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PubMed2005

In vitro activity of tigecycline against 6792 Gram-negative and Gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004).

Tigecycline, a new glycylcycline antibiotic, has shown promising in vitro activity against many common pathogens, including multidrug-resistant strains. To determine the activity of tigecycline against a broad range of pathogens from diverse populations and geographic areas, the Tigecycline Evaluation and Surveillance Trial (TEST Program) commenced in 2003. This study evaluated the activity of tigecycline and commonly used antimicrobials against 6792 clinical isolates from 40 study centers in 11 countries. Tigecycline was the most active agent tested against Gram-positive facultative species including multidrug-resistant strains. MIC90 results (microg/mL) for tigecycline against Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pneumoniae were 0.12, 0.12, 0.25, and 0.25 microg/mL, respectively. Tigecycline was active against Enterobacteriaceae with an MIC90 of 1 microg/mL. Haemophilus influenzae was very susceptible to tigecycline with an MIC90 of only 0.25 microg/mL. Pseudomonas aeruginosa was the least susceptible organism tested against tigecycline. Tigecycline appears to be a promising new glycylcycline agent for the treatment of many types of pathogens with varying resistance phenotypes.

Anti-Bacterial Agents↗

PubMed2005

In vitro activity of tigecycline against 3989 Gram-negative and Gram-positive clinical isolates from the United States Tigecycline Evaluation and Surveillance Trial (TEST Program; 2004).

The Tigecycline Evaluation and Surveillance Trial (TEST Program) determined the in vitro activity of tigecycline over a large population of organisms from geographically diverse sites. Tigecycline was compared to amikacin, ampicillin, amoxicillin/clavulanic acid, imipenem, cefepime, ceftazidime, ceftriaxone, levofloxacin, minocycline, piperacillin/tazobactam, linezolid, penicillin, and vancomycin against 3989 commonly encountered clinical Gram-negative and Gram-positive pathogens collected from sites in the United States during 2004. The tigecycline activity was equivalent to imipenem against Enterobacteriaceae. Tigecycline inhibited extended-spectrum beta-lactamase and AmpC phenotypes at MIC90 values (minimum inhibitory concentration) of < or =2 microg/mL. In vitro results for tigecycline were similar to other broad-spectrum antimicrobial agents against nonfermenters with MIC90 results of 2 microg/mL against Acinetobacter spp. and >16 microg/mL against Pseudomonas aeruginosa. Tigecycline demonstrated potent activity against Staphylococcus aureus (MIC90, 0.25 microg/mL) and enterococci (MIC90, 0.12 microg/mL) regardless of methicillin or vancomycin susceptibility. Tigecycline MIC values were unaffected by penicillin nonsusceptibility and beta-lactamase production among fastidious respiratory pathogens (Streptococcus pneumoniae [MIC90, 0.5 microg/mL] and Haemophilus influenzae [MIC90, 0.25 microg/mL]). Tigecycline offers excellent activity against most of the commonly encountered nosocomial and community-acquired bacterial pathogens.

Anti-Bacterial Agents↗

PubMed2006

Tigecycline: a glycylcycline antimicrobial agent.

