Bille, J.

Calandra, T.

Cometta, A.

Kern, W.

Marchetti, O.

Zinner, S.

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BRIEF REPORTIn vitro antimicrobial activity of moxifloxacin againstbacterial strains isolated from blood of neutropenic cancerpatientsA. Cometta & O. Marchetti & T. Calandra & J. Bille &W. V. Kern & S. Zinner IInfectious Diseases Group of the EuropeanOrganization for Research and Treatment of Cancer(EORTC-IDG)Published online: 1 August 2006# Springer-Verlag 2006The use of fluoroquinolones has increased in neutropeniccancer patients over the past two decades. With respect toempiric treatment of fever in neutropenic patients, the pooractivity of older quinolones against gram-positive cocciprompted physicians to add specific anti-gram-positiveagents to provide better activity against streptococci, whichare frequently isolated from these patients. The efficacy andsafety of oral antibiotic regimens that include fluoroquino-lones for the treatment of low-risk febrile neutropenicpatients have been documented in two large studies [1, 2].The widespread use of fluoroquinolones as prophylacticagents in cancer patients has been associated with theoccurrence of resistance in E. coli and coagulase-negativestaphylococci, organisms which are most often responsiblefor bacteremia in these patients [3].Moxifloxacin is an 8-methoxyquinolone that has en-hanced activity against gram-positive bacteria relative tociprofloxacin and other older fluoroquinolones. Oral moxi-floxacin is 90% bioavailable, and its mean half-life of 12 hallows once-a-day dosing. Peak serum concentrations of3.2–4.5 μg/ml have been achieved following oral doses of400 mg of moxifloxacin, and the agent is widely distributedthroughout the body [4]. The aim of the present study wasto assess the in vitro activity of moxifloxacin against gram-positive and gram-negative bacteria isolated from the bloodof neutropenic cancer patients and to compare it with otherfluoroquinolones and reference antibiotics.The collection of bacterial strains isolated from the bloodof febrile neutropenic cancer patients randomized in two trialsconducted by the Infectious Diseases Group of the EuropeanOrganization for Research and Treatment of Cancer(EORTC-IDG) between 1993 and 2000 [5, 6] yielded 152gram-positive isolates, including 71 coagulase-negativestaphylococci, 29 S. aureus, 19 S. mitis, 19 S. oralis, and14 E. faecalis, and 85 gram-negative strains, including 44 E.coli, 30 K. pneumoniae and 11 P. aeruginosa. These strainswere used in the present study. Bacterial identification wasconfirmed at the Microbiological Reference Center (CHUV,Lausanne) using standardized methods [7].Minimal inhibitory concentrations (MICs) of four fluo-roquinolones (moxifloxacin, levofloxacin, gatifloxacin,ciprofloxacin), as well as cefepime, meropenem, amikacin,vancomycin, penicillin for streptococci and oxacillin forstaphylococci were determined using a microbroth dilutionEur J Clin Microbiol Infect Dis (2006) 25:537–540DOI 10.1007/s10096-006-0175-2A. Cometta (*) :O. Marchetti : T. CalandraInfectious Diseases Service, Department of Internal Medicine,Centre Hospitalier Universitaire Vaudois,1011 Lausanne, Switzerlande-mail: Alain.cometta@ehnv.chJ. BilleInstitute of Clinical Microbiology,Centre Hospitalier Universitaire Vaudois,1011 Lausanne, SwitzerlandW. V. KernCenter for Infectious Diseases and Travel Medicine,Department of Medicine, University Hospital,79106 Freiburg, GermanyS. ZinnerDepartment of