Doi:10.1016/j.ccc.2007.12.007

Praveen K. Mullangi, MD, George A. Pankey, MD Department of Infectious Diseases, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121, USA The emergence and spread of multidrug resistance in many pathogenic bacterial species is increasing at an alarming rate, especially with hospital-acquired infections in the critical care setting Five percent to 35% of pa-tients admitted to the ICU develop hospital-acquired infections In 2002,1.7 million hospital-acquired infections occurred in United States hospitals.
Deaths associated with hospital-acquired infections have exceeded the num-ber attributable to several of the top 10 leading causes of death reported inthe United States The emerging resistance limits the use of older antibi-otics. Tigecycline is a new agent, and this article explores its role in the treat-ment of adults in the critical care setting.
Tigecycline is the first in a new class of antibiotics, the glycylcyclines, licensed by the US Food and Drug Administration (FDA) in June 2005for intravenous (IV) use in adults. Tigecycline is a derivative of minocycline,with a 9-t-butylglycylamido group added to the carbon 1 of the D ring ofminocycline, and it exhibits a broad-spectrum antibacterial activity. Tigecy-cline acts by binding to the 30S ribosomal subunit and prevents the bindingof aminoacyl transfer RNA to the acceptor site on the messenger RNA-ribosome complex. Protein synthesis is ultimately inhibited thereby exertinga bacteriostatic effect.
Tetracycline resistance is mediated by three different mechanisms: (1) ef- flux, (2) ribosomal protection, and (3) chemical modification, but the firsttwo mechanisms are the most clinically significant . Depending on the or-ganisms, the mode of resistance mechanism and the determinants vary. Ste-ric hindrance secondary to change in the molecular structure of tigecycline * Corresponding author.
E-mail address: (G.A. Pankey).
0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2007.12.007 makes it a poor substrate for the tetracycline-specific efflux pumps. Tetracy-cline efflux transporters do not take up tigecycline when present in low con-centrations, although at high concentrations it can be recognized with lowaffinity . Tigecycline binds to bacterial ribosomes that have been modifiedby the tetracycline (Tet-M) protein . As a result it overcomes the two ma-jor resistance mechanisms associated with tetracyclines Tigecyclineseems to be a substrate for multidrug transporter pumps encoded by bacte-rial genes. Experiments with strains producing these multidrug efflux pro-teins revealed an increase in minimum inhibitory concentrations (MICs)of tigecycline Tigecycline has a broad spectrum of activity including gram-positive and -negative aerobes and anaerobes, rapidly growing mycobacteria, myco-plasma, and chlamydophila. It is active against tetracycline-susceptibleand -resistant pathogens FDA set breakpoint susceptibility for thegram-positive cocci is 0.25 to 0.5 mg/mL, making aerobic gram-positivepathogens including (oxacillin) methicillin-sensitive and -resistant Staphylo-coccus aureus (MRSA), vancomycin-intermediate S aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniaesusceptible. Almost all of these organisms are susceptible to tigecycline atthe FDA set breakpoints . An in vitro study investigated the efficacy ofnewer antibiotics against the MRSA embedded in the biofilm of catheter-related bloodstream infections. In this study daptomycin, minocycline,and tigecycline were more efficacious in inhibiting MRSA in the biofilmthan vancomycin and linezolid when used as catheter lock therapy .
Respiratory gram-negative pathogens, such as Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, and Chlamydophila pneu-moniae, have similar FDA breakpoint susceptibilities. In one study, tigecy-cline was tested against a total of 10,763 gram-positive and -negativebacterial isolates from patients with community-acquired respiratory tractinfections (pneumonia, sinusitis, acute exacerbation of chronic bronchitis,and otitis) and hospitalized patients with pneumonia . Tigecycline ex-hibited 100% potency by inhibiting all the community-acquired respiratorytract pathogens irrespective of the b-lactamase production in the case ofH influenzae and penicillin and fluoroquinolone resistance in S pneumoniae.
Among the pathogens causing hospital-acquired pneumonias, tigecycline in-hibited more than 96% of the nosocomial pathogens except Pseudomonas.