BACKGROUND: Tigecycline, the first glycylcycline to be approved by the US Food and Drug Administration, is a structural analogue of minocycline that was designed to avoid tetracycline resistance mediated by ribosomal protection and drug efflux. It is indicated for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections and is available for intravenous administration only. OBJECTIVE: This article summarizes the in vitro and in vivo activities and pharmacologic and pharmacokinetic properties of tigecycline, and reviews its clinical efficacy and tolerability profile. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2006), Iowa Drug Information Service (1966-April 2006), and International Pharmaceutical Abstracts (1970-April 2006) using the terms tigecycline, GAR-936, and glycylcycline. Also consulted were abstracts and posters from meetings of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2006) and documents provided for formulary consideration by the US manufacturer of tigecycline. RESULTS: Like the tetracyclines, tigecycline binds to the 30S subunit of bacterial ribosomes and inhibits protein synthesis by preventing the incorporation of amino acid residues into elongating peptide chains. In vitro, tigecycline exhibits activity against a wide range of clinically significant gram-positive and gram-negative bacteria, including multidrug-resistant strains (eg, oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae), and anaerobes (eg, Bacteroides spp). In pharmacokinetic studies in human adults, tigecycline had a large Vd (7-9 L/kg), was moderately bound to plasma protein (71%-89%), had an elimination t(1/2) of 42.4 hours, and was eliminated primarily by biliary/fecal (59%) and renal (33%) excretion. Dose adjustment did not appear to be necessary based on age, sex, renal function, or mild to moderate hepatic impairment (Child-Pugh class A-B). In patients with severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced by 50%. In 4 Phase III clinical trials in patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, tigecycline was reported to be noninferior to its comparators (vancomycin + aztreonam in 2 studies and imipenem/cilastatin in 2 studies), with clinical cure rates among clinically evaluable patients of >80% (P < 0.001 for noninferiority). The most frequently reported (> or =5 %) adverse events with tigecycline were nausea (28.5%), vomiting (19.4%), diarrhea (11.6%), local IV-site reaction (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%), and headache (5.6%). The recommended dosage of tigecycline is 100 mg IV given as a loading dose, followed by 50 mg IV g12h for 5 to 14 days. CONCLUSIONS: In clinical trials, tigecycline was effective for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. With the exception of gastrointestinal adverse events, tigecycline was generally well tolerated. With a broad spectrum of activity that includes multidrug-resistant gram-positive and gram-negative pathogens, tigecycline may be useful in the treatment of conditions caused by these pathogens.

Animals↗

PubMed2004

Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients.

BACKGROUND: Tigecycline is a broad-spectrum glycylcycline antibiotic being investigated for the treatment of serious infections in hospitalized patients. Tigecycline has been shown to be efficacious against serious infections in animals, and preliminary studies in healthy adults have shown that tigecycline has an acceptable tolerability profile. OBJECTIVE: This study compared the clinical and microbiological efficacy, pharmacokinetic properties, and tolerability of 2 doses of tigecycline in hospitalized patients with a complicated skin and skin-structure infection (cSSSI). METHODS: This Phase II, randomized, open-label study was conducted between September 1999 and March 2001 at 14 investigative centers across the United States. Patients were randomized to receive tigecycline 25 or 50 mg IV q12h for 7 to 14 days. The primary efficacy end point was the clinically observed cure rate among clinically evaluable (CE) patients at the test-of-cure visit. Secondary end points were the clinical cure rate at the end of treatment and bacteriologic response in microbiologically evaluable (ME) patients. Also, in vitro tests of susceptibility to tigecycline were performed for selected pathogens known to cause skin infections, including methicillin-resistant and methicillin-susceptible Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Enterococcus faecium. Tolerability assessments also were conducted. RESULTS: A total of 160 patients received > or =1 dose of tigecycline; 109 patients were CE, and 91 were ME. The majority of patients (74%) were men, and the mean (SD) age was 49.0 (14.8) years. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%-79.3%) and in the 50-mg group was 74% (95% CI, 60.3%-85.0%). In the 25-mg group, 56% of the patients had eradication (95% CI, 40.0%-70.4%) of the pathogens compared with 69% (95% CI, 54.2%-82.3%) in the 50-mg group. Values for the minimum concentration of tigecycline that is inhibitory for 90% of all isolates ranged from 0.06 to 0.50 microg/mL for the selected pathogens. Both tigecycline doses were generally well tolerated. Nausea and vomiting were the most common adverse events. CONCLUSIONS: In this study, tigecycline appeared efficacious and showed a favorable pharmacokinetic profile and an acceptable safety profile in the treatment of hospitalized patients with cSSSI. In patients who received 50-mg doses of tigecycline q12h, the clinical cure rates and microbial eradication rates were 74% and 70%, respectively, and were 67% and 56% in patients who received 25-mg doses.

Adolescent↗

PubMed2005

Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs).