Medicine, Mount Auburn Hospital,Harvard Medical School,Cambridge and Boston,MA, USAInfectious Diseases Group of the European Organizationfor Research and Treatment of Cancer, (EORTC-IDG),Avenue E. Mounier 83, P.O. Box 11, 1200 Brussels, BelgiumTable 1 In vitro activity of moxifloxacin and comparative agents against gram-positive and gram-negative bacteriaOrganism Antibiotic MIC50 (μg/ml) MIC90 (μg/ml) Range (μg/ml) Susceptible (%)CNS (n=71) Moxifloxacin 1 2 0.016–16 45Levofloxacin 2 8 0.016–>64 42Gatifloxacin 2 4 0.032–16 45Ciprofloxacin 8 64 0.016–>64 42Oxacillin 4 >64 0.016–>64 49Cefepime 8 64 0.016–>64 54Meropenem 4 32 0.016–>64 51Vancomycin 2 2 0.125–>64 96S. aureus (n=29) Moxifloxacin 0.064 0.125 0.016–64 90Levofloxacin 0.125 0.25 0.064–32 90Gatifloxacin 0.032 0.125 0.032–32 90Ciprofloxacin 0.25 1 0.125–16 90Oxacillin 0.5 1 0.125–>64 90Cefepime 4 4 2–>64 90Meropenem 0.125 0.5 0.016–32 90Vancomycin 1 1 0.125–1 100S. oralis (n=20) Moxifloxacin 0.25 0.5 0.125–16 90Levofloxacin 1 2 0.125–64 90Gatifloxacin 0.5 2 0.25–32 79Ciprofloxacin 2 8 0.016–32 75Penicillin G 0.016 0.064 0.016–0.25 95Cefepime 0.25 0.5 0.016–2 95Meropenem 0.016 0.016 0.016–0.5 100Vancomycin 0.25 0.5 0.016–0.5 100S. mitis (n=19) Moxifloxacin 0.25 0.5 0.064–8 95Levofloxacin 1 2 0.125–32 95Gatifloxacin 0.5 2 0.125–16 90Ciprofloxacin 1 16 0.016–16 63Penicillin G 0.016 0.5 0.016–64 84Cefepime 0.064 1 0.016–2 78Meropenem 0.016 0.25 0.016–1 95Vancomycin 0.25 0.25 0.016–0.5 100E. faecalis (n=14) Moxifloxacin 0.5 8 0.125–32 71Levofloxacin 2 64 0.25–>64 79Gatifloxacin 1 16 0.125–32 64Ciprofloxacin 2 32 0.25–>64 33Penicillin G 2 4 0.25–8 100Meropenem 4 8 1–16 87Vancomycin 1 2 0.5–2 100Amikacin 1 2 0.5–2 –E. coli (n=44) Moxifloxacin 0.016 16 0.016–32 80Levofloxacin 0.016 8 0.016–64 80Gatifloxacin 0.032 8 0.032–32 80Ciprofloxacin 0.016 16 0.016–>64 80Ceftazidime 0.25 0.5 0.064–32 98Cefepime 0.25 2 0.064–8 100Meropenem 0.064 0.25 0.016–0.5 100Amikacin 4 8 1–8 100K. pneumoniae (n=30) Moxifloxacin 0.064 0.125 0.064–0.25 100Levofloxacin 0.064 0.064 0.016–0.125 100Gatifloxacin 0.032 0.032 0.032–0.125 100Ciprofloxacin 0.016 0.016 0.016–0.064 100Ceftazidime 0.25 8 0.125–64 96Cefepime 0.125 4 0.016–8 100Meropenem 0.25 0.5 0.016–0.5 100Amikacin 2 4 1–16 100538 Eur J Clin Microbiol Infect Dis (2006) 25:537–540technique according to methods recommended by theClinical and Laboratory Standards Institute (CLSI) [8].For all antibiotics tested, the MIC breakpoints recommen-ded by the CLSI were used. Since CLSI did not provideMIC breakpoints for moxifloxacin against any organismsother than staphylococci (<0.5 μg/ml for susceptibility), theMIC breakpoints used for moxifloxacin against all otherorganisms were <1 μg/ml for susceptibility, >2 μg/ml forresistance [9]. Quality control was performed by testingAmerican Type Culture Collection (ATCC) strains E. coli25922 and 35218, S. aureus 29213, E. faecalis 29212 andP. aeruginosa 27853.Moxifloxacin displayed excellent in vitro activity againststaphylococci and viridans streptococci, and compared withall other quinolones, it had the lowest MIC90 againstcoagulase-negative staphylococci, S. aureus, S. oralis andS. mitis (Table 1). The better activity against viridansstreptococci is particularly interesting, and might reduce theneed to add a beta-lactam for the oral treatment of fever inlow-risk neutropenic patients. Compared with ciprofloxa-cin, moxifloxacin exhibits increased, but still only relativelymodest activity against enterococci.Against