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JAC Advance Access originally published online on June 6, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):370-376; doi:10.1093/jac/dkm130
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Published by Oxford University Press 2007

Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin–tazobactam/amoxicillin–clavulanate

Benjamin A. Lipsky1,*, Philip Giordano2, Shurjeel Choudhri3 and James Song4

1 VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA 2 Orlando Regional Medical Center, Orlando, FL, USA 3 Bayer Healthcare, West Haven, CT, USA 4 Replidyne, Milford, CT, USA

* Corresponding author. Tel: +1-206-277-1640; E-mail: benjamin.lipsky{at}med.va.gov

Received 23 February 2007; returned 21 March 2007; revised 28 March 2007; accepted 5 April 2007


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Objectives: Complicated skin and skin structure infections (cSSSIs), including diabetic foot infections (DFIs), are often polymicrobial, requiring combination or broad-spectrum therapy. Moxifloxacin, a broad-spectrum fluoroquinolone, is approved for cSSSI and can be administered by either intravenous (iv) or oral routes. To assess the efficacy of moxifloxacin for treating DFIs, we analysed a subset of patients with these infections who were enrolled in a prospective, double-blind study that compared the efficacy of moxifloxacin with piperacillin–tazobactam and amoxicillin–clavulanate.

Methods: Patients ≥ 18 years of age with a DFI requiring initial iv therapy were randomized to either moxifloxacin (400 mg/day) or piperacillin–tazobactam (3.0/0.375 g every 6 h) for at least 3 days followed by moxifloxacin (400 mg/day orally) or amoxicillin–clavulanate (800 mg every 12 h orally), if appropriate, for 7–14 days. DFI was usually defined as any foot infection plus a history of diabetes. Our primary efficacy outcome was the clinical response of the infection at test-of-cure (TOC), 10–42 days post-therapy.

Results: Among 617 patients enrolled in the original study, 78 with DFIs were evaluable for treatment efficacy. Clinical cure rates at TOC were similar for moxifloxacin and piperacillin–tazobactam/amoxicillin–clavulanate (68% versus 61%) for patients with investigator-defined infection (P = 0.54). Overall pathogen eradication rates in the microbiologically-valid population were 69% versus 66% for moxifloxacin and comparator, respectively (P = 1.00).

Conclusions: Intravenous ± oral moxifloxacin was as effective as iv piperacillin–tazobactam ± amoxicillin–clavulanate in treating moderate-to-severe DFIs. Moxifloxacin may have potential as a monotherapy regimen for DFIs.

Keywords: complicated skin and skin structure infections , fluoroquinolones , penicillins , ß-lactam inhibitors


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Foot infections are frequent causes of morbidity in patients with diabetes.1 About 15% to 20% of patients with diabetes will develop a foot ulcer and ~60% of these will be clinically infected.2 Diabetic foot infections (DFIs) cause morbidity, limit mobility, predispose to depression and worsen patients' quality of life.3 Furthermore, they often necessitate hospitalization, and about half of the patients who develop a DFI have a recurrence within 3 years.3 Most importantly, DFIs are responsible for ~85% of diabetes-related lower-extremity amputations, making them the most frequent cause of non-traumatic amputation.3

Successfully treating a DFI requires proper wound care and often includes pressure off-loading and surgical interventions, but appropriate antibiotic treatment plays a key role.1 The specific antibiotic regimen selected should be based on the severity of the infection and the known or likely causative organisms.4 Classifying the severity of a DFI requires assessing for the extent and depth of the wound and the tissues involved, the presence of systemic toxicity or metabolic aberrations, and the adequacy of limb arterial circulation.5 Acute infections in antibiotic-naive patients tend to be monomicrobial and are usually caused by aerobic Gram-positive cocci. Chronic infections, especially in patients previously treated with antibiotics, are often polymicrobial with Gram-negative and obligate anaerobic pathogens joining the Gram-positive cocci.5 Initial antimicrobial therapy for these infections is usually empirical; because they are so often polymicrobial, clinicians typically prescribe broad-spectrum agents, especially for severe infections. Definitive therapy should then be tailored according to the results of culture and susceptibility tests from specimens obtained from the wound.