OBJECTIVES: To evaluate the penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs). METHODS: PMNs were isolated from fresh whole blood and tested for viability and purity prior to use. Tigecycline drug uptake was evaluated by incubating 5 x 10(6) cells/mL at 37 degrees C up to 3 h at tigecycline concentrations of 1, 2, 5 and 10 mg/L. Drug efflux from PMNs was determined following a 2 h incubation with tigecycline at 10 mg/L. Its intracellular activity against Staphylococcus aureus was evaluated following tigecycline extracellular exposures of 1 mg/L. RESULTS: Tigecycline uptake was rapid and achieved high concentrations within PMNs with maximal penetration noted at 1 h of incubation. At 1 h, dose-dependent intracellular concentrations ranged from 15.83 +/- 11.09 mg/L to 264 +/- 54.60 mg/L at tigecycline 1 and 10 mg/L, respectively. At these exposures, intracellular drug concentrations were approximately 20 and 30 times higher at 1 h than extracellular concentrations. By 3 h, tigecycline displayed sustained high intracellular exposures. Tigecycline cell efflux followed first order kinetics with a half-life of 1.39 h. Tigecycline was bacteriostatic against intracellular S. aureus. CONCLUSIONS: Tigecycline rapidly achieved high intracellular concentrations in PMNs and exhibited static activity against S. aureus supporting its potential clinical utilization.

Anti-Bacterial Agents↗

PubMed2003

Activities of tigecycline (GAR-936) against Legionella pneumophila in vitro and in guinea pigs with L. pneumophila pneumonia.

The activities of tigecycline (Wyeth Research) against extracellular and intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia were studied. The tigecycline MIC at which 50% of strains are inhibited for 101 different Legionella sp. strains was 4 micro g/ml versus 0.125 and 0.25 micro g/ml for azithromycin and erythromycin, respectively. Tigecycline was about as active as erythromycin (tested at 1 micro g/ml) against the F889 strain of L. pneumophila grown in guinea pig alveolar macrophages and more active than erythromycin against the F2111 strain. Azithromycin (0.25 micro g/ml) was more active than (F889) or as active as (F2111) tigecycline (1 micro g/ml) in the macrophage model. When tigecycline was given (7.5 mg/kg of body weight subcutaneously once) to guinea pigs with L. pneumophila pneumonia, the mean peak serum and lung levels were 2.3 and 1.8 micro g/ml (1.2 and 1.5 micro g/g) at 1 and 2 h postinjection, respectively. The serum and lung areas under the concentration time curve from 0 to 24 h were 13.7 and 15.8 micro g. h/ml, respectively. Thirteen of 16 guinea pigs with L. pneumophila pneumonia treated with tigecycline (7.5 mg/kg subcutaneously once daily for 5 days) survived for 7 days post-antimicrobial therapy, as did 11 of 12 guinea pigs treated with azithromycin (15 mg/kg intraperitoneally once daily for 2 days). None of 12 guinea pigs treated with saline survived. Tigecycline-treated guinea pigs had average end of therapy lung counts of 1 x 10(6) CFU/g (range, 2.5 x 10(4) to 3.2 x 10(6) CFU/g) versus <1 x 10(2) CFU/g for azithromycin (range, undetectable to 100 CFU/g). A second guinea pig study examined the ability of tigecycline to clear L. pneumophila from the lung after 5 to 9 days of therapy; bacterial concentrations 1 day posttherapy ranged from log(10) 4.2 to log(10) 5.5 CFU/g for four different dosing regimens. Tigecycline is about as effective as erythromycin against intracellular L. pneumophila, but tigecycline inactivation by the test media confounded the interpretation of susceptibility data. Tigecycline was effective at preventing death from pneumonia in an animal model of Legionnaires' disease, warranting human clinical trials of the drug for the disease.

Animals↗

PubMed2005

A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline.

