gram-negative bacilli from 1 January 2001 to 31 October2006 was retrospectively identified using the Mayo Clinic microbiologylaboratory database, and all were considered for inclusion inthe study. We excluded patients without valid research authorization(n = 57), patients with recurrent episodes of bacteremia causedby gram-negative bacilli (n = 252), patients with Haemophilussp. bacteremia (n = 34), patients younger than 18 years old(n = 118), and those who were treated in the outpatient setting(n = 44). The computer-based antimicrobial-monitoring (CBAM)program at our institution was used to identify hospitalizedpatients who met our definitions of single- and combinationantibiotic therapy. Patients who did not meet the criteria foreither single or combination therapy, including those for whomeither beta-lactams or fluoroquinolones were started more than24 h after blood cultures were obtained (n = 249) and patientsto whom either class of antibiotics was given for less thana total duration of 48 h (n = 348), were excluded. Patientswho received single-fluoroquinolone treatment (n = 362) andthose who received classes of antibiotics with activity againstgram-negative bacilli other than beta-lactams and fluoroquinolones,excluding trimethoprim-sulfamethoxazole prophylaxis (n = 196),were also excluded. The principal investigator (M.N.A.-H.) reviewedthe antibiotic database generated by the CBAM program duringthe index admission for each patient to confirm that they fulfilledthe criteria for inclusion in the study. The principal investigator(M.N.A.-H.) also reviewed the dosages of antibiotic regimensto ensure that included patients received at least the minimumrecommended dose based on the respective creatinine clearance,if renally cleared, according to the institution's CBAM guidelines.The computer programmer was blinded to the study hypothesis,and both the principal investigator and the computer programmerwere blinded to the primary outcome of patients during the caseascertainment phase of the study. We identified 398 and 304unique patients with first episodes of monomicrobial bacteremiacaused by gram-negative bacilli during the study period whomet our definitions for single and combination therapy, respectively.

Statistical analysis. Descriptive statistics were used to summarize the data: meansand standard deviations for continuous variables and countsand percentages for categorical variables. The chi-square orFisher's exact test was used to assess for associations betweencategorical variables and treatment arm, while the Wilcoxonrank-sum test was used to assess for differences in continuousvariables between the two treatment groups. Because the Pittbacteremia score has been shown to be a reliable predictor ofmortality in patients with bacteremia caused by gram-negativebacilli (1, 17, 20), all analyses were stratified on acute severityof illness as measured by the Pitt bacteremia score.

The primary objective was to compare the 28-day all-cause mortalitybetween patients who received a combination of beta-lactam andfluoroquinolone antibiotics within 48 h of the onset of bacteremiaand those who received single-beta-lactam treatment. Patientswere followed for 28 days from the onset of bacteremia causedby gram-negative bacilli or until the last health care encounter.Death was confirmed by reviewing medical records and the Minnesotadeath registry database. Patients who were lost to follow upwithin 28 days of the onset of bacteremia were censored at thedate of the last health care encounter. To compare 28-day mortalitybetween single and combination therapies for both strata (Pittbacteremia scores of <4 and $≥$ 4) separately, a propensity scoreapproach was used to adjust for differences in baseline clinicalcharacteristics across the two treatment groups. First, foreach stratum, multivariable logistic regression was utilizedto estimate the propensity for being treated with a combinationof beta-lactams and fluoroquinolones. Baseline clinical characteristicswere included in the multivariable logistic model if the P valuefor a univariate association with the treatment arm was lessthan or equal to 0.10. Although the identification of a gram-negativeblood culture isolate, the results of in vitro antimicrobialsusceptibility tests, and the primary source of bacteremia maynot have been available to physicians at the time a treatmentdecision was made for all patients in the cohort, these variableswere included in the propensity score model, as they could beindirectly implied from a patient's past medical history orpast exposures. Subsequently, the logit-transformed predictedprobabilities of receiving combination therapy were used asa covariate in the Cox proportional-hazards regression models.Cox proportional-hazards regression was used to compare 28-dayall-cause mortality rates between the two treatment arms, adjustingfor the propensity for being treated with combination therapy.Equivalently, 14-day all-cause mortality was also assessed.Hazard ratios (HR) and 95% confidence intervals (CI) were reported.SAS software version 8 (SAS Institute Inc., Cary, NC) was usedfor all statistical analyses, and an alpha level was set at0.05 for statistical significance. All aspects of the study'sprimary aim were prespecified prior to data collection.

