Staphylococcus epidermidis (methicillin-susceptible strains only)
Streptococcus agalactiae Streptococcus viridans group

Aerobic Gram-negative microorganisms

Citrobacter freundii
Klebsiella oxytoca
Legionella pneumophila

Anaerobic microorganisms

Fusobacterium species
Prevotella species

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of moxifloxacin powder.
The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and methicillin-susceptible Staphylococcus aureus:

For testing Haemophilus influenzae and Haemophilus parainfluenzae ^a:

^a This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1. The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus species including Streptococcus pneumoniae b and Enterococcus faecalis:

^bThese interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2 - 5% lysed horse blood.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard moxifloxacin powder should provide the following MIC values:

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg moxifloxacin to test the susceptibility of microorganisms to moxifloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg moxifloxacin disk should be interpreted according to the following criteria:

The following zone diameter interpretive criteria should be used for testing Enterobacteriaceae and methicillin-susceptible Staphylococcus aureus:

For testing Haemophilus influenzae and Haemophilus parainfluenzae^e:

^e This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2. The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

For testing Streptococcus species including Streptococcus pneumoniae ^f and Enterococcus faecalis:

^f These interpretive standards are applicable only to disk diffusion tests using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for moxifloxacin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg moxifloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

^g These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM)2.

^h These quality control limits are applicable only to tests conducted with S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.

Anaerobic Techniques: For anaerobic bacteria, the susceptibility to moxifloxacin as MICs can be determined by standardized procedures3 such as reference agar dilution methodsⁱ. The MICs obtained should be interpreted according to the following criteria:

ⁱ This interpretive standard is applicable to reference agar dilution susceptibility tests using Brucella agar supplemented with hemin, vitamin K1 and 5% laked sheep blood. Acceptable ranges of MICs (ug/mL) for control strains for reference agar dilution testing ^j:

^jThese quality control ranges are applicable to reference agar dilution tests using Brucella agar supplemented with hemin, vitamin K1 and 5% laked sheep blood.

Animal Pharmacology

Quinolones have been shown to cause arthropathy in immature animals. In studies in juvenile dogs oral doses of moxifloxacin ≥ 30 mg/kg/day (approximately 1.5 times the maximum recommended human dose based upon systemic exposure) for 28 days resulted in arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.

Unlike some other members of the quinolone class, crystalluria was not observed in 6 month repeat dose studies in rats and monkeys with moxifloxacin.

No ocular toxicity was observed in a 13 week oral repeat dose study in dogs with a moxifloxacin dose of 60 mg/kg/day. Ocular toxicity was not observed in 6 month repeat dose studies in rats and monkeys (daily oral doses up to 500 mg/kg and 135 mg/kg, respectively). In beagle dogs, electroretinographic (ERG) changes were observed in a 2 week study at oral doses of 60 and 90 mg/kg/day. Histopathological changes were observed in the retina from one of four dogs at 90 mg/kg/day, a dose associated with mortality in this study.

Some quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs). Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (e.g., seizures) in mice when used in combination with NSAIDs such as diclofenac, ibuprofen, or fenbufen.

In dog studies, at plasma concentrations about five times the human therapeutic level, a QT-prolonging effect of moxifloxacin was found. Electrophysiological in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism. In dogs, the combined infusion of sotalol, a Class III antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation than that induced by the same dose (30 mg/kg) of moxifloxacin alone.

In a local tolerability study performed in dogs, no signs of local intolerability were seen when moxifloxacin was administered intravenously. After intra-arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.

Clinical Studies

Acute Bacterial Exacerbation of Chronic Bronchitis

AVELOX Tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a large, randomized, double-blind, controlled clinical trial conducted in the US. This study compared AVELOX with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. The primary endpoint for this trial was clinical success at 7-17 days post-therapy. The clinical success for AVELOX was 89% (222/250) compared to 89% (224/251) for clarithromycin.

The following outcomes are the clinical success rates at the follow-up visit for the clinically evaluable patient groups by pathogen:

The microbiological eradication rates (eradication plus presumed eradication) in AVELOX treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.

Community Acquired Pneumonia

A large, randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of AVELOX Tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients (382 of whom were valid for the primary efficacy analysis conducted at the 14 - 35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for AVELOX and 95% (178/188) for high dose clarithromycin.

A large, randomized, double-blind, controlled trial was conducted in the US and Canada to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 7-14 days to an IV/PO fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid for the primary efficacy analysis conducted at the 7-30 day post-therapy visit. The clinical success rate was 86% (157/182) for AVELOX therapy and 89% (161/180) for the fluoroquinolone comparators.