Tigecycline, an expanded-broad-spectrum glycylcycline antibiotic is not affected by the classical tetracycline resistance determinants found in Staphylococcus aureus. The in vitro selection of mutants with reduced susceptibility to tigecycline was evaluated for two methicillin-resistant S. aureus strains by serial passage in increasing concentrations of tigecycline. Both strains showed a stepwise elevation in tigecycline MIC over a period of 16 days, resulting in an increase in tigecycline MIC of 16- and 32-fold for N315 and Mu3, respectively. Transcriptional profiling revealed that both mutants exhibited over 100-fold increased expression of a gene cluster, mepRAB (multidrug export protein), encoding a MarR-like transcriptional regulator (mepR), a novel MATE family efflux pump (mepA), and a hypothetical protein of unknown function (mepB). Sequencing of the mepR gene in the mutant strains identified changes that presumably inactivated the MepR protein, which suggested that MepR functions as a repressor of mepA. Overexpression of mepA in a wild-type background caused a decrease in susceptibility to tigecycline and other substrates for MATE-type efflux pumps, although it was not sufficient to confer high-level resistance to tigecycline. Complementation of the mepR defect by overexpressing a wild-type mepR gene reduced mepA transcription and lowered the tigecycline MIC in the mutants. Transcription of tet(M) also increased by over 40-fold in the Mu3 mutant. This was attributed to a deletion in the promoter region of the gene that removed a stem-loop responsible for transcriptional attenuation. However, overexpression of the tet(M) transcript in a tigecycline-susceptible strain was not enough to significantly increase the MIC of tigecycline. These results suggest that the overexpression of mepA but not tet(M) may contribute to decreased susceptibility of tigecycline in S. aureus.

Anti-Bacterial Agents↗

PubMed2002

Antimicrobial activity of tigecycline (GAR-936) against Enterococcus faecium and Staphylococcus aureus used alone and in combination.

STUDY OBJECTIVE: To evaluate the antimicrobial properties of tigecycline, both alone and in combination with other antibiotics, against multidrug-resistant strains of Enterococcus faecium and Staphylococcus aureus. DESIGN: In vitro study. SETTING: University laboratory. MEASUREMENTS AND MAIN RESULTS: Tigecycline, both alone and in combination with other antimicrobial agents, was evaluated against two strains of vancomycin-resistant E. faecium (VREF), three glycopeptide-intermediately resistant S. aureus strains, and one methicillin-resistant S. aureus strain. Tigecycline's activity was compared with that of vancomycin, gentamicin, rifampin, and doxycycline, using time-kill studies and analysis of minimum inhibitory concentrations and minimum bactericidal concentrations. Tigecycline also was evaluated in combination with vancomycin, gentamicin, rifampin, and doxycycline in time-kill studies. The number of log10 colony-forming units/ml at 24 hours was compared among treatment groups and growth control by analysis of variance. All isolates were susceptible to tigecycline, regardless of their susceptibilities to vancomycin or doxycycline. In time-kill studies, tigecycline significantly inhibited the bacterial inoculum of all isolates (p < 0.05). Although none of the tigecycline combinations studied had enhanced killing activity against VREF, when gentamicin was combined with tigecycline, improved effects were found against both strains. Against three of the S. aureus strains tested, the combination of gentamicin and tigecycline demonstrated enhanced or improved activity independently of each strain's susceptibility to gentamicin. CONCLUSION: The multidrug-resistant, gram-positive bacteria tested, including doxycycline-resistant isolates, were susceptible to tigecycline. The combination of tigecycline and gentamicin may have improved or enhanced activity against strains of vancomycin-resistant enterococci and S. aureus.

Anti-Bacterial Agents↗

PubMed2005

Tigecycline: an investigational glycylcycline antimicrobial with activity against resistant gram-positive organisms.