The nosocomial pathogens tested included MRSA, P aeruginosa, Klebsiella sp,S pneumoniae, Acinetobacter sp, Enterobacter sp, Escherichia coli, Serratiamarcescens, Enterococcus sp, Stenotrophomonas maltophilia, and b-hemolyticStreptococci. In vitro studies have shown tigecycline to be an activeagent against extended-spectrum b-lactamase producing E coli, Klebsiella,and multidrug resistant Acinetobacter Gram-negative organisms resistant to carbapenems have been one more concern. The mode of resistance isthought to be caused by reduced permeability because of loss of porins andcarbapenemases. This is seen in a variety of Enterobacteriaceae (Klebsiella,Enterobacter, Escherichia, Salmonella, and Citrobacter sp); however, most casesof outbreaks have been reported with Klebsiella pneumoniae. In vitro studyrevealed that these carbapenem resistant K pneumoniae have been susceptibleto tigecycline .
Tigecycline is also active in vitro against anaerobic bacteria including Clostridium difficile, Bacteroides fragilis, Prevotella, Porphyromonas, andFusobacterium. It is also active against Neisseria gonorrhoeae; Eikenella cor-rodens; and rapidly growing mycobacteria, such as Mycobacterium chelonae,Mycobacterium abscessus, and the Mycobacterium fortuitum group.
Legionella species have higher MIC values attributed to the partial inac- tivation of tigecycline by the iron in the Legionella test medium. Approxi-mately 95% of isolates of Enterobacteriaceae are susceptible to tigecyclineat the FDA susceptibility breakpoint of 2 mg/mL; however, most strainsof Proteus, Providencia, and many strains of Morganella have higher MICvalues and this has been attributed to overexpression of multidrug effluxpump systems, for which tigecycline is a substrate. Most extended-spectrumb-lactamase–producing strains of E coli, Klebsiella, Acinetobacter, and Sten-otrophomonas sp have been shown to be susceptible to tigecycline. Pseudo-monas mechanism has been attributed to the presence of a multidrug effluxpump unique to P aeruginosa An analysis of 9093 gram-positive and -negative isolates collected from patients hospitalized in ICU revealed the most frequently isolated pathogenas S aureus, followed by Enterococcus sp, coagulase-negative Staphylococci,and P aeruginosa Tigecycline was effective against all staphylococci in-cluding MRSA; enterococcus species including vancomycin-resistant entero-cocci; and all streptococcus species. It was active against the most frequentgram-negative pathogens isolated in ICU (E coli, Klebsiella sp, and Entero-bacter sp) including quinolone-resistant and extended-spectrum b-lacta-mase–producing strains.
Tigecycline is only available as an injectable antibiotic because its oral bioavailability is limited. It has a half-life of 1.5 days. Tigecycline exhibitedlinear pharmacokinetics after IV administration in ascending single doses of12.5 to 300 mg and multiple doses of 25 to 100 mg every 12 hours A meta-analysis of data from five phase I studies revealed the area underconcentration time curve of 4.87 Æ 1.41 (micrograms.h per milliliter) withsingle dose of 100 mg and area under the concentration time curve of 3.07 Æ0.38 (micrograms.h per milliliter) at steady state with 50 mg every 12-hour dosing. Tigecycline is currently approved for administration as a 100-mg IV loading dose, followed by 50 mg IV every 12 hours. It is administered asa 30- to 60-minute infusion. It has been shown to be effective, however, evenwhen administered at 100 mg IV once daily in a small number of patients. Tigecycline seems to exhibit both concentration and time-dependent ki-netics based on the dose and frequency of administration Patients are cur-rently being enrolled for a randomized, double-blind, comparison study of thesafety and efficacy of a once-daily dose of tigecycline versus ertapenem for thetreatment of diabetic foot infections Tigecycline has a protein-binding capacity of approximately 78%. It is extensively distributed into the tissues as shown by its high volume of distri-bution. Human and animal studies have demonstrated extensive penetrationin various tissues like skin, colon, lungs, and bone . Experimental studiesin penicillin-resistant strains of S pneumoniae meningitis in rabbits revealedthe tigecycline has adequate CSF penetration with bactericidal activity .
Studies revealed that area under the concentration time curve for tigecyclinein alveolar cells and in lung epithelial lining fluid was approximately 77.5-fold higher and 32-fold higher, respectively, than the area under the concen-tration time curve in serum Given the high achievable concentration oftigecycline in the lung tissue it is being evaluated as an empiric agent in thetreatment of pneumonias. The pharmacokinetics of IV tigecycline does notseem to be affected by age, race, or renal disease. It is mainly excreted un-changed in bile into the feces. Only 10% to 15% of the drug is excreted un-changed in urine, so dose adjustment is not necessary for renal impairmentincluding dialysis . Tigecycline is not dialyzable. Dose adjustment is re-quired for patients with severe hepatic impairment (Child Pugh C); the ini-tial dose should be 100 mg followed by a reduced maintenance dose of 25mg every 12 hours.