To determine whether the effect of combination therapy was dueto a greater likelihood of receiving at least one antibioticwith in vitro activity against a gram-negative isolate in ablood culture or to a possible additive or synergistic effectof two active antibiotics, we performed an additional post hocanalysis. We compared the 28-day mortality in patients withbacteremia caused by gram-negative bacilli who received twoantibiotics with in vitro activity against the gram-negativeisolate to that in patients who received only one antibioticwith in vitro activity. We used the same propensity score modeland stratification method discussed above for this analysis.Finally, we compared the incidences of Clostridium difficilecolitis and infections due to resistant gram-positive organisms,including methicillin-resistant Staphylococcus aureus, and multidrug-resistantgram-negative bacilli during the index admission for patientswho received single and combination therapy.

RESULTS

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RESULTS

Tables 1 and 2 show the baseline clinical characteristics ofpatients with bacteremia caused by gram-negative bacilli withPitt bacteremia scores of <4 and $≥$ 4, respectively, by typeof therapy. Patients who received single- and combination antibiotictherapy in both Pitt bacteremia score strata were comparablein age, site of acquisition of bacteremia caused by gram-negativeorganisms, and most chronic underlying medical conditions, includingthe Charlson comorbidity score (5). There was a significantassociation between therapy type and the gram-negative organismisolated in the blood culture in patients with Pitt bacteremiascores of <4, but not in patients with Pitt bacteremia scoresof $≥$ 4. For patients with Pitt bacteremia scores of <4, combinationtherapy patients had a higher percentage of E. coli and Pseudomonasspecies, whereas single-therapy patients had a higher percentageof Klebsiella species. Likewise, there was a significant associationbetween therapy type and the primary source of bacteremia onlyin patients with Pitt bacteremia scores of <4. For patientswith Pitt bacteremia scores of <4, the most common sourceof bacteremia for patients who received combination therapywas urinary, whereas the most common source for patients whoreceived single therapy was gastrointestinal. In addition, patientswith Pitt bacteremia scores of <4 who received combinationtherapy were significantly less likely to have a current diagnosisof cancer and had higher serum creatinine levels at the onsetof bacteremia than those who received single therapy. On theother hand, patients with Pitt bacteremia scores of $≥$ 4 who receivedcombination therapy were more likely to be immunocompromisedthan patients who received single therapy.

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TABLE 1. Baseline clinical characteristics of patients with bacteremia caused by gram-negative bacilli with Pitt bacteremia scores of <4 by therapy type

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TABLE 2. Baseline clinical characteristics of patients with bacteremia caused by gram-negative bacilli with Pitt bacteremia scores of $≥$ 4 by therapy type

The most frequent empirically used beta-lactam antibiotics within48 h from onset of bacteremia in this study were piperacillin-tazobactam(38.8%), cefepime (36.2%), meropenem (9.2%), ceftriaxone (4.4%),imipenem-cilastin (2.1%), ceftazidime (1.8%), and ertapenem(1.0%), while the most frequently used fluoroquinolone antibioticsin combination therapy were levofloxacin (52.5%) and ciprofloxacin(46.2%). Combination antimicrobial therapy with beta-lactamsand fluoroquinolones was used for a median duration of 3 days(range, 2 to 21 days). Only 31 of 304 patients (10.1%) who receivedfluoroquinolone antibiotic combinations in our study had bacteremiadue to fluoroquinolone-resistant gram-negative bacilli.