E. coli, the MIC90 of all fluoroquinolones testedwas between 8 and 16 μg/ml: 9 of 44 isolates were highlyresistant. These highly resistant organisms were isolatedfrom nine patients hospitalized in six different centers. Sixof the nine patients with fluoroquinolone-resistant E. colihad received quinolone prophylaxis before the occurrenceof the bacteremic episode. In contrast, none of 35 patientsinfected with fluoroquinolone-susceptible E. coli strainshad received fluoroquinolone prophylaxis (Fisher’s testp<0.001). Thus, as previously described in EORTC-IDGtrials, infections due to fluoroquinolone-resistant E. colistill occur in high-risk patients who receive fluoroquinoloneprophylaxis, even though its use decreased from 52% in thetrial performed over 1993–1994 [5] to 33% in the trialperformed over 1997–2000 [6]. Regarding other gram-negative isolates, moxifloxacin is highly active againstKlebsiella spp and was less active than ciprofloxacinagainst P. aeruginosa.Rolston et al. [10] tested the in vitro activity ofmoxifloxacin against 900 strains isolated from cancerpatients: two thirds of these strains were bloodstreamisolates. As in the present study, moxifloxacin was the mostactive fluoroquinolone against coagulase-negative staphylo-cocci, S. aureus and viridans streptococci. These researchersalso reported fluoroquinolone-resistant E. coli related toprevious prophylaxis and lower in vitro activity of moxi-floxacin against P. aeruginosa compared with ciprofloxacin.The susceptibility of the EORTC-IDG strains to variousantibiotics commonly used in neutropenic patients has beentested. As shown for bacteria isolated from neutropenicpatients in US cancer centers [11], the highest rates ofsusceptibility were observed with cefepime and merope-nem, which are active against 100% of viridans streptococ-ci, E. coli and Klebsiella spp. Amikacin is active against allgram-negative bacteria including P. aeruginosa, and cefta-zidime is active against the vast majority of E. coli,Klebsiella spp and P. aeruginosa.In conclusion, this study confirms that moxifloxacinexhibits increased in vitro activity relative to olderfluoroquinolones against gram-positive bacteria isolatedfrom the blood of neutropenic patients. In areas with lowfluoroquinolone resistance among Enterobacteriaceae, thesefindings could support the use of single-drug oral regimensin low-risk febrile neutropenic patients. This in turn mightprovide a potential benefit in terms of compliance,especially for outpatients. Although the moderate in vitroactivity of moxifloxacin against P. aeruginosa might be apotential problem, this non-fermentative bacteria is current-ly isolated only infrequently from the blood of low-riskneutropenic cancer patients. Since the emergence ofresistant E. coli was observed in patients receivingfluoroquinolone prophylaxis, this practice should beavoided in low-risk neutropenic patients as it might limitthe use of fluoroquinolones as oral therapeutic agents.Acknowledgements This work has been supported by a researchgrant from Bayer Vital GmBH, Leverkusen, Germany. We thank Mrs.M. Giddey and Dr. J.D. Baumgartner for their technical assistance.Table 1 (continued)Organism Antibiotic MIC50 (μg/ml) MIC90 (μg/ml) Range (μg/ml) Susceptible (%)P. aeruginosa (n=11) Moxifloxacin 1 64 0.25–64 64Levofloxacin 0.25 16 0.25–64 82Gatifloxacin 0.5 32 0.25–32 82Ciprofloxacin 0.125 8 0.016–32 82Ceftazidime 2 128 2–128 82Cefepime 4 128 2–128 73Meropenem 2 8 1–64 64Amikacin 1 8 0.5–16 