Postantibiotic effect refers to a period of time where bacterial growth continues to be suppressed after the removal of an antibacterial. Tigecyclinehas been shown to exert a postantibiotic effect of 1.8 to 4.1 hours dependingon the pathogen tested Tigecycline is minimally metabolized and doesnot affect the cytochrome P-450 enzymes. It seems to have a low potentialfor drug-drug interaction . Monitoring of activated partial thromboplas-tin time and prothrombin time is recommended, however, for patients onwarfarin being treated with tigecycline.
The efficacy and safety of tigecycline has been evaluated in four phase III, double-blind, comparative trials in hospitalized adults (R18 years). Twostudies were in patients with complicated skin and skin structure infections(cSSSIs), where tigecycline was compared with vancomycin-aztreonam .
cSSSIs included infections (1) requiring surgical intervention; (2) involvingdeep soft tissue; and (3) in patients with comorbid conditions, such as diabetes mellitus, peripheral vascular disease, or peripheral neuropathy. Pa-tients were excluded if they had necrotizing fasciitis, gangrene, osteomyelitis,plasmapheresis, hemoperfusion, neutropenia, severely impaired arterial sup-ply, or any condition or medication that impairs the ability to eradicate in-fections. Patients were randomly assigned 1:1 to receive tigecyclinewith placebo or the combination of IV vancomycin-aztreonam for up to14 days. Aztreonam could be discontinued after 48 hours per clinical judg-ment. In this study, the most common diagnosis was deep soft tissue infec-tion causing cellulitis. Diabetes mellitus was present in about 20% of thepatients. Clinical cure rates for the clinically evaluable population were86.5% for tigecycline and 88.6% for vancomycin-aztreonam group, showinga lack of treatment differences between the two groups. Overall, eradicationrates for all MRSA strains were 78.1% and 75.8% of tigecycline and vanco-mycin-aztreonam treated patients, respectively. Tigecycline consistently hadMIC90 values of less than 0.5 mg/L for the most prevalent isolates in thisstudy Analysis of another similar phase III, double-blind, randomized study in patients with complicated intra-abdominal infections (cIAIs), where tigecy-cline (initial dose of 100 mg over a 30-minute period followed by 50 mgevery 12 hours) was compared with imipenem-cilastatin (500 mg/500 mgevery 6 hours or dose adjusted by creatinine clearance) cIAIs are thosethat require a combination of surgical source control and broad-spectrumantimicrobial therapy. They included intra-abdominal abscesses that devel-oped in a patient following surgery and standard antibacterial therapy(antibiotics for at least 48 hours but not O5 days); perforated appendicitiswith or without a periappendiceal abscess; perforated diverticulitis compli-cated by abscess formation or fecal contamination; complicated cholecystitiswith evidence of perforation, empyema, or gangrene; perforation of gastricor duodenal ulcer with symptoms more than 24-hour duration; and purulentperitonitis associated with fecal contamination. These infections are usuallypolymicrobial. Enterobacteriaceae (E coli, K pneumoniae), enterococci, andB fragilis were isolated most frequently. Patients (N ¼ 1642) were randomlyassigned to tigecycline or IV imipenem-cilastatin for 5 to 14 days. Anintra-abdominal abscess was present in two thirds of patients and multipleabdominal abscesses were present in approximately 10% of patients ineach group. In addition, more than 75% of patients presented with perito-nitis and approximately 20% in each group had fecal peritonitis. Clinicalcure rates were virtually identical between the two treatment groups,80.2% for tigecycline and 81.5% for imipenem-cilastatin groups. Based onall these studies the FDA approved tigecycline usage for cSSSIs and cIAIs(see Two phase III, multicenter, double-blind studies comparing the safety and efficacy of tigecycline with levofloxacin in hospitalized patients withcommunity-acquired pneumonia are being evaluated by the FDA Patients were stratified based on Fine Pneumonia Severity Index Score Box 1. FDA approved indications and in vitro activity Complicated skin and skin structure infectionsStaphylococcus aureus (methicillin susceptible and methicillin Streptococcus pyogenesS agalactiaeS anginosus group (S anginosus, S intermedius, and S Enterococcus faecalis (vancomycin susceptible isolates only)Escherichia coliBacteroides fragilis Complicated intra-abdominal infectionsStaphylococcus aureus (MSSA)Enterococcus faecalis (VSE)S anginosus groupE coliCitrobacter freundiiEnterobacter cloacaeKlebsiella pneumoniaeK oxytocaBacteroides fragilisB thetaiotaomicronB uniformisB vulgatusClostridium