A Guide To Emerging Antibiotics For Diabetic Foot Infections

   Many exciting antibiotics have either recently been approved, received a new FDA indication or will soon become available. Some are well known and have already been incorporated into clinical practice. Many are the first in their respective classes and have novel mechanisms of action. What place, if any, do these drugs have in the treatment of diabetic foot infections (DFIs)?    That said, let us take a look at a number of newer as well as time-tested antibiotics and assess their efficacy for DFIs.    • Linezolid (Zyvox, Pfizer) and quinupristin/dalfopristin (Synercid®, Monarch Pharmaceuticals). While quinupristin/dalfopristin is active against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), the drug has limited clinical use due to its administration via a slow infusion of a large volume or through a central line.    Linezolid, the first-in-class oxazolidinone, has 100 percent bioavailability after oral administration, is active against MRSA and VRE, and has proven efficacy in treating DFIs. Although treatment failures and resistant strains of S. aureus have been reported, linezolid remains a valuable new antibiotic and has received an FDA indication for diabetic foot infections. Both linezolid and quinupristin/dalfopristin are active against Enterococcus faecium but only linezolid is active against E. faecalis. Vancomycin-resistant Enterococcus are almost always E. faecium.

What The Research Reveals About Ertapenem

   • Ertapenem (Invanz, Merck). Ertapenem is a broad-spectrum carbapenem approved for the treatment of complicated skin and skin structure infections (cSSSIs), including diabetic foot infections without osteomyelitis.    Ertapenem has a narrow spectrum of activity compared to imipenem/cilastatin (Primaxin, Merck). It has good activity against methicillin susceptible S. aureus (MSSA), gram negatives and anaerobes. However, it has unreliable activity against Pseudomonas aeruginosa and enterococci. Researchers have shown that ertapenem has excellent in vitro activity against the most common aerobic pathogens and almost all anaerobes recovered from patients with infections of the skin and skin structures.1 It is not active against MRSA.    Perhaps ertapenem’s strongest benefit is its long half life, lending itself to once a day dosing and making it particularly attractive for IV outpatient therapy.    In a prospective, randomized, double-blind trial comparing ertapenem (1 g once daily) to piperacillin-tazobactam (3.375 g every 6 h) as parenteral treatment for 540 adults with complicated skin and skin-structure infections, 82.4 percent of those who received ertapenem and 84.4 percent of those who received piperacillin-tazobactam were cured. The most common infections in the study were deep soft tissue abscess (18.9 percent) and diabetic lower extremity infection (18.1 percent). With the exception of MRSA, almost all of the predominant aerobic pathogens were susceptible to both drugs in the study. Out of the 141 anaerobes tested for susceptibility, 97.2 percent were susceptible to ertapenem and 97.9 percent were susceptible to piperacillin-tazobactam.2    In another study known as SIDESTEP (the Study of Infections in Diabetic Feet Comparing Efficacy, Safety and Tolerability of Ertapenem vs Piperacillin/Tazobactam) Lipsky, et. al., recruited 576 patients to a randomized, double-blinded, multicenter trial. In the trial, 289 patients received 1 g of ertapenem daily and 287 patients received 3.375 g of piperacillin/tazobactam four times daily. All patients had moderate to severe diabetic foot infections. By the end of intravenous therapy, the clinical success rates were 94.2 percent for the ertapenem group and 92.2 percent for the piperacillin/tazobactam group, with no difference in the incidence of drug-related adverse events. The findings support the use of ertapenem as an important treatment option for DFIs.3

What You Should Know About Moxifloxacin

   • Moxifloxacin (Avelox®, Schering-Plough). Like ertapenem, moxifloxacin is not new but it did receive a new indication for complicated skin and skin structure infections (cSSSIs) in July. Although it does not have a formal FDA indication for diabetic foot infections, its spectrum of activity lends itself to single agent therapy of mixed infections.    Moxifloxacin shows good activity against methicillin susceptible strains of Staph aureus, gram negatives and anaerobes. As with all quinolones, it has high bioavailability after oral administration.    Researchers used NCCLS testing methods to determine the in vitro activities of moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, imipenem, piperacillin-tazobactam, clindamycin and metronidazole against 900 surgical isolates. Moxifloxacin exhibited good to excellent antimicrobial activity against most aerobic (90.8 percent) and anaerobic (97.1 percent) microorganisms. Moxifloxacin not only showed good activity against methicillin susceptible strains of Staph aureus (MIC90 = 0.25 mg/liter) but also exhibited excellent activity against B. fragilis, equaling that of metronidazole (MIC90 = 1.0 mg/liter). Moxifloxacin showed poor activity against MRSA.4    Moxifloxacin also does not require dose adjustment for patients with renal impairment. This is an important feature since so many patients with diabetes present with varying degrees of kidney disease. The dose, regardless of renal function, is 400 mg once daily.