Published clinical studies have demonstrated the efficacy of a variety of antibiotic agents for treating DFIs,6–9 but no agent alone or in combination has yet emerged as most effective.1 Fluoroquinolones have a broad spectrum of activity, are rapidly bactericidal, achieve high concentrations in skin and soft tissue, are highly bioavailable when taken orally, and are generally well tolerated.7,10–15 In the past 20 years, various fluoroquinolone agents have been used successfully for treating DFIs.1,16 Moxifloxacin is a newer fluoroquinolone with activity against most aerobic and anaerobic Gram-positive and Gram-negative bacteria; it is currently approved for the treatment of complicated skin and skin structure infections (cSSSIs) caused by designated susceptible pathogens, but not specifically for DFI.17 A recent prospective, randomized, double-blind, multicentre study demonstrated the clinical and bacteriologic efficacy of sequential intravenous (iv)/oral moxifloxacin for treating hospitalized patients with various types of cSSSIs.18 To explore and to further define the role of moxifloxacin in the treatment of DFI, we used the database from this study to analyse the subset of patients from this study who had a DFI.


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The study upon which this analysis is based was a randomized, double-blind, double-dummy, multicentre trial that enrolled men or women at least 18 years of age, with a cSSSI. The cSSSI was defined as an infection present for <21 days that occurred in previously damaged or ischaemic tissues, or that required substantial surgical intervention in addition to antimicrobial therapy, or that involved deep soft tissue sites or resulted from a human or animal bite. Among these infections, we identified DFI by using four possible definitions: infections called DFI by the investigator who enrolled the patient (investigator-defined); investigator-defined DFI plus the documented presence of a foot ulcer; any foot infection in a patient with a history of diabetes; or any foot infection with a documented foot ulcer plus a history of diabetes. Only patients with an investigator-defined DFI were included in the previously published primary efficacy analysis, but for this analysis, we also assessed response rates in the subgroups with the other definitions of DFI. The investigators only enrolled patients with an infection of sufficient severity to require hospitalization and iv antimicrobial therapy. Each enrolled patient had to have at least three of the following signs or symptoms of wound infection: drainage or discharge, erythema, fluctuance, localized heat or warmth, pain or tenderness, swelling or induration, fever, leucocytosis or >15% immature neutrophils on peripheral blood smear.

Within 24 h of initiating treatment with the study drug, investigators obtained specimens for a Gram-stained smear and culture from eligible patients by needle aspiration of purulent material or by tissue biopsy or wound curettage. Investigators also obtained specimens of blood for culture when they deemed this appropriate. We excluded patients who had received antibiotic therapy for >24 h within 3 days prior to study enrolment or those who needed concomitant systemic antibiotic therapy for treatment of other infections. We also excluded patients with a DFI who had suspected or documented osteomyelitis, unless the infected bone was fully or partially resected and any residual soft tissue infection could be adequately treated with study drug for ≤14 days. Patients with peripheral arterial disease were not excluded.

Moxifloxacin has excellent bioavailability by the oral route, but the study was designed to enrol patients who required hospitalization and to gain approval for iv therapy of cSSSI; thus, initial therapy was parenteral. Patients were randomized to receive iv therapy for at least 3 days with either moxifloxacin (400 mg/day) or piperacillin–tazobactam (3.0 g/0.375 g every 6 h). Thereafter, patients could stay on iv therapy or be switched to oral therapy with moxifloxacin 400 mg/day (for the former group) or amoxicillin–clavulanate suspension 800 mg every 12 h (for the latter group), to complete a total treatment duration of 7–14 days. The investigator at each site made the decision about whether and when to switch patients to oral therapy, based on their clinical status and ability to tolerate oral medication. Patients enrolled in the original study each gave investigator review board-approved written informed consent.