BACKGROUND: Bacterial resistance to currently available antimicrobials is an increasing concern, particularly among various gram-positive organisms such as drug-resistant pneumococci, methicillin-resistant staphylococci, and drug-resistant enterococci. Tigecycline is an investigational glycylcycline antibiotic that shows promising activity against these resistant gram-positive organisms. OBJECTIVE: : This paper reviews the pharmacology, pharmacokinetic and pharmacodynamic properties, in vitro and in vivo activity, safety profile, and potential role of tigecycline in the management of gram-positive infections involving resistant microbes. METHODS: Articles included in this review were identified through a search of MEDLINE from 1998 through 2004 using the terms tigecycline and GAR-936. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy from 1998 to 2003 were searched using the same terms. The reference lists of identified articles were also reviewed for pertinent publications. RESULTS: Whereas resistance has developed with many of the earlier tetracycline derivatives, tigecycline appears to have a reduced potential for resistance. Several reports have evaluated the in vitro activity of this agent against a number of organisms. It has exhibited pronounced activity against most gram-positive microbes, including resistant strains (eg, drug-resistant pneumococci, methicillin-resistant staphylococci, resistant enterococci). Tigecycline has also shown useful activity against many clinically important gram-negative microbes. In vivo studies of tigecycline are limited. Only 2 clinical trials have been reported to date, one in patients with complicated skin and skin-structure infections and the other in patients with complicated intra-abdominal infections. In these studies, tigecycline therapy resulted in clinical cures in more than two thirds of evaluable patients. Tigecycline was well tolerated in both studies; nausea and vomiting were the most common adverse events. CONCLUSIONS: Although published clinical trials involving tigecycline are limited and additional trials are needed, preliminary reports on its use in the treatment of gram-positive infections are encouraging. Tigecycline has favorable pharmacokinetic properties and, apart from gastrointestinal adverse events, appears to be well tolerated.

Animals↗

PubMed2006

In vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

Tigecycline is a glycylcycline with promising broad-spectrum activity, including resistant Gram-positive organisms. This study characterizes in vitro activity of tigecycline against quinolone-resistant Streptococcus pneumoniae (QRSP), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). An in vitro pharmacodynamic model generated specific bacterial kill profiles for tigecycline against clinical isolates of QRSP, MRSA and VRE. Tigecycline produced a 6.6 log total reduction and cleared QRSP from the pharmacodynamic model by 18 h. Tigecycline and vancomycin were unable to achieve 3-log reductions in the MRSA and VRE isolates; log reductions in MRSA and VRE were 1.5 and 1.2 logs for tigecycline and 2.8 and zero for vancomycin, respectively. Area under the concentration time curve to minimum inhibitory concentration (AUC/MIC) values for tigecycline ranged from 79 to 158 microg h/mL and tigecycline concentrations remained above the MIC (T>MIC) throughout the simulated dosing interval. Tigecycline showed in vitro activity against the QRSP, MRSA and VRE isolates studied. Low MIC values, prolonged elimination half-life and the associated post-antibiotic effect (PAE) observed with tigecycline are desirable attributes that make it a potentially attractive option for treating resistant Gram-positive organisms.

Anti-Bacterial Agents↗

PubMed2005

Comparative evaluation of tigecycline and vancomycin, with and without rifampicin, in the treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis in a rabbit model.

OBJECTIVES: Staphylococcus aureus is the most common organism isolated in osteomyelitis. Methicillin-resistant S. aureus (MRSA) infections are particularly difficult to treat. We evaluated the efficacy of tigecycline and vancomycin with and without rifampicin in a rabbit model of MRSA osteomyelitis. METHODS: A 28 day antibiotic therapy with a subcutaneous injection of tigecycline (14 mg/kg twice daily), with and without oral rifampicin (40 mg/kg twice daily); or subcutaneous administration of vancomycin (30 mg/kg twice daily), with and without oral rifampicin (40 mg/kg twice daily) were compared. Osteomyelitis was induced with an intramedullary injection of 10(6) colony-forming units of MRSA. Infected rabbits were randomly divided into six groups: tigecycline, tigecycline with oral rifampicin, vancomycin, vancomycin with oral rifampicin, and no treatment control and tigecycline bone penetration groups. Treatment began 2 weeks after infection. After 4 weeks of therapy, the rabbits were left untreated for 2 weeks. Rabbits were then euthanized, and the tibias were harvested. The bones were cultured, and bacterial counts of MRSA were performed. RESULTS: Rabbits that received tigecycline and oral rifampicin therapy (n=14) showed a 100% infection clearance. Rabbits treated with tigecycline (n=10) showed a 90% clearance. Rabbits treated with vancomycin and oral rifampicin (n=10) also showed a 90% clearance. Rabbits treated with vancomycin (n=11) showed an 81.8% clearance. Untreated controls (n=15) demonstrated only a 26% clearance. For the tigecycline bone penetration group, the bone concentrations of tigecycline in the infected tibia were significantly higher than the non-infected ones. CONCLUSIONS: Tigecycline may be an effective alternative to vancomycin in the treatment of MRSA osteomyelitis.

