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Gary E Stein
Professor of Medicine & Pharmacology
Department of Medicine
Michigan State University
East Lansing, MI
Complicated intra-abdominal infections (cIAI) include a group of conditions that require operative intervention or percutaneous drainage.(1) These infections typically involve a mixture of aerobic and anaerobic intestinal flora and are associated with substantial morbidity and mortality.(2) The microbiology of cIAI varies according to the primary process site and whether the infection is community- or hospital-acquired. Enterobacteriaceae are the most frequently isolated organisms, with E coli being most common.
However, other bacteria are often present in varying combinations, including Klebsiella species, Enterobacter species, Streptococcus species and anaerobes such as Bacteroides species, Peptostreptococcus species and Clostridium species.(3) Various therapeutic regimens have been used to treat cIAI, including beta-lactams alone or in combination with a beta-lactamase inhibitor or another antibiotic, an aminoglycoside with clindamycin, or a fluoroquinolone alone or with metronidazole.(4) None of these therapeutic regimens has been consistently demonstrated to be superior or inferior. Consequently, patient care issues such as safety and cost have become important factors for antimicrobial selection.
Tigecycline in intra-abdominal infections
Tigecycline (Tygacil) is the first glycylcycline antibiotic approved for clinical use.(5) This derivative of minocycline has broad-spectrum activity against a wide variety of aerobic Gram-positive and Gram-negative pathogens as well as an anaerobic bacteria. The addition of a butylglycylamido side-chain to minocycline has enabled this drug to overcome major mechanisms of tetracycline resistance: tetracycline-specific efflux pumps and ribosomal protection.
Tigecycline has in-vitro activity against many common clinical pathogens associated with cIAI such as gram-positive cocci (eg, Streptococcus species and Enterococcus species), Gram-negative bacilli (eg, E coli and Klebsiella species), and anaerobic bacteria (Bacteroides species, Clostridium species and Peptostreptococcus species) (see Table 1).(6) Resistant isolates usually contain overexpressed multidrug efflux pump systems.(7) Tigecycline is a bacteriostatic antibiotic that blocks the entry of tRNA molecules to the 30S ribosomal subunit, thus preventing protein synthesis, and generally exhibits neither synergy nor antagonism with other antimicrobials.
Tigecycline is poorly absorbed after oral administration. Following intravenous administration, the drug exhibits linear pharmacokinetics. Following a loading dose of 100mg, the maximum concentration in healthy volunteers was 0.9ml after a one-hour infusion. Multiple maintenance doses of 50mg every 12 hours produce a maximum concentration of 0.6ml and an area under the curve of 3g.h/ml.Tigecycline has a large volume of distribution and high tissue penetration, especially into lung and bowel tissue.(8) Its major route of excretion is through the faeces via biliary excretion, and less than 20% is excreted unchanged in urine. The elimination half-life of tigecycline is approximately 40 hours, which is not altered by renal insufficiency or moderate liver impairment.(8)
Tigecycline has been approved by the US Food & Drug Administration for complicated intra-abdominal infections. This approval was based upon two randomised, double-blind studies in patients with community-acquired infections.(9) In both trials, tigecycline (100mg, followed by 50mg every 12 hours) was compared with imipenem/cilastatin (500mg every six hours). Treatment was for 5-14 days, and clinical response was evaluated at 12-42 days after therapy. The clinically evaluable population contained 1,382 patients (585 received tigecycline and 607 received imipenem/cilastatin), of whom 1,262 had a pretherapy isolate recovered from their infection site.
Complicated appendicitis (50%) was the most common infection diagnosis, followed by complicated cholecystitis (14%). Severely ill patients, such as those with malignancy, APACHE II scores >30, gangrenous cholecystitis or necrotising pancreatitis, were excluded from this study. The severity of illness was similar in each treatment group (APACHE II score is approximately 6).Overall, clinical cure rates were similar (86%) in the two treatment groups. Bacterial eradication rates were also similar between groups. For E coli, the most commonly isolated pathogen, eradication rates were 86% for tigecycline and 87% for imipenem/cilastatin. Twelve (80%) of 15 patients with extended-spectrum Î²-lactamase (ESBL)-producing E coli or Klebsiella pneumoniae achieved bacterial eradication after receiving tigecycline. Two patients had isolates (K pneumoniae and M morganii) that were initially susceptible to tigecycline but were subsequently found to be resistant (MIC value for each, 8Î¼g/ml) following therapy; these patients experienced clinical failure. Eradication rates for anaerobic bacteria were similar to those for aerobic organisms. For example, tigecycline’s eradication rates for isolates of B fragilis and Clostridium perfringens were 78% and 95%, respectively.
A similar success rate against these anaerobic pathogens was observed in patients who received imipenem/cilastatin. Forty patients who received tigecycline had concomitant bacteraemia, and 33 (82%) of these patients experienced a clinical cure. Treatment failures with tigecycline were not associated with resistant isolates, and only one patient with E coli bacteraemia (MIC 0.5Î¼g/ml)had a positive blood culture result after initiation of therapy. The clinical cure rate was 80% (40 of 50 patients) for patients with concomitant bacteraemia who received imipenem/cilastatin.
Clinically significant organ toxicity has rarely been observed with tigecycline. In phase III trials, few clinically important or unexpected changes in haematological or serum chemistry test results, vital signs or electrocardiogram data were associated with ï¿½tigecycline treatment.(10) Of note, prothrombin times were prolonged in some patients. Because of ï¿½tigecycline’s similarity to minocycline, potential adverse effects may include hepatitis, pancreatitis, vertigo, hearing loss and lupus erythematous-like syndrome.
The most frequently reported adverse effects associated with the use of tigecycline are nausea and vomiting.(10) These effects are dose-limiting and not diminished by slowing the rate of drug infusion. Subjects who were fed or received antiemetics at the time of administration had improved tolerability of tigecycline. In phase III clinical trials, nausea occurred in 30% of patients, but the majority of cases were mild in nature (patients were able to ingest food and water). The nausea usually occurred in the first two days of treatment and was transient in most patients.
The overall discontinuation rate during tigecycline treatment was 5%, which was similar to the comparative treatment antibiotics. Diarrhoea was also common in these clinical trials, but no tigecycline-treated patient tested positive for Clostridium difficile toxin or developed C difficile associated diarrhoea. Skin reactions that occur with tetracyclines may also occur with tigecycline, so anyone reporting an allergy to a tetracycline should be considered hypersensitive to tigecycline. Tigecycline has a pregnancy category D label and should not be given to pregnant women. Tigecycline is not a substrate, inhibitor or inducer of common cytochrome P450 enzymes and is not highly (about 70%) protein bound.(5) This suggests that pharmaco-kinetic drug interactions will be uncommon with tigecycline, although concomitant use with warfarin can decrease the clearance of its isomers.
Tigecycline is a new broad-spectrum antimicrobial that will be useful as empirical therapy for polymicrobial infections, especially in cases where deep tissue penetration is needed or where multidrug-resistant pathogens are suspected. Use in patients with Î²-lactam hypersensitivity, renal failure or ï¿½receiving numerous medications are also important considerations for tigecycline use.(11)