The primary objective of this analysis was to assess the clinical response at the test-of-cure (TOC) visit, 10–42 days after completing the study therapy, for the subset of patients with a DFI. The investigators evaluated signs and symptoms of infection using designated clinical assessments at the following time points: prior to antibiotic therapy, at the switch from iv to oral therapy or at day 3 to 5 during therapy, at the end of therapy, and at the TOC visit. Clinical response at the TOC visit was defined as cure (resolution of all acute signs and symptoms related to the infection or sufficient improvement such that additional antimicrobial therapy was not required), failure (insufficient resolution of the signs and symptoms of acute infection, necessitating additional or alternative antimicrobial therapy), or indeterminate (assessment not possible for any reason).

Bacteriologic response was based on the results of cultures of specimens of infected skin or soft tissue or blood. At the TOC visit, the bacteriologic response was categorized as confirmed eradication (if all of the original pathogens were absent from a post-baseline specimen); presumed eradication (if there was no post-baseline culture but the patient had clinically responded to study therapy); persistence (presence of a baseline pathogen in a post-baseline specimen from a tissue biopsy or needle aspiration of fluid contiguous to the primary infected area in a patient who failed clinical therapy, or from blood); or indeterminate (inability to determine the bacteriologic response to treatment). Study drug safety was evaluated on the basis of any reported adverse event findings of physical examination, routine laboratory assessments (haematology, chemistry and urinalysis) or electrocardiogram monitoring. Serious adverse events (those that were fatal or life-threatening, necessitated hospitalization, resulted in disability or otherwise endangered the patient) were recorded up to the time of the TOC visit.

The intention-to-treat (ITT) and safety populations were defined as all randomized patients who received at least one dose of study medication. The efficacy-valid population consisted of patients who met the entry criteria, had an investigator-defined DFI, received study medication for the minimum duration (2 days if a clinical failure and ≥5 days if a clinical cure), received no non-study systemic or topical antibiotic agent for >72 h prior to enrolment (except for the treatment of isolated pathogens that were resistant in vitro to empirical antibiotic therapy, or if the patient was a clinical failure, and except for narrow-spectrum Gram-positive agents for the treatment of isolated resistant organisms, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci) and had no protocol violations that would have influenced treatment efficacy. Patients in the microbiologically-valid population consisted of those in the efficacy-valid population with one or more causative organism(s) identified at enrolment.

Statistical methods

We compared the clinical success and bacteriologic eradication rates between the two treatment groups at the TOC visit in the valid-for-efficacy population using {chi}2 test or Fisher's exact test. Bacteriologic eradication rates were summarized by individual organism and by treatment group. Similarly, we summarized the demographics and other baseline characteristics, as well as safety data by treatment group for the ITT population.


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Baseline and demographics

The original study was conducted from 12 December 2000 to 20 December 2003 in six countries at 68 centres (70% in the USA). Among 617 patients enrolled, 306 were randomized to the moxifloxacin group and 311 to the comparator group. In our analysis, the ITT population of patients with DFI at baseline consisted of 127 patients—63 in the moxifloxacin group and 64 in the comparator group (Table 1). All enrolled patients were hospitalized for their infection. Among these patients, 7 (11%) in the moxifloxacin group and 13 (20%) in the comparator group had DFI with an associated osteomyelitis. The mean duration of iv therapy was 6.7 days for patients in the moxifloxacin group and 6.3 days for patients in the comparator group. Among the patients valid for the safety analysis, 37 (59%) on moxifloxacin and 43 (67%) on comparator were switched to oral therapy. The mean durations of oral therapy were 7.4 days for moxifloxacin and 7.9 days for comparator.