Animals↗

PubMed2006

Acinetobacter baumannii bloodstream infection while receiving tigecycline: a cautionary report.

OBJECTIVES: Tigecycline has shown in vitro activity against Acinetobacter baumannii. Yet, published clinical experience with tigecycline use outside clinical trials is lacking. We describe, for the first time, bloodstream infection caused by tigecycline-non-susceptible A. baumannii occurring in patients receiving tigecycline for other indications. The possible mechanisms of resistance and pharmacokinetic limitations of the drug are addressed. METHODS: The clinical records of involved patients were systematically reviewed. Tigecycline susceptibility testing was initially performed using the Etest method and confirmed by agar dilution. Involved isolates underwent PFGE and exposure to phenyl-arginine-beta-naphthylamide (PAbetaN), an efflux pump inhibitor. RESULTS: Two patients developed A. baumannii bloodstream infection while receiving tigecycline. Tigecycline was administered for other indications for 9 and 16 days, respectively, before the onset of A. baumannii infection. Patient 1 died of overwhelming A. baumannii infection and Patient 2 recovered after a change in antibiotic therapy. The MICs of tigecycline were 4 and 16 mg/L, respectively. Both isolates had a multidrug-resistant phenotype and were genotypically unrelated. After exposure to PAbetaN, the MICs reduced to 1 and 4 mg/L, respectively. CONCLUSIONS: To our knowledge, this is the first clinical description of bloodstream infection caused by tigecycline-non-susceptible A. baumannii. Such resistance appears to be at least partly attributable to an efflux pump mechanism. Given the reported low serum tigecycline levels, we urge caution when using this drug for treatment of A. baumannii bloodstream infection.

Acinetobacter baumannii↗

PubMed2005

Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects.

Tigecycline, a novel glycylcycline antibiotic, exhibits strong activity against gram-positive, gram-negative, aerobic, anaerobic, and atypical bacterial species, including many resistant pathogens, i.e., vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. The safety and tolerability of tigecycline administered as single or multiple doses or at various infusion rates were explored in three phase 1, randomized, double-blind, placebo-controlled studies in healthy subjects. Full pharmacokinetic profiles of tigecycline were determined in two of these studies. Subjects in the single-dose study received 12.5 to 300 mg of tigecycline, which differed with respect to the duration of infusion, subjects' feeding status, and ondansetron pretreatment. Subjects in the ascending multiple-dose study received 25 to 100-mg doses of tigecycline as a 1-h infusion every 12 h. The variable volume and infusion rate study consisted of administration of 100-mg loading dose of tigecycline, followed by 50 mg every 12 h for 5 days. Serum samples were analyzed for tigecycline by validated high-pressure liquid chromatography or liquid chromatography/tandem mass spectrometry methods. Systemic clearance ranged from 0.2 to 0.3 liters/h/kg, and the tigecycline half-life ranged from 37 to 67 h. Tigecycline had a large volume of distribution (7 to 10 liters/kg), indicating extensive distribution into the tissues. Food increased the maximum tolerated single-dose from 100 to 200 mg, but the duration of infusion did not affect tolerability. Side effects, mainly nausea and vomiting, which are common to the tetracycline class of antimicrobial agents, were seen in these studies. Tigecycline exhibits linear pharmacokinetics and is safe and well tolerated in the dose ranges examined.

Adolescent↗

PubMed2005

Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae.