perfringensPeptostreptococcus micros Other in vitro activityStaphylococcus epidermidis (methicillin susceptible and S haemolyticusStreptococcus pneumoniaeEnterococcus faecalis (vancomycin resistant isolates)E faecium (vancomycin susceptible and vancomycin resistant E aviumE casseliflavusE gallinariumListeria monocytogenesCitrobacter koseriEnterobacter aerogenesAeromonas hydrophila Pasteurella multocidaSerratia marcescensAcinetobacter baumanniiStenotrophomonas maltophiliaNeisseria gonorrheaeChlamydophila pneumoniaeBacteroides distasonisB ovatusPorphyromonas speciesPrevotella speciesClostridium difficileMycobacterium abscessusM chelonaeM fortuitum and randomly assigned (in a 1:1 ratio) to compare treatment regimens of aninitial dose of tigecycline, 100 mg IV followed by 50 mg doses every 12 hours,versus IV levofloxacin, 500 mg once daily or every 12 hours for at least 7days. In another study, patients should be hospitalized for a minimum of3 days with the option to be switched to oral levofloxacin after 3 days ofIV treatment with either tigecycline or levofloxacin group to complete a totalof 7 days and not to exceed 14 days. Demographic characteristics and riskfactors were similar for the two treatment groups. Clinical cure rates for clin-ically evaluable patients in both phase III studies were not significantly differ-ent between the two treatment groups (89.7% for tigecycline group and86.3% for levofloxacin group). A third phase III study comparing tigecyclinewith imipenem-cilastatin for the treatment of hospital-acquired pneumonia isin progress.
Tigecycline is well tolerated by most patients. The most frequent side ef- fects associated with the use of tigecycline have been confined to the gastro-intestinal system. Incidence of treatment-associated adverse events asreported in phase III clinical studies included nausea (30%), vomiting(20%), and diarrhea (13%), but they were generally classified as mild tomoderate. Although tigecycline is a derivative of minocycline, dizzinesswas seen only in a small number of patients (3.6%). There have been twocase reports of diffuse hyperpigmentation of skin in patients treated withboth tigecycline and polymyxin B . The use of tigecycline in patientsless than 18 years is not recommended because of lack of usage data. Tige-cycline is labeled as a Category D (positive evidence of human fetal risk, butthe benefits from use in pregnant women may be acceptable despite the risk [eg, if the drug is needed in a life-threatening situation or for a serious dis-ease for which safer drugs cannot be used or are ineffective]) drug in preg-nancy. There have been no reports of C difficile–associated diarrhea orpositive toxin assays associated with tigecycline use . This phenomenoncould be explained by tigecycline’s potent activity against C difficile. In vitrostudies revealed that tigecycline exhibited the best activity of all antibioticstested against C difficile isolates, including metronidazole and vancomycin. Given this fact and that tigecycline can cause diarrhea as a side effect,patients with diarrhea on tigecycline should not be started on metronidazoleor oral vancomycin empirically.
The structure of tigecycline results in the avoidance of the two major re- sistance mechanisms of tetracyclines. Overexpression of multidrug effluxpumps has shown to decrease susceptibility to tigecycline. These pumpsare seen in P aeruginosa, Proteus, and Morganella sp; hence, tigecyclinemay not be effective against these pathogens. Resistance-nodulation-divi-sion type multicomponent efflux transporters have been reported as causeof decreased susceptibility of Acinetobacter to tigecycline Tigecyclinehas not been shown to exhibit cross-resistance with other classes of antimi-crobials .
Rapid development of Acinetobacter baumannii resistance to tigecycline has been reported. In one case report, a 53-year-old woman experienceda multidrug-resistant A baumannii urinary tract infection 5 months aftera liver and kidney transplant . She was treated with 100 mg IV tigecy-cline followed by 50 mg every 12 hours for 2 weeks. The initial MIC ofthe isolate for tigecycline was 1.5 mg/mL. The infection resolved. Threeweeks later she had multidrug-resistant A baumannii isolated from sputumwith clinical evidence of pneumonia; she was also noted to have a paraspinalabscess and spinal osteomyelitis. Tigecycline was restarted; cultures of spinalfluid grew A baumannii with MIC of 24 mg/mL. Two recent abstracts alsodescribe elevated tigecycline MICs for A baumannii after tigecycline expo-sure Although it was unclear as to the exact cause of developmentof resistance, A baumannii has at least two efflux pumps belonging to resis-tance-nodulation-division family of transporters.