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  		Table 1. Demographic and clinical characteristics of patients with a DFIa at baseline (ITT populationb)

 
As shown in Table 1, there were no statistically significant differences between patients in the two treatment groups in their demographic or clinical characteristics at baseline [P > 0.05 for all variables except community versus healthcare site infection (P = 0.0049)]. Just over 70% of patients were male and their mean age was ~57 years. Infection was community-acquired (rather than healthcare-associated) in about three-quarters of the patients. The median time from onset of symptoms to study enrolment was 5 days. More than half of the patients in each group (63% overall) had received systemic antibiotic therapy prior to enrolment in the study. At baseline, almost a third of patients were febrile (>38°C); the mean white blood cell count was just over 10 000 and was higher than that in almost half the patients. In almost half of the patients, wound cultures demonstrated that the infection was polymicrobial.

About half of the patients had some type of foot surgery on the affected limb. Among these patients, more than a third had a procedure prior to treatment with the study drug and more than 60% had surgery during treatment. Most of the procedures during treatment were done within 2 days of initiating treatment with the study drug. The most frequently performed procedures were minor (local debridement or drainage in about half of all patients who had surgery), but some needed extensive debridement or a vascular procedure. Over a quarter of the procedures were lower extremity amputations.

Efficacy

Primary efficacy analysis: clinical cure rate. A total of 78 patients, 61% of the baseline ITT population, met the criteria for being included in the efficacy-valid population. Reasons for invalidity of inclusion into the efficacy-valid population in both treatment groups included violation of inclusion/exclusion criteria (9), breaking of randomization code (1), non-compliance with study drug (2), insufficient duration of therapy (6), withdrawal of informed consent (1), invalid or missing essential data (9), loss to follow-up (3) and use of prohibited concomitant, pre-treatment or post-treatment medication (18).

Among the included patients, as shown in Table 2, the clinical cure rates in the ‘per investigator’ populations were 68% for 37 who received moxifloxacin and 61% for 41 who received the comparator agents (P = 0.54). Clinical cure rates were not significantly different between the two groups using the three other DFI definitions.


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  		Table 2. Clinical cure rates at the TOC visit (10–42 days post-therapy) in the efficacy-valid population,a by DFI definition

 
Bacteriologic response. There were 61 cases in which we could determine a bacteriologic response, 37 (61%) of which were polymicrobial infections. The most commonly isolated bacteria were aerobic Gram-positive cocci, especially S. aureus. Relatively small numbers of patients had aerobic Gram-negative or anaerobic isolates. Bacteriologic eradication rates for the microbiologically-valid population at TOC for patients in the moxifloxacin and comparator treatment arms were not statistically significantly different overall (69% versus 66%, P = 1.00). The eradication rates for specific pathogens were generally similar between the two treatment groups (Table 3). The eradication rates for moxifloxacin and the comparator for the most frequently isolated pathogens were 81% and 67% for S. aureus and 58% and 61% for Streptococcus spp., respectively.


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  		Table 3. Causative pathogens and bacteriologic eradicationa rates for these pathogens in the microbiologically-valid populationb at the TOC visitc

 
Safety

Table 4 shows the adverse events for patients with DFI by treatment group. Almost a quarter of patients experienced a serious adverse event, and in ~11% this led to their study drug being discontinued prematurely. The frequency of these events was similar between the two treatment groups. More patients in the moxifloxacin group than in the comparator group experienced a drug-related adverse event (28 versus 8); no severe drug-related adverse events occurred in any patient in the moxifloxacin group, compared with two that occurred in patients in the comparator group. As shown in Table 4, the most commonly reported adverse events were diarrhoea (in eight patients taking moxifloxacin and six taking the comparator), and three events each of headache and pruritus in the moxifloxacin group. There were no significant differences between the groups in the number of patients with elevations of blood glucose levels (one with moxifloxacin and none with the comparator) or of clinically significant hypoglycaemia (six episodes with moxifloxacin and three with the comparator). Of the six DFI patients with clinically significant hypoglycaemia, four received moxifloxacin and two the comparator; none was considered related to the study drug.