The unadjusted 28-day all-cause mortalities for patients withbacteremia caused by gram-negative bacilli who received singleand combination therapy were 8.8% (28 of 319) and 4.2% (9 of214), respectively, for patients with Pitt bacteremia scoresof <4 and 27.8% (22 of 79) and 25.6% (23 of 90) for patientswith Pitt bacteremia scores of $≥$ 4 who received single and combinationtherapy, respectively (Fig. 1). In order to adjust for differencesin baseline clinical characteristics between the two treatmentgroups, the baseline variables that showed different distributionsbetween the two treatment groups were included in a propensityscore multivariate logistic regression model (Table 3). Afteradjusting for the propensity to treat with combination therapy,the 28-day all-cause mortality was lower in patients who receivedcombination therapy than in those who received single therapyin less severely ill patients with Pitt bacteremia scores of<4 (HR, 0.44; 95% CI, 0.20 to 0.98; P = 0.044). For criticallyill patients with Pitt bacteremia scores of $≥$ 4, the 28-day mortalitywas not different between patients who received combinationtherapy and those who received single therapy (HR, 0.87; 95%CI, 0.47 to 1.62; P = 0.660). These results were consistentwhen 14-day all-cause mortalities were compared. The 14-dayall-cause mortality was significantly lower in patients whoreceived combination therapy than in those who received singletherapy in less severely ill patients with Pitt bacteremia scoresof <4 (HR, 0.34; 95% CI, 0.12 to 0.92; P = 0.035). For criticallyill patients with Pitt bacteremia scores of $≥$ 4, the risk of 14-daymortality was not different for patients who received combinationtherapy and those who received single therapy (HR, 0.99; 95%CI, 0.50 to 1.96; P = 0.966).

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FIG. 1. Kaplan-Meier survival curves for patients with bacteremia caused by gram-negative bacilli who received single- and combination antibiotic therapy based on Pitt bacteremia scores. Combo, combination therapy with beta-lactams and fluoroquinolones; Single, beta-lactam alone.

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TABLE 3. Multivariable logistic regression modeling the propensity to treat with combination antibiotic therapy

Less severely ill patients with a Pitt bacteremia score of <4who received two antibiotics with in vitro activity againstthe gram-negative isolate also had lower 28-day mortality thanthose who received one antibiotic with in vitro activity (HR,0.32; 95% CI, 0.12 to 0.84; P = 0.021). For critically ill patientswith Pitt bacteremia scores of $≥$ 4, the risk of 28-day mortalitywas not different between patients who received one or two antibioticswith in vitro activity against the respective gram-negativeisolate (HR, 0.89; 95% CI, 0.47 to 1.71; P = 0.728) (Fig. 2).

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FIG. 2. Kaplan-Meier survival curves for patients with bacteremia caused by gram-negative bacilli who received one and two in vitro active antibiotics based on Pitt bacteremia scores. Combo, combination therapy with two in vitro active antibiotics; Single, single therapy with one in vitro active antibiotic.

We did not observe an increased incidence of adverse eventsin patients who received combination therapy compared to thosewho received single therapy. Eleven (3.6%) of 304 patients developedC. difficile colitis with combination therapy during the indexadmission compared to 9 (2.3%) of 398 with single therapy (P= 0.361). There was also no significant difference in the incidenceof infections due to multidrug-resistant gram-negative organismsin patients who received combination and single therapy (10/304[3.3%] and 13/398 [3.3%], respectively; P > 0.999). Similarly,there was no significant increase in the incidence of infectionsdue to resistant gram-positive organisms, such as methicillin-resistantS. aureus, following combination and single therapy (3/304 [1.0%]and 3/398 [0.8%], respectively; P > 0.999).

DISCUSSION

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DISCUSSION

To our knowledge, no previously reported studies have examinedthe utility of combination antibiotic therapy with beta-lactamsand fluoroquinolones in patients with bacteremia caused by gram-negativebacilli. In the current investigation, combination therapy wasassociated with lower 14-day and 28-day all-cause mortalityrates among less severely ill patients with Pitt bacteremiascores of <4, and they represented 75.9% (533 of 702) ofthe entire cohort. There was a suggestion of a synergistic oradditive effect of combination therapy, because less severelyill patients who received two antibiotics with in vitro activityagainst the respective blood isolate had lower mortality thandid those who received one antibiotic with in vitro activityagainst the blood culture isolate.

