Update on Moxifloxacin (Avelox): New Indications
Special Feature (Part 1 of 3-part Series)
By Joanne Hsu, PharmD Candidate, Cindy Tat, PharmD Candidate, Jessica C. Song, MA, PharmD, Joanne Hsu and Cindy Tat are PharmD Candidates at the University of the Pacific, School of Pharmacy, and Jessica Song is Pharmacy Residency Coordinator at SCVMC, Assistant Professor of Pharmacy Practice
University of the Pacific, Stockton, CA. Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Joanne, Cindy, and Jessica report no consultant, stockholder, speaker’s bureau, research, or other financial relationship with any company related to this field of study.
Since the fda approval of moxifloxacin in December 1991 for the treatment of community-acquired pneumonia, sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated skin/skin structure infections, its indications for use has been expanded to include the treatment of complicated skin/skin structure infections2 and complicated intra-abdominal infections.3 A variety of factors must be taken into consideration when making decisions about which fluoroquinolones to include in the formulary. These factors include safety, clinical efficacy, spectrum of indications, and cost. In view of the fact that moxifloxacin’s indications for use were expanded to include 2 new indications within the past 6 months, clinicians should be educated on these new developments. This article will: 1) review the clinical efficacy of moxifloxacin for the treatment of complicated intra-abdominal infections and 2) review the clinical efficacy of moxifloxacin for the treatment of complicated skin/skin structure infections.
Complicated Intra-Abdominal Infections
Complicated intra-abdominal infections are defined as infections that extend beyond the hollow viscus of origin into the peritoneal space, and are associated with abscess formation or peritonitis. Furthermore, resolution of these types of infections requires either operative or percutaneous intervention.4 There is a wide variety of conditions associated with intra-abdominal infections, including perforated gastroduodenal ulcers, biliary tract infections, small bowel perforations, appendicitis, and diverticulitis.5 The pathogens causing complicated intra-abdominal infections vary depending on whether the infection is community-acquired or health care associated. Empirical treatment will, thus, be dependent on the type of infection the patient presents with on hospital admission.
According to the 2003 Infectious Diseases Society of America (IDSA) Guidelines, empiric antimicrobial agents for community-acquired intra-abdominal infections should cover enteric gram-negative aerobic and facultative bacilli and beta-lactam-susceptible gram-positive cocci. Additionally, coverage for obligate anaerobic bacilli is needed for distal small-bowel and colon-derived infections and for more proximal perforations when obstruction is present. Narrower spectrum agents that are not commonly used for nosocomial infections are preferred over broader spectrum antimicrobials for mild-to-moderate community-acquired intra-abdominal infections. These agents include ampicillin/sulbactam, ticarcillin/clavulanate, ertapenem, (cefazolin or cefuroxime) plus metronidazole, or a fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin, or gatifloxacin) plus metronidazole. High-severity infections (higher APACHE II scores, significant cardiovascular disease, poor nutritional status, immunosuppression) may benefit from antimicrobials, with a broader spectrum of activity against facultative and aerobic gram-negative pathogens. These agents include piperacillin/tazobactam, imipenem/cilastatin, meropenem, a third- or fourth-generation cephalosporin (cefotaxime, ceftriaxone, ceftizoxime, ceftazidime, or cefepime) plus metronidazole, ciprofloxacin plus metronidazole, or aztreonam plus metronidazole.4
Health care associated intra-abdominal infections occur as a result of complications of previous elective or emergent intra-abdominal operations, and are caused by more resistant pathogens, including Pseudomonas aeruginosa, Enterobacter spp, Proteus spp, methicillin-resistant Staphylococcus aureus, enterococci, and Candida spp. These infections often require complex multi-drug regimens, where local nosocomial resistance patterns dictate empirical treatment. Once results of microbiology workup of infected fluid are obtained, antimicrobial therapy should be adjusted accordingly.4
Previously, moxifloxacin was only recommended as dual-therapy with metronidazole for the treatment of mild-to-moderate community-acquired intra-abdominal infections. Malongoni and colleagues conducted a prospective, randomized, double-blind, multicenter, Phase III study (n = 379) comparing the efficacy of moxifloxacin (400 mg once-daily sequential IV/PO) with that of piperacillin/tazobactam (3.375 mg IV 4 times daily), followed by amoxicillin/clavulanate (800 mg PO twice daily) for the treatment of complicated intra-abdominal infections in adult patients (total treatment duration of 5-14 days). The primary efficacy end point was based on clinical response rate at the test-of-cure visit (25-50 days after study entry). Baseline patient demographics and infection characteristics (85% community-acquired; complicated appendicitis, appendix abscess, gangrenous appendix, large or distal small bowel perforations, diverticulitis) were similar in both study groups. The 2 most common causative pathogens were E. coli and B. fragilis, with a majority of the patients having polymicrobial infections in both the moxifloxacin-treated group and the comparator group, 84% and 79.1% respectively.6
