Tigecycline: First-in-Its-Class, Broad-Spectrum Antibiotic a Potent Tool against Resistant Bacteria

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Article

November 8, 2005

Internal Medicine World Report

November 2005

Volume

Tigecycline: First-in-Its-Class, Broad-Spectrum Antibiotic a Potent Tool against Resistant Bacteria

Tigecycline (Tygacil) is the first in a new class of antibiotics called glycylcyclines that has shown activity against a wide range of pathogens and circumvents 2 of the main resistance mechanisms against antibiotics.

It avoids the efflux pumps, which quickly purge the antibiotic out of the bacteria and are responsible for most of the acquired resistance to tetracyclines and minocycline in Enterobacterand Acinetobacter spp and to tetracycline in staphylococci.

It binds more avidly to the 30S bacterial ribosomes modified by the Tet(M) protein, which occurs in gram-positive cocci and Neisseria spp and blocks all available tetracyclines from impeding bacterial protein synthesis.

In addition to restoring “classical tetracycline sensitivity to these bacteria, tigecycline demonstrates activity against a whole host of bacteria that are currently resistant to many different types of antibiotics,” explains Evan Loh, MD, vice president at Wyeth Pharmaceuticals and the lead physician who developed tigecycline. “We created a class of compounds that has a spectrum of activity that proved to be broader [in vitro] than any other antibiotic on the market today.”

David Weber, MD, of the University of North Carolina at Chapel Hill, agrees that tigecycline has a broad reach, covering aerobic and anaerobic gram-positive bacteria as well as many gram-negative ones. “That’s the good news. The bad news is that it does not work against Pseudomonas aeruginosa.” In addition, the agent is only available for intravenous administration, and gastrointestinal side effects (eg, nausea, vomiting) are a concern with the glycylcyclines but, he adds, “they’re not life-threatening.”

Antibiotic Resistance

The latest data from the National Nosocomial Infections Surveillance (Am J Infect Control.2004;32:470-485) show that 60% of Staphylococcus aureus isolates are now resistant to methicillin, oxacillin, or nafcillin (Figure). Of note, the number of Klebsiella pneumoniaeisolates that are resistant to third-generation cephalosporins climbed by almost 50% between 2002 and 2003.

S aureus is the responsible pathogen in approximately 30% to 40% of complicated skin and skin structure infections (J Antimicrob Chemother.1999;44:19-23). From 70% to 90% of S aureus isolates are resistant to penicillins and aminopenicillins.

Common bacteria associated with community-acquired complicated intra-abdominal infections include Escherichia coli, enterococci, and viridans streptococci, along with anaerobes such as Bacteroides fragilisand related species (J Antimicrob Chemother. 2004;53(suppl S2):ii29-ii36). Nosocomial infections tend to be caused by more drug-resistant flora, such as P aeruginosa, Enterobacter spp, Proteus spp, methicillin-resistant S aureus (MRSA), enterococci, and Candidaspp (Clin Infect Dis. 2003;37:997-1005).

Dr Loh notes that MRSA is now common in community-acquired infections as well as in nosocomial ones. He points to a Sports Illustrated article (February 28, 2005) that described how MRSA had infiltrated several professional, college, and high school football teams. One high school football player died from an MRSA deep skin and muscle infection.

“We have a variety of drugs that can work for MRSA—classic and gold standards such as vancomycin [Vancocin, Vancoled] and other drugs such as daptomycin [Cubicin], which is effective against vancomycin-resistant enterococci—both of which are narrow-spectrum gram-positive drugs,” says Dr Weber. “They’re very good drugs…[but] tigecycline is the first broad-spectrum drug that covers resistant gram-positive pathogens as well as giving you gram-negative coverage.”

Tigecycline: Efficacy

A recent study analyzed 2 double-blind, phase 3 studies that compared tigecycline with the combination of vancomycin and aztreonam (Azactam) in a total of 1116 patients with skin and skin structure infections (Clin Infect Dis.2005;41(suppl 5):S341-S353). Tigecycline was found to be as effective as the vancomycin-aztreonam dual-antibiotic combination, with cure rates of 86.5% versus 88.6% among the 833 patients who were clinically evaluable. Adverse events were also similar; the tigecycline group had increased nausea and vomiting, and the vancomycin-aztreonam group had increased rash and elevated hepatic aminotransferase levels.