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  		Table 4. Adverse events by treatment groupa

 

   Discussion
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Clinicians employ a variety of antimicrobial agents to treat DFIs. Because these infections are frequently polymicrobial, most clinicians select either a broad-spectrum agent or a combination of antibiotics that provide broad-spectrum coverage. Over the past decade, two relatively broad-spectrum ß-lactam/ß-lactamase inhibitor compounds, piperacillin–tazobactam (iv) and amoxicillin–clavulanate (orally), have been among the most commonly used agents for these infections, both by practicing clinicians and in comparative research studies.1,8,15,18–21 The results of this study showed that sequential iv/oral moxifloxacin was as effective and well tolerated as iv piperacillin–tazobactam followed by oral amoxicillin–clavulanate for patients with DFIs.

Our analysis showed that there were no statistically significant differences between moxifloxacin and the comparators in clinical and bacteriologic response rates at 10–42 days after the end of treatment in the protocol-defined, valid-for-efficacy DFI patients. Patients in the moxifloxacin group also had similar clinical success rates as in the valid-for-efficacy patients, using the other three possible DFI definitions. Although this analysis was conducted on a subset of patients enrolled in the original study that evaluated moxifloxacin for cSSSIs, and formal non-inferiority testing was not planned for the DFI subjects, the analysis of the clinical cure rates in the ITT population reveals a lower boundary of the 95% confidence interval of –13.3%. This is above the –15% non-inferiority margin used for the primary efficacy analysis for all types of cSSSIs combined. The validity (inclusion) rate for the DFI patients in this analysis was 61%, which was very close to the overall validity rate for the original study.

The demographic features of our patients were similar to those in other published studies of DFIs, and the two groups were comparable at baseline. Although the DFI guidelines recently published by committees of the Infectious Diseases Society of America and International Working Group on the Diabetic Foot1,5 were not available when this study was conducted, a substantial percentage of the enrolled patients would be classified as having a ‘severe’ infection, based on having fever or leucocytosis. Thus, it is not surprising that all were hospitalized and received parenteral antibiotic therapy (at least initially) and that the majority required surgical procedures on the foot, over a quarter of which were amputations. Nor is it surprising that the clinical cure rates for both treatment groups were in the mid 60% range. Most previous studies of patients with moderate-to-severe DFIs have reported similar results at the post-therapy follow-up visit.

The results of this study support the findings of other investigations using moxifloxacin for treating uncomplicated and complicated skin and skin structure infections.18,22 In vitro studies with moxifloxacin demonstrate a broad spectrum of activity against common pathogens,23–30 including those isolated from patients with DFIs.31 Among 900 surgical isolates from DFIs and intra-abdominal infections, moxifloxacin also exhibited good antimicrobial activity against most aerobic (90.8%) and anaerobic (97.1%) microorganisms.32 Moxifloxacin has been shown to achieve therapeutic levels in plasma and tissues in diabetic patients with soft tissue infections.33 Its once-daily dosing, high oral bioavailability and ability to be used in penicillin-allergic patients are additional advantages. Moxifloxacin, like other broad-spectrum antibiotics, is most appropriate for polymicrobial infections. The major limitation of moxifloxacin for treating DFIs is its lack of consistent activity against methicillin-resistant S. aureus, an increasingly common cause of DFI.24

Selecting an appropriate empirical antibiotic for treating a DFI requires consideration of factors related to the individual patient, the specific type of infection and the likely causative pathogens.34 Current DFI guidelines1,5 favour using agents with proven efficacy for this type of infection. Although a number of regimens have shown efficacy in patients with DFIs, only trovafloxacin, piperacillin–tazobactam, linezolid and ertapenem are specifically FDA-approved for the indication, and no agent has demonstrated superiority for these infections.1 Moxifloxacin has broad activity against most of the aerobic and anaerobic organisms that typically cause these infections. The results from this study, along with previous studies of moxifloxacin,35 suggest that this agent is a welcome addition to parenteral and oral agents shown to be effective in treating DFIs.