Of note, the study population was comprised mainly of relatively younger and otherwise healthy patients, as the average patient age was approximately 46 years, and an APACHE II score of 6.9 ± 4.2 was reported for the moxifloxacin-treated group, and a score of 5.9 ± 4.2 was observed in the comparator-treated group. Additionally, the study lacked infections caused by more resistant pathogens, such as Pseudomonas aeruginosa, MRSA, extended-spectrum b-lactamase-producing (ESBL) Klebsiella pneumoniae, and had a limited number of infections caused by Enterococcus faecalis, all of which may complicate the treatment of health care associated intra-abdominal infections.6
At the test-of-cure visit, moxifloxacin IV/PO monotherapy was shown to be noninferior to standard therapy of IV piperacillin/tazobactam, followed by oral amoxicillin/clavulanate, as 79.8% of the moxifloxacin-treated patients and 78.2% of the comparator-treated patients achieved an overall clinical response (95% CI, - 7.6 to 9.2). The clinical cure rates for patients with abscess were 76.3% for the moxifloxacin group and 77.6% for the comparator group. Patients with community-acquired infections achieved a clinical cure rate of 79.4% in the moxifloxacin group vs 82.5% in the comparator group. Overall bacterial eradication rates for the moxifloxacin and the comparator group were 77.9% and 77.4%, respectively. Time to recovery, duration of hospitalization, clinical response rates and improvement in APACHE scores at day 3-5, and microbiologic success rates were all comparable in both groups, with no statistically significant difference. Overall safety profile was also similar in the 2 groups, with the percentage of patients who prematurely discontinued the study due to an adverse event being 10.4% in the moxifloxacin group and 8.5% in the control group.6
From this study, moxifloxacin gained FDA approval for the treatment of complicated intra-abdominal infections, including polymicrobial infections, such as abscesses caused by Gram-positive pathogens (Enterococcus faecalis, Streptococcus anginosus, Streptococcus constellatus), Gram-negative pathogens (Escherichia coli, Proteus mirabilis), and anaerobic pathogens (Bacteroides fragilis, Bacteroides thetaiotaomicron, Clostridium perfringens, Peptostreptococcus species).7 Moxifloxacin is the only marketed fluoroquinolone antibiotic approved by the FDA as monotherapy to treat this indication.
Complicated Skin/Skin-Structure Infections
Complicated skin and skin-structure infections (cSSSI) are defined as infections involving deeper soft tissue, requiring significant surgical intervention, or occurring in compromised hosts. Complicated infections include secondary infections of diseased skin, as well as post-operative/traumatic wound infections, bite-related infections, venous stasis ulcers, pressure sores, diabetic foot infections, and perianal cellulitis with or without abscess.8,9 The most common pathogens involved in skin infections are gram-positive cocci, Staphylococcus aureus, and streptococci. However, complicated infections often involve enteric gram-negative bacilli and anaerobic bacteria, especially for patients with underlying risk factors (diabetic, immunocompromised, vascular compromise). Common gram negative pathogens include Escherichia coli, Klebsiella spp., Enterobacter spp., and Pseudomonas aeruginosa.8-10
The 2005 Infectious Disease Society of America (IDSA) guidelines for the treatment of skin and soft-tissue infections (SSTI) recommend several antibiotics as effective therapy of various types of skin and skin-structure infections. Management of cSSSI involves empirical broad-spectrum antibiotic therapy to cover the likely polymicrobial etiology of the infection in conjunction with appropriate surgical interventions.9 Table 1 summarizes the IDSA recommendations for the treatment and management of the most commonly encountered cSSSIs, including cellulitis and diabetic foot infections. Cellulitis cases are typically caused by ?-hemolytic streptococci and rarely Staphylococcus aureus, unless underlying abscess or penetrating trauma is present.11 Diabetic foot infections predominantly involve aerobic gram-positive cocci, specifically Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). Enterobacteriaceae, Pseudomonas aeruginosa, and obligate anaerobic pathogens may also be present in patients with chronic wounds, recent antibiotic therapy, or foot ischemia or gangrene.12 Therapy should be based on clinical severity of the infection and targeted to cover the appropriate pathogens.8,11,12
Moxifloxacin was previously indicated for uncomplicated skin and skin-structure infections caused by Staphylococcus aureus and Streptococcus pyogenes. Recently, moxifloxacin gained FDA-approval for the treatment of complicated skin and skin-structure infections involving methicillin-susceptible Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter clocae.7 It has been shown to have broad-spectrum in vitro activity against the common cSSSI pathogens, along with rapid bactericidal action and adequate tissue concentrations at skin and soft tissue infection sites.13,14