100CNS coagulase-negative staphylococciEur J Clin Microbiol Infect Dis (2006) 25:537–540 539References1. Kern WV, Cometta A, de Bock R, Langenaeken J, Paesmans M,Gaya H, for the International Antimicrobial Therapy Coopera-tive Group of the European Organization for Research andTreatment of Cancer (1999) Oral versus intravenous empiricalantimicrobial therapy for fever in patients with granulocytopeniawho are receiving cancer chemotherapy. N Engl J Med341:312–3182. Freifeld A, Marchigiani D, Walsh T, Chanock S, Lewis L, HiemenzJ, Hiemenz S, Hicks JE, Gill V, Steinberg SM, Pizzo PA (1999) Adouble-blind comparison of empirical oral and intravenous antibi-otic therapy for low-risk febrile patients with neutropenia duringcancer chemotherapy. N Engl J Med 341:305–3113. Cometta A, Calandra T, Bille J, Glauser MP (1994) Escherichiacoli resistant to fluoroquinolones in patients with cancer andneutropenia. N Engl J Med 330:1240–12414. Keating GM, Scott LJ (2004) Moxifloxacin: a review of its use inthe management of bacterial infections. Drugs 64:2347–23775. Cometta A, Calandra T, Gaya H, Zinner SH, de Bock R, DelFavero A, Bucaneve G, Crokaert F, Kern WV, Klastersky J,Langenaeken J, Micozzi A, Padmos A, Paesmans M, Viscoli C,Glauser MP, for The EORTC International Antimicrobial TherapyCooperative Group (1996) Monotherapy with meropenem versuscombination therapy with ceftazidime plus amikacin as empirictherapy for fever in granulocytopenic patients with cancer.Antimicrob Agents Chemother 40:1108–11156. Cometta A, Kern WV, de Bock R, Paesmans M, Vandenbergh M,Crokaert F, Engelhard D,Marchetti O, Akan H, Skoutelis A, KortenV, Vandercam B, Gaya H, Padmos A, Klastersky J, Zinner SH,Glauser M, Calandra T, Viscoli C, for the International Antimicro-bial Therapy Group of the European Organization for Research andTreatment of Cancer (2003) Vancomycin versus placebo forpersistent fever in neutropenic cancer patients given piperacillin/tazobactam monotherapy: an EORTC-IATG multicenter, double-blind, placebo-controlled trial. Clin Infect Dis 37:382–3897. Murray PQ (2003) Manual of clinical microbiology. 8th edition.ASM, Washington DC. pp 185–2078. Clinical and Laboratory Standards Institute (CLSI) (2005)Performance standards for antimicrobial susceptibility testing.Fifteenth informational supplement. CLSI document, vol 25(1):M100–S159. Soussy CJ, Nguyen J, Goldstein F, Dabernat H, Andremont A,Leclercq R, Drugeon H, Cavallo P, Chardon H, Etienne J, Rio Y,Courvalin P (2003) In vitro antibacterial activity of moxifloxacinagainst hospital isolates: a multicentre study. Clin Microbiol Infect9:997–100510. Rolston KV, Frisbee-Hume S, LeBlanc B, Streeter H, Ho DH(2003) In vitro antimicrobial activity of moxifloxacin compared toother quinolones against recent clinical bacterial isolates fromhospitalized and community-based cancer patients. Diagn Micro-biol Infect Dis 47:441–44911. Ramphal R (2004) Changes in the etiology of bacteremia infebrile neutropenic patients and the susceptibilities of the currentlyisolated pathogens. Clin Infect Dis 39 (Suppl 1):25–31540 Eur J Clin Microbiol Infect Dis (2006) 25:537–540

In vitro antimicrobial activity of moxifloxacin against bacterial strains isolated from blood of neutropenic cancer patients

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In vitro antimicrobial activity of moxifloxacin against bacterial strains isolated from blood of neutropenic cancer patients

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