Ertapenem effective for diabetic foot infections
SIDESTEP trial shows it's as powerful as piperacillin/tazobactam
Foot wounds are a major cause of morbidity for patients with diabetes. With their peripheral nerves damaged, diabetics are unusually prone to develop foot injuries. Far worse, these wounds are more likely to get infected, as the diabetic's immune and circulatory systems-both necessary for timely and appropriate wound healing-are often compromised.
Diabetic foot infections account for the bulk of lower-extremity amputations in developing countries and most of diabetes-related hospital admissions in the developed ones. The seriousness of the disease warrants a combination of treatments: proper wound care, timely surgical intervention, and appropriate antibiotic coverage. The choice of chemotherapeutic agent is particularly challenging: it requires an antibiotic that addresses the polymicrobial nature of the infection but evades the threat of multidrug resistance with long-term broad-spectrum-antibiotic use.
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The results of the ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP) trial offer clinicians an alternative to conventionally used drugs for diabetic foot infections. One of the few prospective, randomized, controlled, and double-blind studies comparing antibiotic efficacy among diabetic patients with foot infections, SIDESTEP demonstrated that ertapanem, a carbapenem, is a safe and equally effective alternative to the conventionally used piperacillin/tazobactam combination in the treatment of moderate to severe diabetic foot infections.
"Clinical and microbiological outcomes for patients treated with ertapenem were equivalent to those for patients treated with piperacillin/tazobactam, suggesting that this once-daily antibiotic should be considered for parenteral therapy of diabetic foot infections, when deemed appropriate," the authors led by Dr. Benjamin Lipsky of the University of Washington School of Medicine wrote in The Lancet.
In the study, 586 adults with diabetes and moderate to severe foot infection were randomly assigned to receive either of the two drugs parenterally. After five days of intravenous therapy, all patients were clinically assessed for improvement or resolution of pretherapy signs and symptoms: purulent drainage, lymphangitis, fever, pain, edema, and erythema, among others. Oral amoxicillin/clavulanic acid may then be given for up to 23 days, depending on the clinical status of the patient. Patients were again assessed for improvement after discontinuation of the oral medications, and 10 days after the last intake of either oral or intravenous antibiotic (follow-up assessment).
After cessation of parenteral treament, 94 percent of patients on ertapenem who were clinically evaluable had favorable clinical responses. On the other hand, 92 percent of the patients on piperacillin/tazobactam showed improvement. On follow-up assessment, 87 percent of patients on ertapenem and 83 of those on piperacillin/tazobactam showed favorable clinical responses. In short, both parenteral regimens were equally clinically effective.
The infections were polymicrobial in 47 percent of the evaluable patients, with nine percent having both Gram-positive and Gram-negative aerobic organisms. The most commonly isolated pathogen was Staphylococcus aureus identified in 44 percent of patients treated with ertapenem and 40 percent of those given piperacillin/tazobactam.
The authors also noted "no clinically important differences in the clinical response rates" between the two groups for patients with Gram-positive, Gram-negative, or anaerobic pathogens. The clinical response rates for patients with methicillin-resistant S. aureus (MRSA) were 77.8 percent in the ertapenem group and 66.7 percent in the piperacillin/tazobactam group. The response rates were also similar in patients with isolates of Enterococcus (86.8 percent for ertapenem v. 80.8 percent for piperacillin/tazobactam) and P. aeruginosa (83.3 v. 70 percent).
Both drugs were also well tolerated. The more common adverse effects of ertapenem were diarrhea (eight percent v. 14 percent for piperacillin/tazobactam), nausea (19 v. seven percent), and headache (four v. six percent). "Our findings concur with those of previous trials of the treatment of moderate to severe diabetic foot infections, and show that ertapenem is as safe and effective as piperacillin/tazobactam," the authors said.
Ertapenem is active against the more common pathogens seen in diabetic patients with foot infections-methicillin-susceptible S. aureus (MSSA), streptococci, enterobacteriaceae, and anaerobes. But, unlike the aminopenicillin/B-lactamase inhibitor piperacillin/tazobactam, it is inactive against most enterococci and pseudomonas. The SIDESTEP study, along with other recent trials on diabetic foot infections, however, suggests that enterococci and pseudomonas are mere colonizers or contaminants: not clinically important sources of infection. This is supported by the fact that significant clinical improvements-whether they are receiving ertapenem or piperacillin/tazobactam-were noted in patients with these organisms in their isolates.
