Establishing the Role of Tigecycline in an era of Antimicrobial Resistance

Jason J. Schafer; Debra A. Goff

Disclosures

Expert Rev Anti Infect Ther. 2008;6(5):557-567. 

In This Article

Microbiology

Tigecycline has demonstrated in vitro activity in several investigations against Gram-positive, Gram-negative, anaerobic and atypical bacteria.[13,14,15,16,17,18,19] One international study tested tigecycline activity in bacterial pathogens collected from patients hospitalized in intensive-care units.[13] The comparative activities of tigecycline and other antimicrobials in this study are listed in Table 2 . Aside from isolates of P. aeruginosa, tigecycline displayed potent activity against prevalent intensive care unit bacteria, including the drug-resistant pathogens MRSA, VRE and A. baumannii.

In a separate report of tigecycline's in vitro activity, over 26,000 bloodstream-infection isolates were collected from institutions on six continents.[15] Again, with the exception of P. aeruginosa and indole-positive or -negative Proteae, tigecycline exhibited potent activity against a broad spectrum of pathogens. Diminished activity and elevated MIC90 values have also been encountered elsewhere in species of Providencia and Morganella morgannii.

Further investigations have attempted to demonstrate tigecycline activity against MDR bacterial isolates.[16,20,21,22,23,24,25,26,27,28,29,30,31] These studies include isolates of glycopeptide-intermediate S. aureus (GISA), A. baumannii, Stenotrophomonas maltophilia and extended-spectrum β-lactamase (ESBL)-producing Enterobacterieaceae.

Resistant Gram-positive In Vitro Activity

Tigecycline's activity against resistant Gram-positive pathogens has been demonstrated in several in vitro investigations.[14,16,24,25] One analysis studied this activity against pathogens collected from 76 medical centers within nine regions of the USA.[25] Among the various US regions, Enterococcus faecium resistance to vancomycin ranged from 45.5 to 85.3%, methicillin resistance in S. aureus ranged from 27.4 to 62.4% and penicillin-nonsusceptible S. pneumoniae ranged from 23.3 to 54.5%. Tigecycline displayed potent activity with MIC90 values of 0.06-0.12 and 0.06-1 µg/ml for E. faecium and S. pneumoniae, respectively. All S. aureus isolates tested, including MRSA strains, were susceptible to tigecycline, vancomycin and linezolid.

In a separate study, tigecycline activity in 1989 community-associated MRSA isolates was determined[16] The majority of isolates were USA300, Scc mec type IV and Panton-Valentine leukocidin-positive. Overall, 98.2% of isolates were susceptible to tigecycline, which was comparable to the other agents tested, including glycopeptides, quinupristin/dalfopristin and linezolid.

Tigecycline activity against S. aureus strains with reduced glycopeptide susceptibility (i.e., GISA) has also been studied. In one analysis that compared the activity of tigecycline with various other agents against resistant Gram-positive pathogens, tigecycline demonstrated similar activity against methicillin-susceptible S. aureus (MSSA), MRSA and GISA isolates.[24] In a separate study, a time-kill analysis demonstrated significantly greater activity of tigecycline versus vancomycin against GISA isolates.[32]

Resistant Gram-negative In Vitro Activity

Many recent in vitro studies have investigated the activity of tigecycline against multidrug-resistant Gram-negative pathogens, including ESBL producers and carbapenem-resistant isolates.[20,21,22,23,26,27,28,29,30,31,33,34]

One investigation studied the in vitro susceptibility of tigecycline against carbapenem-susceptible and -resistant Klebsiella and Enterobacterspp.[28] There were 869 total isolates included (540 isolates of Klebsiella spp. and 329 isolates of Enterobacter spp.) Ertapenem resistance was identified in 89 and 65 isolates of Klebsiella and Enterobacter species, respectively. Of these isolates, seven and 19 Klebsiella, and 21 and 15 Enterobacter, also displayed resistance to imipenem and meropenem, respectively. Although tigecycline modal MIC values remained within the susceptible range overall (MIC ≤1), resistance to tigecycline was identified. Of particular note, carbapenem-resistant Enterobacter isolates were susceptible less often to tigecycline than carbapenem-susceptible strains (31 vs 13%). This trend was not present in the Klebsiella isolates tested.

A similar investigation studied the activity of multiple antibiotics, including tigecycline, against Enterobacteriaceae isolates producing serine carbapenemase or metallo-β-lactamase (MBL) enzymes.[23] A total of 104 isolates were collected worldwide, which included strains that produced the following enzymes: KPC-2 or -3 (n = 73), VIM-1 (n = 14), IMP-1 (n =1 1), SME-2 (n = 5), and NMC-A (n = 1). The rank order of in vitro activity against these strains for tested antimicrobials was tigecycline (100% susceptible) having greater activity than polymyxin B (88.1%), which had greater activity than that of amikacin (73%), whose activity was greater than that of imipenem (37.5%).

The in vitro activity of tigecycline for MBL-producing Enterobacteriaceae was further demonstrated in a collection of 109 clinical isolates collected over 3 years at a Greek medical center.[34] All isolates were intermediate or fully resistant to carbapenem agents and were identified as having VIM-type MBL enzymes. Tigecycline inhibited 99% of these isolates at a concentration lower than 2 mg/l.

Lastly, the effect of porin loss on tigecycline and imipenem activity in the presence of ESBL- and/or AmpC-type enzymes in Klebsiella pneumonia was recently investigated.[22] Although porin loss affected the activity of imipenem in isolates producing both ESBL and AmpC enzymes, tigecycline activity was unaffected. Both antimicrobials retained activity regardless of porin loss in isolates producing ESBL enzymes only.

Additional evidence of in vitro tigecycline activity in MDR Gram-negative pathogens has been performed for isolates of A. baumannii.[20,21,27,29,30,31] Several investigations have demonstrated tigecycline activity for A. baumannii irrespective of susceptibility to other antimicrobials, including carbapenems and polymyxin.[20,21,27] One study collected 107 isolates of A. baumannii from nine medical centers in Italy as part of a surveillance study. Nearly 50% of these isolates displayed multidrug resistance with decreased susceptibility to more than three antimicrobial agents, including 50 and 59% that were resistant to imipenem and meropenem, respectively. Tigecycline retained activity in 93% of isolates, including 100% of those resistant to carbapenems. Furthermore, a time-kill analysis performed on five isolates from this trial demonstrated that tigecycline activity was similar in all strains tested, irrespective of their resistance to carbapenem agents.[27] Comparable results of tigecycline activity against A. baumannii despite imipenem resistance have been found in similar studies and surveillance data.[17,20,31] Additionally, an in vitro investigation of antimicrobial susceptibility in 3707 polymyxin-resistant and -susceptible A. baumannii isolates found tigecycline to remain the most active agent, tested independent of polymyxin susceptibility.[20]

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