Giordano and colleagues conducted a prospective, randomized, multicenter, double-blind, active-control Phase IIIb trial, in which once daily moxifloxacin 400 mg intravenously (IV) followed by oral moxifloxacin was compared with piperacillin/tazobactam 3.375 g IV every 6 hours followed by oral amoxicillin-clavulanic acid suspension 800 mg twice daily for cSSSI. Adult patients (n = 617) were randomized to one of the 2 treatment regimens for 7-14 days, with at least 3 days consisting of intravenous therapy, of which 367 were eligible for inclusion in the efficacy-valid population (180 moxifloxacin,187 control) and 237 were determined to be microbiologically-evaluable (119 moxifloxacin, 118 control). The most commonly reported cSSSIs in this trial included abscess, cellulitis, and diabetic foot infections. Surgical procedures were performed in 34% of piperacillin-tazobactam-treated patients and in 31% of moxifloxacin-treated patients. The primary end point was efficacy, which was defined by clinical response at the test-of-cure (TOC) visit 10-42 days post-therapy. Safety and tolerability were evaluated by monitoring adverse events, routine laboratory assessments, and physical examinations.9
Moxifloxacin was shown to have similar clinical cure rates at TOC compared to the control regimen of piperacillin/tazobactam, as 79% of the moxifloxacin group and 82% of the comparator group achieved a clinical response (95% CI -12.0%, 3.3%). The clinical cure rates were also comparable among different infection types between the treatment groups, with the exception of abscesses. Patients with abscess had a higher response rate in the control group (79% vs 93%, P = 0.04). Bacteriological eradication rates were also similar between treatment groups. The most frequently encountered pathogen, methicillin-sensitive Staphylococcus aureus (54% moxifloxacin, 50% control), showed comparable bacteriological eradication with moxifloxacin versus the control regimen (78% vs 80%; 95% CI -14.8%, 5.2%). As expected, both groups had lower eradication rates for MRSA (60% moxifloxacin, 71% control). Moxifloxacin also provided comparable bacteriological eradication of other common pathogens of cSSSI, including Streptococcus pyogenes, Escherichia coli, Klebsiella pneumonia, and Enterobacter cloacae. The safety and tolerability data showed no clinically significant difference between moxifloxacin and the comparator. The only drug-related adverse events that occurred in > 3% of patients were diarrhea (5% moxifloxacin, 8% control) and nausea (4% moxifloxacin, 2% control).9
However, it is important to realize that although moxifloxacin has significant coverage for the common cSSSI pathogens, it is not indicated for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Skin infections caused by Pseudomonas aeruginosa are more often associated with nosocomially-acquired infections, and less commonly seen in the community. The presence of Pseudomonas aeruginosa in some diabetic foot infections is sometimes considered a contaminate or colonization, rather than a pathological infection. However, it can be the cause of wound infections following fresh water exposure, hot-tub folliculitis, or deep foot infections from a sports shoe puncture.8
There is a growing concern regarding MRSA skin infections, as these infections are occurring not only in hospitals, but also increasingly in the community in patients with no other risk factors.8,15 If MRSA is a suspected pathogen of cSSSI, moxifloxacin is not indicated for MRSA and will not provide adequate coverage. Community isolates of MRSA have been shown to display susceptibility to tetracyclines (doxycycline, minocycline), clindamycin (no resistance to erythromycin), and trimethoprim-sulfamethoxazole.11,16 Vancomycin, linezolid, and daptomycin should be reserved for use in the treatment of patients with MRSA skin infections that necessitate hospitalization, or if earlier eradication measures have failed.11
Other antibiotics (marketed in the United States) that show much potential for the management and treatment of cSSSI include ertapenem and tigecycline. Like moxifloxacin, ertapenem covers most of the common pathogens of cSSSI, including MSSA, streptococci, enterobacteriaceae, anaerobes, but not most Enterococcus or Pseudomonas species. The once-daily dosed ertapenem (1 g every 24h) was shown to be as safe and effective as piperacillin-tazobactam (3.375 g every 6h) in a randomized, double-blinded study consisting of 540 adults with cSSSI.17 Recently, a once-daily dose ertapenem (1 g every 24h) was shown to be as safe and effective as piperacillin-tazobactam (3.375 g every 6h) in a randomized, double-blinded study consisting of 586 diabetic adults with moderate-to-severe foot infection (S. aureus (80% methicillin-sensitive) identified in ~40% of subjects).18 Tigecycline is also indicated for cSSSI infections attributable to Escherichia coli, Enterococcus faecalis (vancomycin susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus pyogenes, and Bacteroides fragilis.19 The advantage of tigecycline over moxifloxacin is its coverage against MRSA. However, as with ertapenem, tigecycline is only available as a parenteral product whereas moxifloxacin has both a parenteral and oral formulation.
