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Tigecycline M Bhattacharya1, A Parakh2, M Narang11 Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi-110 002, India 2 Department of Pediatrics, University College of Medical Sciences and Guru Teg Bahadur Hospital, Shadhara, Delhi-110 095, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.48443
Infection with resistant pathogens can adversely affect clinical, microbiological and economic outcomes. New agents for the treatment of many such serious infections are acutely needed in hospital practice. Tigecycline is a novel glycylcycline antimicrobial for intravenous use. It has an expanded broad-spectrum antibacterial activity including multi-drug resistant pathogens, like methicillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci , multi-drug resistant Streptococcus pneumoniae , extended-spectrum β-lactamase-producing gram-negative bacteria and Acinetobacter baumannii . Tigecycline however is not active against Proteus, Providencia and Pseudomonas species. Its currently approved indications include complicated skin and skin structure infections and complicated intra-abdominal infections. It has also been found to be effective for the treatment of community- as well as hospital-acquired and ventilator-associated pneumonia and bacteremia, sepsis with shock and urinary tract infections. Tigecycline appears to be a valuable treatment option for the management of superbugs, especially where conventional therapy has failed. Keywords: Glycylcycline antibiotics, newer antibiotics, Tigecycline
Antibiotic resistance is a serious problem worldwide, and has increased morbidity, mortality and healthcare costs. With emerging serious infections especially nosocomial, clinicians are running short of antibiotics. There is a need to develop new agents that overcome existing mechanisms of resistance displayed by multidrug-resistant bacteria. Tigecycline (Tygacil, Wyeth) is a new FDA-approved glycylcycline antimicrobial with an expanded microbiological spectrum for intravenous (IV) use. This review aims to summarize its clinical and microbiological efficacy, safety data and explore its potential place in clinical practice and hospital formularies of the future.
Structure Similar to tetracyclines, the glycylcyclines contain a central four-ring carbocyclic skeleton, with a substitution of an N- alkyl-glycylamido group on the D-9 position, [1] which enables a broader spectrum of activity and protects against development of resistance. [2]
Tigecycline is bacteriostatic in vitro. It inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit, but with five times higher affinity than the tetracyclines. [3] It also has post antibiotic effect (PAE) ranging from 2-5 h against gram-negative bacteria to approximately 9 h against S. pneumonia. [4],[5] No cross-resistance has been observed with other antibiotic classes. [6]
Tigecycline has potent antibacterial activity against a broad spectrum of gram-positive, gram-negative and anaerobic organisms. It also has good activity against many multi-drug-resistant pathogens. [7] Gram-positive bacteria : Staphylococcus aureus (both methicillin susceptible and resistant) , Streptococcus spp, Entrococcus faecalis (vancomycin susceptible and resistant), Staphylococcus epidermidis (vancomycin susceptible and resistant), Enterococcus faecium , Listeria monocytogenes . Gram-negative bacteria : Citrobacter freundii, Citrobacter koseri, Klebsiella oxytoca, Klebsiella pneumoniae, Aeromonas hydrophilia, Pasteurella multocida, Serratia marcescens, Enterobacter aerogenes Anaerobic pathogens: Bacteriodes spp, Clostridium perfringes Peptoseptococcus micros . Multi-drug-resistant pathogens: Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), vancomycin-resistant enterococcus (VRE), Acinetobacter baumannii ; Stenotrophomonas maltophilia, penicillin-resistant Streptococcus pneumoniae (PRSP) and tetracycline, aminoglycoside, carbapenem and fluoroquinolone-resistant, extended spectrum β-lactamase-producing and Amp C β- lactamase-producing Enterobacteiaceae . In contrast, minimum inhibitory concentrations (MIC) against Pseudomonas aeruginosa, Proteus mirabilis and B. cepacia are higher. Provisional tigecycline MIC breakpoints of < 2 µg/ml for susceptibility and >8 µg/ml for resistance have been proposed. [8],[9]