Despite the substantial decline in mortality from bacteremiacaused by gram-negative bacilli over the past 3 decades, ourresults are consistent with those of an investigation from 30years ago that showed improved clinical response with combinationtherapy compared to single therapy in patients with bacteremiadue to different gram-negative bacilli (2). Other studies thatreported a benefit from combination therapy were, for the mostpart, limited to selected gram-negative organisms (4, 14, 17).Our survey included patients with all types of bacteremia causedby gram-negative bacilli. The findings of our work have greaterclinical application because they are not restricted in microbiologicalscope, and they are useful because treatment is begun in mostpatients before the identification of a blood culture isolateis done.

Unlike studies that showed a survival benefit from combinationtherapy only in critically ill patients with bacteremia causedby gram-negative bacilli who had very high mortality (17), theeffect of combination therapy on mortality in our study wasseen in less severely ill patients with Pitt bacteremia scoresof <4 who had relatively low mortality, but not in criticallyill patients with Pitt bacteremia scores of $≥$ 4. One possibleexplanation is that mortality in critically ill patients mightbe impacted by factors other than bacteremia, such as systemicinflammatory response, multiorgan failure, and other acute comorbidities.On the other hand, mortality in less severely ill patients shouldbe limited to bacteremia caused by gram-negative bacilli andits immediate complications.

Based on the sizable difference in mortality between patientswith Pitt bacteremia scores of <4 and those with scores of $≥$ 4 (6.9% versus 26.6%, respectively, in our study), stratifyingpatients by acute severity of illness is crucial in studiesof bacteremia caused by gram-negative bacilli. Without suchstratification, the overall mortality would be a reflectionof the proportion of critically ill patients included in thestudy. Moreover, if patients in a certain treatment arm weremore likely to be critically ill than those in the other treatmentarm, not stratifying by acute severity of illness would maska clinical benefit for that specific therapy. This lack of assessmentis commonplace, as 6 (35%) of 17 studies included in a recentmeta-analysis did not include an assessment of severity of illnessin patients with bacteremia caused by gram-negative bacilli(25). Finally, it is unlikely that the clinical benefit of addingfluoroquinolones in our investigation was due to overcomingresistance to beta-lactam antibiotics because the overall resistanceof gram-negative bacilli to beta-lactam antibiotics was low.

The strength of our study is mainly its large sample size andthe inclusion of adequate power in the primary overall analysis.Nevertheless, the study was not empowered to detect a differencein mortality in subgroups of patients divided on the basis ofbacteremia due to a particular gram-negative organism, primarysource of infection, or an individual class of beta-lactam antibioticsreceived. Using all-cause mortality as a primary outcome, blindingduring the case ascertainment phase of the study, and definingthe study hypothesis and aims prior to data collection reducedsubjectivity and added strength to the study. Additionally,only 42 of 702 patients (6.0%) were lost to follow-up within28 days of the onset of bacteremia, which is very impressivefor a retrospective cohort study.

A propensity score analysis was utilized in order to adjustfor the bias that can result in a retrospective design in whichthe treatment allocation is not randomized. Selection bias,or confounding due to important prognostic baseline differencesamong patients, often leads to biased estimates in observationalstudies (13). For example, bias can result from unmeasured interactionsin the diagnostic and treatment process, such as patients' orphysicians' preferences. An individual's propensity score isdefined as his/her conditional probability of a particular exposureversus another (i.e., combination versus single therapy), giventhe observed confounders. Therefore, akin to a randomized trial,there is balance of the measured confounders between exposuregroups after adjusting for the propensity score (7, 23, 24).To our knowledge, this is the first study of bacteremia causedby gram-negative organisms to use a propensity score analysisto examine the effect of combination antibiotic therapy on outcome.