An open-label ex-US study that enrolled 628 patients compared AVELOX to sequential IV/PO amoxicillin/clavulanate (1.2 g IV q8h/625 mg PO q8h) with or without high-dose IV/PO clarithromycin (500 mg BID). The intravenous formulations of the comparators are not FDA approved. The clinical success rate at Day 5-7 (the primary efficacy timepoint) for AVELOX therapy was 93% (241/258) and demonstrated superiority to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. 2.9%, 13.2%]. The clinical success rate at the 21-28 days post-therapy visit for AVELOX was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. 2.6%, 16.3%]. The clinical success rates by pathogen across four CAP studies are presented below:

Clinical Success Rates By Pathogen (Pooled CAP Studies)

Community Acquired Pneumonia caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*

Avelox was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant Streptococcus pneumoniae MDRSP* isolates. Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients (95.0%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates based on the number of patients treated are shown in the table below.

* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 μg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Clinical and Bacteriological Success Rates for Moxifloxacin-Treated MDRSP CAP Patients (Population: Valid for Efficacy):

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in the table below:

Acute Bacterial Sinusitis

In a large, controlled double-blind study conducted in the US, AVELOX Tablets (400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the primary efficacy determination. Clinical success (cure plus improvement) at the 7 to 21 day post-therapy test of cure visit was 90% for AVELOX and 89% for cefuroxime.

An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with AVELOX 400 mg once daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical success rates and eradication/ presumed eradication rates at the 21 to 37 day follow-up visit were 97% (29 out of 30) for Streptococcus pneumoniae, 83% (15 out of 18) for Moraxella catarrhalis, and 80% (24 out of 30) for Haemophilus influenzae.

Uncomplicated Skin and Skin Structure Infections

A randomized, double-blind, controlled clinical trial conducted in the US compared the efficacy of AVELOX 400 mg once daily for seven days with cephalexin HCl 500 mg three times daily for seven days. The percentage of patients treated for uncomplicated abscesses was 30%, furuncles 8%, cellulitis 16%, impetigo 20%, and other skin infections 26%. Adjunctive procedures (incision and drainage or debridement) were performed on 17% of the AVELOX treated patients and 14% of the comparator treated patients. Clinical success rates in evaluable patients were 89% (108/122) for AVELOX and 91% (110/121) for cephalexin HCl.

Complicated Skin and Skin Structure Infections

Two randomized, active controlled trials of cSSSI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 7-14 days to an IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 617 patients, 335 of which were valid for the primary efficacy analysis. A second open-label International study compared AVELOX 400 mg QD for 7-21 days to sequential IV/PO beta-lactam/beta-lactamase inhibitor control in the treatment of patients with cSSSI. This study enrolled 804 patients, 632 of which were valid for the primary efficacy analysis. Surgical incision and drainage or debridement was performed on 55% of the moxifloxacin treated and 53% of the comparator treated patients in these studies and formed an integral part of therapy for this indication. Success rates varied with the type of diagnosis ranging from 61% in patients with infected ulcers to 90% in patients with complicated erysipelas. These rates were similar to those seen with comparator drugs. The overall success rates in the evaluable patients and the clinical success by pathogen are shown below:

Overall Clinical Success Rates in Patients with Complicated Skin and Skin Structure Infections

Clinical Success Rates by Pathogen in Patients with Complicated Skin and Skin Structure Infections

Complicated Intra-Abdominal Infections

Two randomized, active controlled trials of cIAI were performed. A double-blind trial was conducted primarily in North America to compare the efficacy of sequential IV/PO AVELOX 400 mg QD for 5-14 days to IV/ piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI, including peritonitis, abscesses, appendicitis with perforation, and bowel perforation. This study enrolled 681 patients, 379 of which were considered clinically evaluable. A second open-label international study compared AVELOX 400 mg QD for 5-14 days to IV ceftriaxone plus IV metronidazole followed by PO amoxicillin/clavulanic acid in the treatment of patients with cIAI. This study enrolled 595 patients, 511 of which were considered clinically evaluable. The clinically evaluable population consisted of subjects with a surgically confirmed complicated infection, at least 5 days of treatment and a 25-50 day follow-up assessment for patients at the Test of Cure visit. The overall clinical success rates in the clinically evaluable patients are shown below:

Clinical Success Rates in Patients with Complicated Intra-Abdominal Infections

REFERENCES: 1. Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth Edition. Approved Standard CLSI Document M7-A6, Vol. 23, No. 2, CLSI, Wayne, PA, January, 2003.

2. Clinical and Laboratory Standards Institute, Performance Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition. Approved Standard CLSI Document m²-A8, Vol. 23, No. 1, CLSI, Wayne, PA, January, 2003.

3.  Clinical and Laboratory Standards Institute, Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard CLSI Document M11-A6, Vol. 24, No. 2, CLSI, Wayne, PA, 2004.

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