An in vitro study of tigecycline against 82 clinical isolates (19 different clones by pulsed field gel electrophoresis of multidrug-resistant A baumannii)revealed that 66% of the isolates were resistant (MIC O8 mg/L) and 12%were intermediate (MIC 4–6 mg/L) to tigecycline .
Cost analysis of a 10-day course of antibiotics as administered in the vancomycin-aztreonam $1216 as in cSSSIs; versus imipenem-cilastatin$1632 as in cIAIs. There is no significant difference or tigecycline is cheapercompared with the current standard antibiotics There is an added ad-vantage of less frequent administrations thereby saving nursing time, freeingthe number of accessible ports or lines to administer other essential medica-tions in critically ill patients. No levels need to be monitored as in use ofvancomycin, which also contributes to the total savings.
Patients hospitalized in the ICU are at particular risk of acquiring noso- comial infections with drug-resistant organisms, or have been in the hospitalfor a prolonged period and have experienced multiple antibiotics. Clinicaldata support that antimicrobial resistance among pathogenic bacteria leadsto worsening patient outcomes. Choice of empiric therapy in serious infec-tions and bacteremia is critical because inappropriate therapy increasesmortality.
Given the broad spectrum of activity against gram-positive and gram- negative pathogens, atypical organisms, and anaerobes, tigecycline may bea suitable alternative as monotherapy in critically ill patients as an empiricagent for cSSSIs and cIAIs, unless P aeruginosa, Proteus, Providencia, andmultidrug resistant Acinetobacter species are suspected. Studies are beingsubmitted to the FDA for approval of tigecycline in treatment of commu-nity-acquired pneumonia and hospital-acquired pneumonias.
Tigecycline is an agent that can be used empirically for critically ill mul- tidrug-resistant gram-positive and -negative pathogens except if Pseudomo-nas, Proteus, Providencia, Morganella and multidrug-resistant Acinetobacterare suspected. It also can be an agent of choice for b-lactam–intolerant pa-tients. More clinical information is needed to assess the benefit of usingtigecycline in combination with other antimicrobials. There are no reportsof any synergism or antagonism in vitro or in vivo. High potency with broadspectrum of activity including multidrug-resistant pathogens, ease of admin-istration, and low propensity for adverse effects and drug interactions makesit an agent to be considered in critically ill patients with cSSSIs or cIAIs.
Tigecycline has been reported as an antibiotic with low potential for de- veloping resistance; however, it seems to be susceptible to resistance by somemulticomponent efflux pumps. Given that it is a relatively new agent, devel-opment of resistance to tigecycline needs careful monitoring as tigecycline isincreasingly used.
[1] National Nosocomial Infections Surveillance System. National Nosocomial Infections Sur- veillance System (NNIS) report, data summary from January 1992 through June 2004, issuedOctober 2004. Am J Infect Control 2004;32:470–85.
[2] Eggimann P, Pittet D. Infection control in ICU. Chest 2001;120:2059–93.
[3] Klevens M, Edwards J, Richards C, et al. Estimating health care-associated infections and deaths in U.S. Hospitals, 2002. Public Health Rep 2007;122:160–6.
[4] Zhanel GG, Homenuik K, Nichol K, et al. The glycylcyclines: a comparative review with the tetracyclines. Drugs 2004;64(1):63–88.
[5] Hirata T, Saito A, Nishino K, et al. Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother 2004;48(6):2179–84.
[6] Petersen PJ, Jacobus NV, Weiss WJ, et al. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Anti-microb Agents Chemother 1999;43:738–44.
[7] Pankey G. Tigecycline. J Antimicrob Chemother 2005;56:470–80.
[8] Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis 2006;43:518–24.
[9] Raad I, Hanna H, Jiang Y, et al. Comparative activities of daptomycin, linezolid and tige- cycline against catheter-related methicillin-resistant staphylococcus bacteremic isolatesembedded in biofilm. Antimicrob Agents Chemother 2007;51(5):1656–60.