Tigecycline is an expanded broad-spectrum antibacterial agent that is active against many clinically relevant species of bacterial pathogens, including Klebsiella pneumoniae. The majority of K. pneumoniae isolates are fully susceptible to tigecycline; however, a few strains that have decreased susceptibility have been isolated. One isolate, G340 (for which the tigecycline MIC is 4 microg/ml and which displays a multidrug resistance [MDR] phenotype), was selected for analysis of the mechanism for this decreased susceptibility by use of transposon mutagenesis with IS903phikan. A tigecycline-susceptible mutant of G340, GC7535, was obtained (tigecycline MIC, 0.25 microg/ml). Analysis of the transposon insertion mapped it to ramA, a gene that was previously identified to be involved in MDR in K. pneumoniae. For GC7535, the disruption of ramA led to a 16-fold decrease in the MIC of tigecycline and also a suppression of MDR. Trans-complementation with plasmid-borne ramA restored the original parental phenotype of decreased susceptibility to tigecycline. Northern blot analysis revealed a constitutive overexpression of ramA that correlated with an increased expression of the AcrAB transporter in G340 compared to that in tigecycline-susceptible strains. Laboratory mutants of K. pneumoniae with decreased susceptibility to tigecycline could be selected at a frequency of approximately 4 x 10(-8). These results suggest that ramA is associated with decreased tigecycline susceptibility in K. pneumoniae due to its role in the expression of the AcrAB multidrug efflux pump.

Bacterial Proteins↗

PubMed2006

Peritoneal fluid penetration of tigecycline.

OBJECTIVE: To describe the peritoneal fluid penetration of tigecycline. CASE SUMMARY: A 33-year-old critically ill man who had undergone orthotopic liver and cadaveric renal transplant presented with sepsis. The patient required empiric antimicrobial coverage, continuous veno-venous hemofiltration, prolonged mechanical ventilation, tracheostomy placement, and maintenance immunosuppressive therapy. After multiple infections with multi-drug resistant pathogens, the patient developed vancomycin-resistant Enterococcus faecium peritonitis. Tigecycline 50 mg was administered every 12 hours, and ascites fluid drug concentrations were obtained. Drug concentrations in the peritoneal fluid were determined by high-performance liquid chromatography and revealed a tigecycline concentration of 0.074 microg/mL. Despite aggressive measures, the patient's condition continued to decline; he died 2 weeks after tigecycline initiation. DISCUSSION: As of October 3, 2006, these are the first data to describe tigecycline peritoneal fluid penetration. Tigecycline was aggressively administered at twice the recommended dosage for overt liver failure in light of the severity of this patient's condition. A tigecycline peritoneal fluid concentration of 44-54% of serum concentration was calculated based on the patient's peritoneal fluid drug concentration and previously published serum concentrations from a similar population. CONCLUSIONS: Peritoneal penetration of tigecycline was approximately 50% in this critically ill patient. Establishment of site-specific breakpoints for tigecycline may be necessary. Future studies will need to evaluate the penetration of tigecycline into peritoneal fluid and other tissues.

Adult↗

PubMed2004

In vitro activities of tigecycline against clinical isolates from Shanghai, China.

To evaluate the in vitro activity of tigecycline, the minimum inhibitory concentrations (MICs) of tigecycline against 1,201 strains of recent clinical isolates from 10 hospitals in Shanghai, China were determined and compared with selected comparators. Results showed that tigecycline had broad-spectrum antimicrobial activity. It was highly active against Gram-positive cocci, including methicillin-resistant Staphylococcus spp., penicillin-intermediate Streptococcus pneumoniae, Enterococcus faecalis and E. faecium. Tigecycline also had good activity against most strains of Enterobacteriaceae, Haemophilus influenzae, Neisseria gonorrhoeae, and Moraxella catarrhalis. However, it was poorly active against Acinetobacter baumannii and Pseudomonas aeruginosa. Tigecycline was highly active against anaerobic Gram-positive cocci such as Peptococcus spp. The in vitro activity of tigecycline was significantly better than that of minocycline and tetracycline. It was as active as or slightly more active than vancomycin and teicoplanin in the activity against resistant aerobic Gram-positive cocci. Tigecycline was bactericidal against all Gram-positive cocci tested except Enterococcus spp. Inoculum size but not pH of medium or concentration of human serum in broth had significant effect on the in vitro activity of tigecycline. Aged media (48-72 hours after preparation) used in the test and specific resistance problem in China may have some effects on MIC values of tigecycline.