The study has some limitations. First, this is a retrospectivecohort study, so treatment allocation was not randomized. Despiteadjusting for a large number of potential known confoundersusing propensity score analysis, it remains possible that thereare unknown confounders that are not accounted for in the study.Other limitations are related to the generalizability of thestudy results. We used strict inclusion and exclusion criteriain the study. This allowed the elimination of considerable backgroundnoise by excluding patients with polymicrobial and recurrentbacteremia caused by gram-negative bacilli. In addition, excludingpatients who received antimicrobial regimens that did not conformto our study's definitions of single- and combination antibiotictherapy limited the number of potential confounders and ultimatelystrengthened the statistical model. On the other hand, usingstrict criteria limited the study to a subset of patients withbacteremia caused by gram-negative bacilli, rather than theentire group. For example, many critically ill patients withP. aeruginosa bacteremia were excluded from the study due tothe administration of aminoglycosides. Furthermore, in vitroresistance rates of gram-negative bacillus blood culture isolatesto fluoroquinolone antibiotics at each institution need to beconsidered when interpreting the study results. There may beless benefit with fluoroquinolone combinations at institutionswhere higher resistance rates exist. Finally, we did not collectdata on all adverse events, including QT interval prolongation.Our analysis of adverse events was limited to those events thatoccurred during the index hospital admission for bacteremiacaused by gram-negative bacilli.

A double-blinded randomized clinical trial is the gold standarddesign to attempt to definitely confirm the notion that combinationtherapy for bacteremia caused by gram-negative bacilli is beneficial.Nonetheless, performing such a study requires a large budgetand a prolonged period to enroll enough patients to secure anadequately powered study. During this time, resistance patternsof gram-negative bacilli could change, and new antimicrobialsthat make the study results clinically less relevant may becomeavailable. In addition, in an intention-to-treat analysis, manypatients can receive alternative regimens to what they wererandomly allocated to receive. For example, attending physiciansmay override the study protocol and administer a preferred antimicrobialregimen, particularly if patients clinically deteriorate.

Historically, studies of bacteremia caused by gram-negativebacilli have included beta-lactams with or without another classof antimicrobials. An examination of fluoroquinolone monotherapyfor treatment of bacteremia caused by gram-negative bacillihas not been generally recommended; therefore, we excluded thisgroup of patients. Based on the popularity of fluoroquinoloneuse in the adult population, however, subsequent investigationsshould include an examination of fluoroquinolone monotherapyin the treatment of this syndrome.

In summary, our results show that the empirical use of combinationbeta-lactam and fluoroquinolone antibiotics for bacteremia causedby gram-negative bacilli in the first 48 to 72 h after obtainingblood cultures, while awaiting identification of a gram-negativeorganism and the results of in vitro antimicrobial susceptibilitytests, is beneficial in areas where gram-negative isolates haverelatively low rates of resistance to fluoroquinolones. Consideringthe nephrotoxicity and minimal overall benefit from aminoglycosideantibiotic combinations in previous studies, combination therapywith fluoroquinolone and beta-lactam antibiotics for bacteremiacaused by gram-negative bacilli appears more promising. Furtherexamination is required before combination therapy can be routinelyrecommended.

ACKNOWLEDGMENTS

We thank Randy Wendt and the CBAM program staff at the MayoClinic, Rochester, MN, for their help in generating the antibioticdatabase for this study.

The study received funding from the Baddour Family funds andthe Small Grants program at the Mayo Clinic, Rochester, MN.

M.N.A.-H., J.W.W., B.D.L., K.M.T., J.E.E., E.A.V., I.M.T., andL.M.B. have no conflict of interest.

M.N.A. and B.D.L. had full access to all of the data in thestudy and take responsibility for the integrity of the dataand the accuracy of the data analysis.

FOOTNOTES

* Corresponding author. Mailing address: University of Kentucky Chandler Medical Center, 800 Rose Street, Room MN 672, Lexington, KY 40536. Phone: (859) 323-8178. Fax: (859) 323-8926. E-mail: majdi.alhasan{at}uky.edu

Published ahead of print on 21 January 2009.

REFERENCES

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