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B. A. L. has served as a consultant to, and received honoraria for speaking for, Schering–Plough Corporation and Bayer Corporation. P. G. has received honoraria for speaking at symposia organized by Schering–Plough Corporation. S. C. is employed by Bayer Corporation and owns Bayer stock. J. S. does not have any declarations.


   Acknowledgements
 
This paper was presented in part at the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2006. We thank Jose Iglesia and Shabber Abbas, for providing editorial assistance. Schering–Plough Corporation and Bayer Pharmaceuticals Corporation provided funding for this study.


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1 Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis (2004) 39:885–910.[CrossRef][Web of Science][Medline]

2 Lavery LA, Armstrong DG, Wunderlich RP, et al. Risk factors for foot infections in individuals with diabetes. Diabetes Care (2006) 29:1288–93.[Abstract/Free Full Text]

3 Frykberg RG. A summary of guidelines for managing the diabetic foot. Adv Skin Wound Care (2005) 18:209–14.[Medline]

4 Armstrong DG, Lipsky BA. Advances in the treatment of diabetic foot infections. Diabetes Technol Ther (2004) 6:167–77.[CrossRef][Medline]

5 Lipsky BA. A report from the international consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev (2004) 20(Suppl_1):S68–77.[CrossRef][Web of Science][Medline]

6 Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin–sulbactam/amoxicillin–clavulanate. Clin Infect Dis (2004) 38:17–24.[CrossRef][Web of Science][Medline]

7 Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol (1999) 26:267–76.[CrossRef][Web of Science][Medline]

8 Lipsky BA, Armstrong DG, Citron DM, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet (2005) 366:1695–703.[CrossRef][Web of Science][Medline]

9 Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother (2005) 55:240–5.[Abstract/Free Full Text]

10 Muller M, Stass H, Brunner M, et al. Penetration of moxifloxacin into peripheral compartments in humans. Antimicrob Agents Chemother (1999) 43:2345–9.[Abstract/Free Full Text]

11 Muller M, Brunner M, Hollenstein U, et al. Penetration of ciprofloxacin into the interstitial space of inflamed foot lesions in non-insulin-dependent diabetes mellitus patients. Antimicrob Agents Chemother (1999) 43:2056–8.[Abstract/Free Full Text]

12 Raghavan M, Linden PK. Newer treatment options for skin and soft tissue infections. Drugs (2004) 64:1621–42.[CrossRef][Web of Science][Medline]

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14 Fung HB, Chang JY, Kuczynski S. A practical guide to the treatment of complicated skin and soft tissue infections. Drugs (2003) 63:1459–80.[CrossRef][Web of Science][Medline]

15 Graham DR, Talan DA, Nichols RL, et al. Once-daily, high-dose levofloxacin versus ticarcillin–clavulanate alone or followed by amoxicillin–clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial. Clin Infect Dis (2002) 35:381–9.[CrossRef][Web of Science][Medline]

16 Daniel R. Once-daily oral trovafloxacin in the treatment of diabetic foot infections—results of an open-label, noncomparative, multicentre trial. Drugs (1999) 58:291–2.[CrossRef][Web of Science]

17 Keating GM, Scott LJ. Moxifloxacin: a review of its use in the management of bacterial infections. Drugs (2004) 64:2347–77.[CrossRef][Web of Science][Medline]

18 Giordano P, Song J, Pertel P, et al. Sequential intravenous/oral moxifloxacin versus intravenous piperacillin–tazobactam followed by oral amoxicillin–clavulanate for the treatment of complicated skin and skin structure infection. Int J Antimicrob Agents (2005) 26:357–65.[CrossRef][Web of Science][Medline]