Anti-Bacterial Agents↗

PubMed2005

Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates.

Steadily increasing resistance among the Enterobacteriaceae to beta-lactams, fluoroquinolones, aminoglycosides, tetracyclines, and trimethoprim/sulfamethoxazole has compromised the utility of these commonly used antimicrobial classes for many community- or hospital-acquired infections. The development of tigecycline, the sentinel representative of a novel class of broad-spectrum agents (the glycylcyclines), represents an important milestone in addressing this critical need. Resistance to tigecycline might be expected to occur via the same mechanisms that produce tetracycline resistance; however, tigecycline remains stable and largely unaffected by the commonly occurring efflux and ribosomal protection resistance mechanisms. In this study, an international collection of Enterobacteriaceae (11327 isolates; 32.8% tetracycline-resistant) from global surveillance studies (2000-2004) were evaluated against tigecycline and other comparator antimicrobials. Although the most active agents were the carbapenems and aminoglycosides (97.5-99.7% susceptible), tigecycline displayed high potency (MIC50 and MIC90, 0.25 and 1 microg/mL) with 95.7% of all strains being inhibited at < or =2 microg/mL. Despite higher MIC values observed with Serratia spp. and Proteae, between 90.5% and 97.5% of isolates were inhibited by < or =4 microg/mL of tigecycline. Tetracycline-resistant populations demonstrated only modest decreases in potency to tigecycline, which appeared to be species-dependent (up to 2-fold only for Escherichia coli, Salmonella spp., Shigella spp., and Panteoa agglomerans; and up to 4-fold for Klebsiella spp., Enterobacter spp., and Citrobacter spp.). Among E. coli (263 isolates) and Klebsiella spp. (356) that meet recognized screening definitions for extended-spectrum beta-lactamase production, 100.0% and 94.4% were inhibited by tigecycline at 2 microg/mL, respectively. These findings confirm that tigecycline exhibits potency, breadth of spectrum, and stability to the commonly occurring resistance mechanisms found in contemporary Enterobacteriaceae isolates, attributes that make this parenteral agent an attractive candidate for use against serious infections produced by these species.

Anti-Bacterial Agents↗

PubMed2005

Effect of medium type, age and aeration on the MICs of tigecycline and classical tetracyclines.

BACKGROUND: Tigecycline is a minocycline derivative, belonging to a chemical class prone to oxidation and to medium-related effects on susceptibility. We therefore studied the effect of medium type and age on the tigecycline MICs found in broth and on agar by the Clinical Laboratory Standards Institute and British Society for Applied Chemotherapy methods. METHODS: MICs of tigecycline, minocycline and tetracycline were determined for 96 non-fastidious bacteria and 20 streptococci using Mueller-Hinton broth (MHB), Mueller-Hinton agar (MHA), Iso-Sensitest broth (ISB) and Iso-Sensitest agar (ISA) as: (i) freshly-prepared media; (ii) fresh media but with the antibiotic added 1 day before inoculation and (iii) media stored for 7 days before antibiotic addition and use. RESULTS: MICs of tigecycline in fresh MHB were up to two doubling dilutions higher than on or in MHA, ISA or ISB. Media with tigecycline or classical tetracyclines added a day before use gave raised MICs, though rarely by more than one dilution. MICs of tigecycline (less so classical tetracyclines) were increased in 7-day-old MHB or ISB, even though the antibiotic was freshly added. This latter effect was greatest for the most susceptible strains and was absent or much reduced for organisms with MICs > or = 8 mg/L; it did not occur in the corresponding agar dilution tests. Addition of blood to MHB largely abrogated the effect, as did steaming the broth before adding the antibiotic. CONCLUSIONS: The raised MICs of tigecycline in aged broth probably reflect inactivation by dissolved oxygen. This accords with the lack of any MIC increase in newly-steamed (i.e. degassed) MHB or on aged agar (which is melted at 100 degrees C before use). Blood, which also abrogated the effect, may increase reducing capacity, protecting the tigecycline. At a practical level, broth MIC determinations for tigecycline should always employ fresh media.

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