Indications and usage Tigecycline is currently indicated for the treatment of complicated skin and skin structure infections (cSSIs) and complicated intra-abdominal infections (cIAI). Dosage and administration The recommended dose is a 100 mg loading followed by 50 mg IV 12-hourly. The duration of therapy is usually 5-14 days. It is available as a 50 mg vial with lyophilized powder (stored at 2° to 8°C) for IV infusion. It is reconstituted with normal saline or 5% dextrose and infused in 100 mL normal saline or ringer lactate (maximum concentration 1 mg/mL) over 30-60 min. Reconstituted solution may be stored at room temperature for up to 24 h and at 2° to 8°C for up to 45 h. [10] Pharmacokinetics Tigecycline exhibits linear pharmacokinetics. Its plasma protein binding ranges from 71-89%. It has a large volume of distribution (500-700L, 7-9 L/kg), indicating extensive tissue distribution. Tigecycline does not undergo extensive metabolism. It works independently of the cytochrome P-450 isoenzyme system and therefore does not affect medications metabolized by these enzymes. Biliary or fecal excretion accounts for 59% of the administered dose, 32% is excreted renally and 22% is excreted unchanged in urine. [10] Contraindications It is contraindicated for use in patients with known hypersensitivity to Tigecycline. [10]
Tigecycline is moderately protein-bound and is not metabolized by the cytochrome P-450 isoenzyme system, explaining its lack of significant drug interactions. Tigecycline when used with warfarin demonstrated an increased C max of 38%. Although this did not result in significant changes in the International Normalized Ratio (INR), patients receiving warfarin should have regular monitoring of INR. [10] As minocycline reduces insulin requirements in diabetics and efficacy of oral contraceptives, and increases blood urea nitrogen levels in patients with renal impairment on diuretics, Tigecycline should also be used cautiously in patients taking these drugs simultaneously. [7]
Several double-blind randomized controlled trials (RCT) have evaluated the efficacy and safety of Tigecycline. The results of these trials are summarized in [Table 1]. Complicated skin and skin structure infections (cSSI). [11],[12],[13],[14] Tigecycline was compared with vancomycin-aztreonam combination in adults with cSSSI (defined by polymicrobial etiology, need for surgical intervention, suspected or confirmed deep soft tissue involvement and/or comorbidities such as diabetes mellitus, peripheral vascular disease or peripheral neuropathy.). The primary end-point was clinical response at the test-of-cure (TOC) visit (12-92 days after end of treatment). Clinical cure rates were equivalent between two treatment groups. Tigecycline was also microbiologically effective against methicillin-resistant S. aureus . Overall, eradication rate for all MRSA stains were reported in 78.1% and 75.8% of Tigecycline and Vancomycin-Azteonam treated patients, respectively. Based on the results Tigecycline was non-inferior to vancomycin-aztreonam combination in the treatment of cSSIs. Complicated intra-abdominal infections (cIAI). [15],[16] Tigecycline has been compared with imipenem/cilastatin in adult patients with cIAI (defined as those requiring a surgical procedure for an intra-abdominal abscess or peritonitis associated with an abscess or perforation) for 5-14 days. The primary end-point was clinical cure at the TOC visit (14-35 days after therapy). The most frequent diagnosis was complicated appendicitis. Clinical cure rates at TOC visit (14-35 days after first dose of the studt drug) were 80.6% for Tigecycline versus 82.4% for imipenem/cilastatin. The authors concluded that Tigecycline was non-inferior to imipenem/cilastatin. Community-acquired respiratory tract infections and nosocomial pneumonia [including ventilator-associated pneumonia (VAP)]. Fritsche et al. , [17] evaluated Tigecycline spectrum and potency against a global collection of pathogens recovered from community-acquired respiratory infections (7580 strains) or from hospitalized patients with pneumonia (3183 strains). Among community-acquired infections, the pathogens were Haemophilus influenzae (52.9%; 21% ampicillin-resistant), S. pneumoniae (39.2%; 23.7% penicillin-nonsusceptible), and Moraxella More Details catarrhalis (7.9%). Tigecycline