A second study analyzed 2 double-blind, phase 3 trials that compared tigecycline with the combination agent imipenem-cilastatin (Primaxin) in a total of 1642 adults with complicated intra-abdominal infections (Clin Infect Dis.2005;41(suppl 5):S354-367). Again, clinical cure rates were comparable with tigecycline monotherapy and combination therapy (86.1% vs 86.2%). For adverse events, respective figures were 24.4% vs 19% for nausea, 19.2% vs 14.3% for vomiting, and 13.8% vs 13.2% for diarrhea.

Indications, Dosage, Side Effects

Tigecycline was approved by the FDA in June 2005 for the treatment of complicated skin and skin structure infections and complicated intra-abdominal infections in adults caused by a wide range of bacteria, including MRSA (Table). If culture and susceptibility information is not available, it may be used for empiric therapy depending on local epidemiology and susceptibility patterns.

Tigecycline should not be used by patients with a known hypersensitivity to it or to tetracyclines. It should not be used during pregnancy due to the risk of fetal harm (Pregnancy Category D). Use during tooth development can cause permanent discoloration of the teeth. It should be used with caution in patients suspected of having Pseudomembranous colitis or intestinal perforation.

Tigecycline is administered intravenously at an initial dose of 100 mg, followed by 50 mg every 12 hours. The infusion should be given over approximately 30 to 60 minutes. Duration of therapy can range from 5 to 14 days, depending on the severity of the infection and condition of the patient. In patients with severe hepatic impairment (creatinine clearance <30 mL/min), after the initial 100-mg dose, the maintenance dosage should be reduced to 25 mg every 12 hours. Such patients should be monitored closely.

The most common side effects reported in clinical trials are nausea (30%), vomiting (20%), and diarrhea (13%). Side effects occurring in fewer than 10% of patients include local reactions, infection, fever, abdominal pain, and thrombocythemia.

How to Avoid Resistance

Although tigecycline is not plagued with the familiar cross-reactivity resistance, some bacterial strains appear to have intrinsic resistance or reduced susceptibility to tigecycline.

Nonspecific multidrug efflux pump-related resistance has been identified in P aeruginosastrains that prompted investigators to conclude that narrower-spectrum tetracyclines (eg, doxycycline and minocycline) may be better choices for treatment. The same mechanism has been implicated in decreased susceptibility among enteric gram-negative bacteria, including Proteus mirabilis, Morganella morganii, and strains of E coliand Klebsiella pneumoniae. An efflux-mediated resistance was also identified in tigecycline-resistant laboratory mutants of S aureus. However, no resistant strains of S aureus or any other gram-positive organism have yet to be found in nature.

Physicians can follow these suggestions to avoid new resistance:

·Don’t prescribe antibiotics when they are not needed

·Always get cultures before starting antibiotics

·Base empiric antibiotic therapy on what needs to be covered, patient allergies, the flora in the hospital, and hospital and community resistance patterns

·Remember that rates of resistance for gram-positive and gram-negative organisms continue to grow in the United States and worldwide, in the community and hospital settings

·Choose an antibiotic with broad coverage to minimize the chances of missing a potentially causative pathogen

·Once culture and sensitivity results are back (usually >48 hours after initial culture sampling), focus the antibiotic choice on the causative pathogen(s) isolated.

“When it comes to antibiotics, every therapy is basically empiric,” Dr Loh points out. “Because you will not be able to identify the responsible pathogens for between 48 and 72 hours, you treat based on probability assessment in your own mind, based on your clinical learning and experience.”

While some physicians may worry only about only gram-positive pathogens when someone presents with a skin infection, Dr Loh says “we’re seeing a lot more diabetics coming in who often have gram-negative pathogens as part of their skin flora.” He feels that tigecycline, with its coverage of both gram-positive (including MRSA) and —negative organisms, can eliminate the need for 2 or 3 different types of antibiotics, thus lessening the risk of an adverse reaction.

“There are good data out there showing that if you make the wrong choice initially, patient outcomes are worse,” says Dr Loh. “The infections become more difficult to treat, leading to longer periods of hospitalization. Other complications can develop, such as deeper tissue infections that require surgical intervention and, of course, the worst outcome, death from these complicated infections.”

Table. Indications for tigecycline treatment

Complicated skin and skin structure infections caused by:

Bacteroides fragilis

Enterococcus faecalis(vancomycin-susceptible isolates only)

Escherichia coli

Staphylococcus aureus(methicillin-susceptible and -resistant isolates)

Streptococcus agalactiae

Streptococcus anginosusgroup (including S anginosus, Streptococcus intermedius, and

Streptococcus constellatus)

Streptococcus pyogenes

Complicated intra-abdominal infections caused by:

B fragilis