At present, moxifloxacin is indicated for the treatment of community-acquired pneumonia, sinusitis, acute bacterial exacerbation of chronic bronchitis, complicated skin/skin structure infections, uncomplicated skin/skin structure infections, and complicated intra-abdominal infections. This drug is the only marketed fluoroquinolone approved by the FDA as monotherapy for the indication of complicated intra-abdominal infection. While moxifloxacin has been shown to be as effective as piperacillin-tazobactam in the treatment of complicated intra-abdominal infection, it should be noted that this finding primarily applies to patients with community-acquired infections, where more resistant causative organisms, such as Pseudomonas aeruginosa, Enterococcus faecalis, and MRSA are unlikely pathogens. Similarly, moxifloxacin has been shown to provide comparable clinical cure rates to that of piperacillin-tazobactam for patients with complicated skin/skin structure infection, comprised of cellulitis, abscess, and diabetic foot infections. However, because of the growing concern of MRSA skin infections, it is important to realize that coverage against this pathogen will not be provided by monotherapy with moxifloxacin or any of the other fluoroquinolones.
- Prescription Medicine Datasheets. Avelox. www.bleedingedge.net/Drugs/Avelox.aspx Accessed on January 9, 2006.
- Schering-Plough News Release. Schering-Plough Announces FDA Approval of Avelox-Once Daily Dosing Provides Effective and Convenient Treatment Option. www.gcigroup.com/prerelease/archives/2005/00/30/16/04/00/ Accessed on January 9, 2006.
- Schering-Plough News Release. FDA Approves New Indication for Avelox for Treatment of Complicated Intra-Abdominal Infections. www.schering-plough.com/schering_plough/news/release.jsp?releaseID=791234 Accessed on January 9, 2006.
- Solomkin JS, et al. Guidelines for the Selection of Anti-Infective Agents for Complicated Intra-Abdominal Infections. Clin Infect Dis. 2003;37:997-1005.
- Goldstein EJ. Intra-Abdominal Anaerobic Infections: Bacteriology and Therapeutic Potential of Newer Antimicrobial Carbapenem, Fluoroquinolone, and Desfluoroquinolone Therapeutic Agents. Clin Infect Dis. 2002;35:S106-S111.
- Malongoni M, et al. Sequential IV/PO Moxifloxacin Vs IV Piperacillin-Tazobactam + PO Amoxicillin-Clavulanate for Treatment of Complicated Intra-Abdominal Infections. Forty-Fourth Interscience Conference on Antimicrobial Agents and Chemotherapy (2004). Washington DC, U.S.A. Abstract #L-990.
- Moxifloxacin (Avelox®) Prescribing Information. West Haven, CT: Bayer Pharmaceuticals; December 2005.
- DiNubile MJ, Lipsky BA. Complicated Infections of Skin and Skin Structures: When the Infection is More Than Skin Deep. J Antimicrob Chemother. 2004;53:ii37-ii50.
- Giordano 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;26:357-365.
- Rennie RP, et al. Occurrence and Antimicrobial Susceptibility Patterns of Pathogens Isolated from Skin and Soft Tissue Infections: Report from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 2000). Diagn Microbiol Infect Dis. 2003;45:287-293.
- Stevens DL, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections. Clin Infect Dis. 2005;41:1373-1406.
- Lipsky BA, et al. Diagnosis and Treatment of Diabetic Foot Infections. Clin Infect Dis. 2004;39:885-910.
- Blondeau JM, et al. In Vitro Susceptibility of 4903 Bacterial Isolates to Gemifloxacin—An Advanced Fluoroquinolone. Int J Antimicrob Agents. 2003;22:147-154.
- Peric M, Jacobs MR, Appelbaum PC. Antianaerobic Activity of a Novel Fluoroquinolone, WCK 771, Compared To Those of Nine Other Agents. Antimicrob Agents Chemother. 2004;48:3188-3192.
- Fridkin SK, et al. Methicillin-Resistant Staphylococcus aureus Disease in Three Communities. N Engl J Med. 2005;352:1436-1444.
- Deresinski S. Methicillin-Resistant Staphylococcus aureus: An Evolutionary, Epidemiologic, and Therapeutic Odyssey. Clin Infect Dis. 2005;40:562-573.
- Graham DR, et al. Ertapenem Once Daily Versus Piperacillin-Tazobactam 4 Times Per Day for Treatment of Complicated Skin and Skin-Structure Infections in Adults: Results of a Prospective, Randomized, Double-Blind Multicenter Study. Clin Infect Dis. 2002;34:1460-1468.
- Lipsky BA, et al. Ertapenem Versus Piperacillin/Tazobactam for Diabetic Foot Infections (SIDESTEP): Prospective, Randomized, Controlled, Double-Blinded, Multicentre Trial. Lancet. 2005; 366:1695-1703.
- Tigecycline (Tygacil®) Prescribing Information. Philadelphia, PA: Wyeth Pharmaceuticals, Inc.: June 2004.