[10] Fritsche T, Sader H, Stilwell M, et al. Antimicrobial activity of tigecycline tested against or- ganisms causing community-acquired respiratory tract infection and nosocomial pneumonia.
Diagn Microbiol Infect Dis 2005;52:187–93.
[11] Hoban D, Bouchillon S, Dowzicky M. Antimicrobial susceptibility of extended-spectrum beta lactamase producers and multidrug-resistant Acinetobacter baumannii throughout theUnited States and comparative in vitro activity of tigecycline, a new glycylcycline antimicro-bial. Diagn Microbiol Infect Dis 2007;57:423–8.
[12] Moellering R, Graybill J, McGowan J, et al. Antimicrobial resistance prevention initiative-an update: proceeding of an expert panel on resistance. Am J Med 2007;120(7):S4–25.
[13] Dean CR, Visalli MA, Projan SJ, et al. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother 2003;47(3):972–8.
[14] Sader H, Jones R, Dowzicky M, et al. Antimicrobial activity of tigecycline tested against nos- ocomial bacterial pathogens from patients hospitalized in the intensive care unit. Diagn Mi-crobiol Infect Dis 2005;52:203–8.
[15] Muralidharan G, Micalizzi M, Speth J, et al. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005;49:220–9.
[16] Cunha BA. Once-daily tigecycline therapy of multidrug-resistant and non-multidrug-resis- tant gram-negative bacteremias. J Chemother 2007;19:232–3.
[17] Wyeth. Clinical trial number: NCT 00366249. Available at: .
[18] Wart V, Owen J, Ludwig E, et al. Population pharmacokinetics of tigecycline in patients with complicated intra-abdominal or skin and skin structure infections. Antimicrob AgentsChemother 2006;50(11):3701–7.
[19] Conte JE, Golden JA, Kelly MG, et al. Steady-state serum and intrapulmonary pharmaco- kinetics and pharmacodynamics of tigecycline. Int J Antimicrob Agents 2005;25(6):523–9.
[20] Slover C, Rodvold K, Danziger L. Tigecycline: a novel broad-spectrum antimicrobial. Ann [21] Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparisonstudies with vancomycin-aztreonam. Clin Infect Dis 2005;41:S341–53.
[22] Babinchak T, Ellis-Grosse EJ, Dartois N, et al. The efficacy and safety of tigecycline for the treatment of complicated intra abdominal infections: analysis of pooled clinical trial data.
Clin Infect Dis 2005;41:S354–66.
[23] Wyeth Pharmaceuticals. Data on file, Study 308 (CSR-63128).
[24] Wyeth Pharmaceuticals. Data on file, Study 313 (CSR-61261).
[25] Dukart G, Dartois N, Cooper C, et al. Integrated results of 2 phase 3 studies comparing tigecycline with levofloxacin in patients with community-acquired pneumonia [abstract].
San Francisco (CA): ICAAC; 2006.
[26] Knueppel R, Rahimian J. Diffuse cutaneous hyperpigmentation due to tigecycline and poly- myxin B. J Clin Infect Dis 2007;45:136–7.
[27] Giamarellou H. Treatment options for multidrug-resistant bacteria. Expert Rev Anti Infect [28] Peleg A, Adams J, Paterson D. Tigecycline efflux as a mechanism for nonsusceptibility in Acinetobacter baumannii. Antimicrob Agents Chemother 2007;51(6):2065–9.
[29] Rello J. Bench-to-bedside review: therapeutic options and issues in the management of ventilator-associated bacterial pneumonia. Crit Care 2005;9:259–65.
[30] Reid G, Grim S, Aldeza C, et al. Rapid development of Acinetobacter baumannii resistance to tigecycline. Pharmacotherapy 2007;27(8):1198–2001.
[31] Wickens J, Warr C, Jespon A, et al. An outbreak of multi-drug resistant Acinetobacter bau- mannii infections on an intensive care unit (ICU), and treatment with tigecycline [abstract].
American Society for Microbiology 2006;357.
[32] Schaffer JJ, Goff DA, Stevenson KB, et al. Experience with tigecycline for multi-drug resis- tant Acinetobacter baumannii ventilator-associated pneumonia and bacteremia [abstract].
American Society for Microbiology 2006;357.
[33] Venezia S, Leavitt A, Carmeli Y. High tigecycline resistance in multidrug-resistant Acineto- bacter baumannii. J Antimicrob Chemother 2007;59:772–4.
[34] Medication costs as calculated from information on website. Available at:

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