The authors noted that ertapenem's once-daily dosing is an advantage over piperacillin/tazobactam, which is given every six hours. "It [is] a convenient alternative in the hospital setting and especially useful in the outpatient setting," they said.. M
New drugs needed to fight resistant bugs
Infectious-diseases specialist cites power of tigecycline
Saying the medical community must find ways to "reduce the pressure on hospital bacterial ecology," infectious-diseases specialist Manolito Lao Chua cited the need "for therapeutic alternatives to the broad-spectrum cephalosporins, fluoroquinolones, carbapenem, and beta-lactamase-inhibitor combination that we have."
The need, he said, arises from the growing resistance by pathogenic bacteria to the current antimicrobial regimens, a concern that has prompted the Infectious Diseases Society of America a few years ago to call for raising awareness on the problem.
Speaking in a recent symposium organized by the Philippine Society of Microbiology and Infectious Diseases, Chua noted that from 2002 to 2003, the National Nosocomial Infections Surveillance Systems Report showed a significant increase in the resistance rates of pathogens isolated from patients with nosocomial infection in the intensive-care setting, notably a 47-percent rise in the resistance rate of K. pneumoniae to third-generation cephalosporins. Similar dismal patterns were seen in the SENTRY antimicrobial surveillance program in the Asia-Pacific region. A 1999 report showed a high prevalence of oxacillin-resistant S. aureus in skin, soft-tissue, respiratory-tract, and urine isolates among hospitalized patients.
"In the Philippines, we have reported around five to six percent of these cases of ESßL (extended-spectrum beta-lactamase)-producing E. coli. With regard to Klebsiella, the Philippines has been noted to be reporting more than 20 percent, [consistent] with the studies that have been done at the Philippine General Hospital and Makati Medical Center," Chua said.
Chua said "the introduction of the first in a new class of broad-spectrum antibiotics, the family of the glycylcyclines, represented by [the] prototype drug tigecycline" offers hope of addressing this "medical crisis."
Tigecycline (Tygacil) resembles tetracycline in molecular structure. What sets it apart is the addition of an N,N,-dimethylclyclyamido group at the D-9 position of the minocycline molecule-a moiety that gives tigecycline its unique properties. Like its older relative, tigecyline blocks the amino-acid-carrying tRNA from binding to the 30S subunit of the bacterial ribosome, prevents elongation of the peptide chain, and inhibits bacterial growth. The modified molecule, however, binds five times stronger to its target than tetracycline-and this accounts for its broader spectrum of antibacterial action in vitro and its "avoidance of tetracyline-resistant mechanisms."
Chua said this enhanced activity or binding could be responsible for tigecycline's ability to overcome resistance.
Tigecycline possesses in vitro activity against Gram-positive, Gram-negative, and anaerobic organisms. More importantly, difficult-to-treat Gram-positive and Gram-negative bacteria are also susceptible. Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) are susceptible, as are the methicillin-susceptible S. aureus and S. agalactiae. The drug's in vitro activity against MRSA is comparable to that of linezolid, vancomycin, and the other minocyclines. The minocylines, however, are weak against E. faecium and E. faecalis (VRE); and vancomycin is completely helpless. Only linezolid equals tigecycline's performance against VRE.
Tigecycline also boasts of excellent Gram-negative coverage in vitro. Explained Chua: "This is in contrast with linezolid and vancomycin, [which have] limited spectrum of activity ... to Gram-positives. This time, in addition to MRSA, tigecycline can actually cover most … Gram-negative organisms with the exception of Pseudomonas. It has very good activity against E. coli, Klebsiella, and Enterobacter ... even organisms like Serratia ... and Acinetobacter baumannii."
The ESßL phenotypes of K. pneumoniae and E. coli, Acinetobacter spp., and Stenotrophomonas maltophilia are also susceptible to tigecycline. Tigecycline also targets anaerobic organisms such as Bacteroides and Clostridium and atypical pathogens.
The United States Food and Drug Administration has approved tigecycline for use in complicated skin and soft-tissue infections (cSSTI) and complicated intraabdominal infections (cIAI). At present, tigecycline is being given twice a day (100 mg loading dose followed by 50 mg IV every 12 hours). But this may soon change. Assumed to be a time-dependent antibiotic early in its development, tigecycline later proved to be a concentration-dependent antibiotic and a once-daily dosing is currently being explored by researchers.
Two double-blind, randomized, multicenter trials compared the efficacy of tigecycline with standard regimens for cSSTI and cIAI. Tigecycline was as effective as a vancomycin and aztreonam combination in the treatment of soft-tissue infections, abscesses, infected ulcers, and burns, among others. The microbiological response to tigecycline and vancomycin-aztreonam was also comparable. Tigecyline was also as effective as the combination of imipinem and cilastatin against intra-abdominal infections. M
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