Key Considerations With Tigecycline

   • Tigecycline (Tygacyl™, Wyeth Pharmaceuticals). Tigecycline, a parenteral minocycline derivative, received FDA approval in June for the treatment of cSSSIs and intraabdominal infections. It is a first-in-class glycylcycline antibiotic. Although it does not have a formal indication for DFIs, tigecycline is of interest because it is a broad spectrum drug with activity against MRSA, gram negatives and anaerobes.    In clinical trials, empiric monotherapy with tigecycline provided comparable clinical cure rates in cSSSIs to combination therapy with vancomycin/aztreonam. Empiric monotherapy with tigecycline also provided clinical cure rates comparable with those of imipenem/cilastatin.5    Unfortunately, tigecycline’s potential use as single agent therapy for diabetic foot infections may be offset by its adverse event profile. The most common treatment-emergent adverse events listed in the Manufacturers Prescribing Information were nausea (29.5 percent) and vomiting (19.7 percent).    Although there have been no human trials involving osteomyelitis, animal studies suggest tigecycline may have a role in treating bone infection. After a 28-day course of treatment of experimentally induced osteomyelitis, rabbits receiving tigecycline/oral rifampicin showed a 100 percent infection clearance. Subjects treated with vancomycin/oral rifampicin showed a 90 percent clearance. For the tigecycline group, the bone concentrations of tigecycline in the infected tibia were significantly higher than the non-infected ones. Tigecycline, at least in preliminary studies, shows promise as an effective alternative to vancomycin in the treatment of MRSA osteomyelitis. It remains to be seen if these results will carry over to human subjects.6

Assessing The Potential Of Daptomycin And Dalbavancin

   • Daptomycin (Cubicin®, Cubist Pharmaceuticals). Daptomycin is a novel, parenteral lipopeptide and the first drug in its class in clinical use. It is the only once-daily agent approved for treating MRSA in cSSSIs.    Daptomycin is bactericidal and has activity against resistant gram-positive pathogens including methicillin resistant and vancomycin resistant (VRSA) strains of S. aureus.7    Lipsky and Stoutenburgh conducted a study comparing the effectiveness of daptomycin against semi-synthetic penicillins or vancomycin. The authors concluded that among 103 clinically evaluable patients, the clinical and microbiological efficacy and safety of daptomycin was not statistically different from comparator antibiotics (66 percent versus 70 percent respectively) for treating infected diabetic foot ulcers caused by gram-positive pathogens.8    Although one should consider daptomycin for treating diabetic foot infections, its lack of gram-negative and anaerobic activity may necessitate combination therapy for moderate and severe diabetic foot infections when these organisms are a concern.    • Dalbavancin (Vicuron Pharmaceuticals/Pfizer). Dalbavancin is a novel, parenteral liopoglycopeptide antibiotic with strong activity against gram-positive organisms including resistant staphylococci (MRSA). Its long half-life allows for once-a-week dosing. Still awaiting FDA new drug approval for the treatment of cSSSIs, dalbavancin should become available in early 2006. As with daptomycin, combination therapy with an agent active against gram-negatives and anaerobes may be necessary in moderate to severe diabetic foot infections.    Telavancin, another antibiotic of the same class, has a similar spectrum of activity but with once daily rather than once weekly dosing.

In Conclusion

   Many other new agents are in the pipeline and will be available in the coming years. Although currently available cephalosporins have no activity against MRSA, one agent under study is ceftobiprole. It is the first of a new class of broad-spectrum cephalosporins with bactericidal activity against gram-positive resistant bacteria including MRSA. Its gram-negative coverage is similar to that of third-generation cephalosporins. Trials are currently ongoing in patients with cSSSIs as well as nosocomial pneumonia.9 Dr. Kosinski is a Professor in the Department of Medicine at the New York College of Podiatric Medicine. He is a member of the Infectious Diseases Society of America. Dr. Joseph is a Consultant in lower extremity infectious diseases and is a Fellow of the Infectious Diseases Society of America. He is an Attending Podiatrist at the Coatesville Veterans Affairs Medical Center in Coatesville, Pa. Dr. Steinberg (pictured) is an Assistant Professor in the Department of Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.
 

References:

1. Goldstein E, Citron DM, Merriam CV, Warren Y, Tyrrell KL, Gesser RM. General microbiology and in vitro susceptibility of anaerobes isolated from complicated skin and skin-structure infections in patients enrolled in a comparative trial of ertapenem versus piperacillin-tazobactam. Clin Infect Dis 2002 Sep 1:35 (Suppl 1):S119-125.
2. Graham DR, Lucasti C, Malafaia O, Nichols RL, Holtom P, Perez NQ, McAdams A, Woods GL, Ceesay TP, Gesser R. Ertapenem once daily versus piperacillin-tazobactam four 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 Jun 1; 34(11):1460-8.
3. Lipsky, et. al. SIDESTEP Study IDSA Poster 3776, 2004.
4. Edmiston CE, Krepel CJ, Seabrook GR, Somberg LR, Nakeeb A, Cambria RA, Towne JB. In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intraabdominal and diabetic foor infections. Antimicrobial Agents and Chemotherapy March 2004 48(3):1012-6.
5. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E, Tigecycline 300 cSSSI Study Group, Tigecycline 305 cSSSI Study Group. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of two double-blind phase three comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005 Sept 1; 41 (Suppl 5):S341-53.
6. Yin LY, Lazzarini L, Li F, Stevens CM, Calhoun JH. Comparative evaluation of tigecycline and vancomycin with and without rifampicin, in the treatment of methicillin resistant Staphylococcus aureus experimental osteomyelitis in a rabbit model. J Antimicrob Chemother 2005 Jun; 55(6):995-1002.
7. Bosso JA. The antimicrobial armamentarium: evaluating current and future treatment options. Pharmacotherapy 2005 Sept; 25(9):55S-62S.
8. 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 Feb 55(2):240-5.
9. Appelbaum PC, Jacobs MR. Recently approved investigational antibiotics for treatment of severe infections caused by Gram-positive bacteria. Curr Opin Microbiol 2005 Oct; 8(5):510-7.