displayed potent activity by inhibiting 100% of the three species at clinically achievable concentrations. The 10 most common pathogens producing 94.3% of nosocomial pneumonias were S. aureus (48.5% of strains; 49.4% oxacillin-resistant), Pseudomonas aeruginosa (15.6%), Klebsiella spp. (5.6%), S. pneumoniae (4.6%), Acinetobacter spp. (4.5%), Enterobacter spp. (4.0%), Escherichia More Details coli (3.8%), Serratia marcescens (2.5%), Enterococcus spp. (2.3%), Stenotrophomonas maltophilia  , and beta-hemolytic streptococci (1.1%). Tigecycline inhibited >96% of these pathogens (exception, P. aeruginosa ). In one study, 25 patients with VAP, bacteremia or VAP with bacteremia were treated with either Tigecycline alone or in combination with other antibiotics. Tigecycline was effective in most of these patients. [18] In a Phase III RCT Tigecycline was found to be non-inferior to levofloxacin in the treatment of community-acquired pneumonia. [19] Further clinical studies should evaluate the role of Tigecycline in the treatment of severe respiratory tract infections, both of nosocomial and community origin.Severe sepsis with septic shock. Tigecycline resulted in markedly lowered mortality in patients with severe sepsis with shock in surgical intensive care unit. [20] Urinary tract infections. Tigecycline has been found to be effective in eradicating infection in recurrent urosepsis. [21] Tigecycline was approved by FDA for use in cSSI and cIAI on 28 January 2005 but the agent has shown promise in other infections as well. Tigecycline has also been approved by the European Commission and the Drug Controller General of India. The question now is how to deploy Tigecycline. The most attractive application seems to be in surgical wound infections, particularly following abdominal surgery, where the likely pathogens include MRSA Enterobacteriaceae, streptococci and anaerobes. No other agent covers this spectrum alone. Wider empirical use in cSSSI also seems attractive, especially in settings where MRSA and gram-negative pathogens are likely. There is less obvious immediate need in those intra-abdominal infections that are likely to involve only the gut flora itself and not MRSA, where β-lactamase inhibitor combinations, cephalosporins/metronidazole or carbapenem treatments remain effective in the majority of cases. This agent should also be evaluated in other therapeutic indications such as bacterial peritonitis in renal dialysis, diabetic foot ulcer infections, osteomyelitis, prosthetic joint or tissue infections and catheter or line-related bacteremia. All these infections are often due to multi-resistant organism/s and often require parenteral antimicrobial therapy. It should be assessed in combination with other agents.
Hepatic insufficiency No dosage adjustment is warranted in mild to moderate hepatic impairment (Child Pugh A and B). However, in severe hepatic impairment (Child Pugh C), the initial dose should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 h. [7] Renal insufficiency No dosage adjustment is necessary. [7] Carcinogenesis, mutagenesis, impairment of fertility Tigecycline is a pregnancy Category D antimicrobial. It should be avoided unless the benefit clearly outweighs the risk to the fetus. Since its secretion in breast milk is not known, women should withhold breastfeeding during treatment. [10] Pediatrics Since the safety and efficacy in children less than 18 years have not been established it is not recommended below this age. [10] Geriatric No dosage adjustment is necessary. [10]
The most commonly reported adverse effects are nausea (28.4%), vomiting (19.4%), diarrhea (11.6%), local reaction at IV site (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%) and headache (5.6%). [7]
Tigecycline appears to be a promising new antimicrobial with favorable in vitro activity against a wide variety of organisms, including multi-drug-resistant pathogens barring Proteus, Providencia and Pseudomonas species. It can be used as monotherapy in polymicrobial infections. Its present indications are cSSSIs and cIAIs, where it is non-inferior to the comparators. Other upcoming indications are hospital-acquired and ventilator-associated pneumonia, severe sepsis with shock and urinary tract infection.
[Table 1]
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