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20 Harkless L, Boghossian J, Pollak R, et al. An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt) (2005) 6:27–40.[CrossRef][Medline]

21 Grayson ML, Gibbons GW, Habershaw GM, et al. Use of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis (1994) 18:683–93.[Web of Science][Medline]

22 Parish LC, Routh HB, Miskin B, et al. Moxifloxacin versus cephalexin in the treatment of uncomplicated skin infections. Int J Clin Pract (2000) 54:497–503.[Web of Science][Medline]

23 Malathum K, Singh KV, Murray BE. In vitro activity of moxifloxacin, a new 8-methoxyquinolone, against gram-positive bacteria. Diagn Microbiol Infect Dis (1999) 35:127–33.[CrossRef][Web of Science][Medline]

24 Jones ME, Visser MR, Klootwijk M, et al. Comparative activities of clinafloxacin, grepafloxacin, levofloxacin, moxifloxacin, ofloxacin, sparfloxacin, and trovafloxacin and nonquinolones linezolid, quinupristin–dalfopristin, gentamicin, and vancomycin against clinical isolates of ciprofloxacin-resistant and -susceptible Staphylococcus aureus strains. Antimicrob Agents Chemother (1999) 43:421–3.[Abstract/Free Full Text]

25 Esposito S, Noviello S, Ianniello F. Comparative in vitro activity of older and newer fluoroquinolones against respiratory tract pathogens. Chemotherapy (2000) 46:309–14.[CrossRef][Web of Science][Medline]

26 Esposito S, Noviello S, Ianniello F, et al. In vitro activity of moxifloxacin compared to other fluoroquinolones against different erythromycin-resistant phenotypes of group A ß-hemolytic Streptococcus. Chemotherapy (2000) 46:23–7.[CrossRef][Web of Science][Medline]

27 Esposito S, Noviello S, Ianniello F. Bactericidal activity of moxifloxacin compared to grepafloxacin and clarithromycin against Streptococcus pneumoniae and Streptococcus pyogenes investigated using an in vitro pharmacodynamic model. J Chemother (2000) 12:475–81.[Web of Science][Medline]

28 Fass RJ. In vitro activity of Bay 12-8039, a new 8-methoxyquinolone. Antimicrob Agents Chemother (1997) 41:1818–24.[Abstract]

29 Ackermann G, Schaumann R, Pless B, et al. In vitro activity of telithromycin (HMR 3647) and seven other antimicrobial agents against anaerobic bacteria. J Antimicrob Chemother (2000) 46:115–9.[Abstract/Free Full Text]

30 Ackermann G, Schaumann R, Pless B, et al. Comparative activity of moxifloxacin in vitro against obligately anaerobic bacteria. Eur J Clin Microbiol Infect Dis (2000) 19:228–32.[CrossRef][Web of Science][Medline]

31 Goldstein EJ, Citron DM, Nesbit CA. Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases. Diabetes Care (1996) 19:638–41.[Abstract]

32 Edmiston CE, Krepel CJ, Seabrook GR, et al. In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intra-abdominal and diabetic foot infections. Antimicrob Agents Chemother (2004) 48:1012–6.[Abstract/Free Full Text]

33 Joukhadar C, Stass H, Muller-Zellenberg U, et al. Penetration of moxifloxacin into healthy and inflamed subcutaneous adipose tissues in humans. Antimicrob Agents Chemother (2003) 47:3099–103.[Abstract/Free Full Text]

34 Lipsky BA. Empiric therapy for diabetic foot infections: are there clinical clues to guide antibiotic selection? Clin Microbiol Infect (2007) 13:351–3.[CrossRef][Web of Science][Medline]

35 Malangoni M, Song J, Herrington J, et al. Randomized controlled trial of moxifloxacin compared with piperacillin–tazobactam and amoxicillin–clavulanate for the treatment of complicated intra-abdominal infections. Ann Surg (2006) 244:204–11.[CrossRef][Medline]


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