Antibiotic Resistance Monitoring & Reference Laboratory, Centre for Infections, Health Protection Agency, 61 Colindale Avenue, London NW9 5HT, UK
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Keywords: tetracyclines , glycylcyclines , GAR-936
Tigecycline (Wyeth, formerly GAR-936), was licensed by the USA's Food and Drug Administration in June 2005. It is the first glycylcycline to be launched and the first new tetracycline analogue since minocycline over 30 years ago. It is also unique among the small raft of anti-MRSA and anti-enterococcal drugs now reaching the market because it additionally has substantialanti-Gram-negative activity, encompassing not only most Enterobacteriaceae,1,2 but alsoat least in vitromultiresistant Acinetobacter baumannii.3,4 Whilst many microbiologists and clinicians viscerally feel tetracyclines are not powerful antibiotics in the way of ß-lactams, aminoglycosides and quinolones, it is striking that tigecycline showed equivalence to imipenem in intra-abdominal infections5,6 and to vancomycin plus aztreonam in skin and skin structure infections.7,8 Such successes imply that the old prejudices about tetracyclines may be inappropriate for tigecycline, or unduly pessimistic for tetracyclines and glycylcyclines as a whole.
Research into glycylcyclines began at Lederle in the early 1990s, when it was realized that addition of a modified glycylamido- to carbon 1 of the D ring (Figure 1) allowed both efflux and ribosomal type resistances to be overcome. Two N,N-dimethylglyclamido- derivatives were progressed initially,9 but neither proved suitable for pharmaceutical development and progress stalled until Wyeth, who bought Lederle in 1994, decided to progress the t-butylglyclamido derivative of minocycline.10 This is the compound now being launched as tigecycline.
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The compound's antibacterial spectrum reflects this evasion of acquired resistance along with its continued vulnerability to chromosomally-mediated efflux in Pseudomonas and Proteeae: MIC distributions for Enterobacteriaceae species are unimodal with only a slight positive skew: typical values are 0.12 to 0.25 mg/L for Escherichia coli and 0.51 mg/L for Klebsiella, Enterobacter and Citrobacter spp., with fewer than 2% of isolates of these latter species having MICs >2 mg/L.1,2,18 Acinetobacter spp. are mostly susceptible at 0.52 mg/L3,4 and Bacteroides spp. at 18 mg/L,19 whilst MICs for Proteeae are mostly 28 mg/L and those for P. aeruginosa are 832 mg/L.1,2,18 Tigecycline MICs for enterococci, staphylococci, and streptococci are mostly 0.060.25 mg/L, again with little or no skew to the distribution.1,2,18 MIC values vary a little with the medium, being about a dilution lower in Iso-Sensitest media than MuellerHinton broth; whether this will impact on susceptibility categorizations will depend on the breakpoints ultimately adopted by the CLSI and EUCAST, but it seems unlikely to be a source of major discrepancies.20 Like classical tetracyclines, tigecycline is prone to oxidation, and MIC values, particularly for the most susceptible isolates, may be raised if the drug is added to broth that has become oxygenated during storage, or if drug-containing media are stored before inoculation.20 These problems are avoided by the use of freshly autoclaved broth or recently melted agar, and do not arise with discs or Etests.
In contrast to classical tetracyclines, tigecycline can only be administered parenterally, and the regimen validated in clinical trials involved a 100 mg loading dose followed by 50 mg twice daily.58 A provisional susceptibility breakpoint MIC of 2 mg/L (as determined by CLSI methods) was used in these trials, whereas the FDA has subsequently proposed susceptibility breakpoints of
0.25 mg/L for streptococci,
0.5 mg/L for staphylococci,
2 mg/L for Enterobacteriaceae and
4 mg/L for anaerobes, based largely (it seems) on the MICs for responsive pathogens in clinical trials. Breakpoints from the CLSI and EUCAST/BSAC are awaited and their definition on pharmacodynamic criteria will be challenging owing to tigecycline's pharmacokinetics. These involve a terminal half-life of 36 h, and a very large volume of distribution which, as with azithromycin, reflects rapid and extensive transfer from the bloodstream to the tissues.21 Depending on the site of infection, this behaviour may be clinically advantageous, and the outcome data imply that breakpoints cannot be set solely in relation to the serum Cmax, which was only 0.911 mg/L after a single 100 mg dose infused over 1 h and only 0.62 mg/L after 10 days of a twice-daily 50 mg regimen.21 On the other hand, the low Cmax must be of some concern if bacteraemia is present.
Two pairs of Phase III clinical trials were undertaken for licensing: one pair comparing tigecycline with imipenem plus cilastatin in intra-abdominal infection,5,6 the other comparing tigecycline with aztreonam plus vancomycin in skin and skin structure infections.7,8 Over 2850 patients were treated in these trials, each of which showed equivalence between its two arms. The skin and soft tissue trials supported Phase II data for tigecycline indicating 74% efficacy.22 Trials on community- and hospital-acquired pneumonias are in progress and, if positive, will form the basis of a licence extension. Trials in urinary tract infections were abandoned on pre-completion review, because excretion proved to be largely biliary, with limited urinary recovery of the active drug. In addition, there are ongoing trials against infections caused by specific multiresistant pathogens, along with an extensive compassionate-use programme. The main side effect, seen in 24.4% of patients in the intra-abdominal infection studies and 34.5% in the skin and skin structure infection studies, was nausea, sometimes with vomiting. Although these frequencies are high, the severity was low and the overall treatment discontinuation rate for nausea in the Phase III studies was under 1.5%.58 As with classical tetracyclines, use in children and women who are (or may be) pregnant is to be avoided owing to potential effects on bone development.
The big question now is how to deploy tigecycline. The most attractive on-label application seemsto this authorto be in surgical wound infections, particularly following abdominal surgery, where the likely pathogens include MRSA (except in Scandinavia and the Netherlands) as well as Enterobacteriaceae, streptococci and anaerobes.23 No other single agent covers this spectrum and combination regimens, whilst arguably more flexible, add cost and complexity. Wider empirical use in skin and skin structure infections also seems reasonable, especially in settings where either or both 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 ß-lactamase inhibitor combinations, cephalosporin/metronidazole or carbapenem treatments remain highly effective in the great majority of cases. Nevertheless, tigecycline would be a reasonable alternative in penicillin-allergic patients, and is likely to become increasingly attractive as extended-spectrum ß-lactamases (ESBLs) become more widely disseminated among the endogenous gut Enterobacteriaceae that seed these infections. ESBLs, and particularly the CTX-M types, are now spreading rapidly in many countries, including the UK.24 Recent studies around York and in Shropshire found ESBL-positive Enterobacteriaceae in 22.5% of stool specimens from diarrhoeal outpatients and up to 4.5% of those from inpatients.25,26 Most ESBL-producing E. coli in the UK have the CTX-M-15 enzyme and are multiresistant to quinolones, aminoglycosides and (owing to simultaneous production of OXA-1 enzyme) to ß-lactamase inhibitor combinations, leaving only the carbapenems and tigecycline as reliably active,24 along with a few agents with limited application, notably fosfomycin and nitrofurantoin. At present, though, the major site for infections with ESBL producers remains the urinary tract, a setting where tigecycline is not an obvious first choice owing to its biliary excretion profile.
Acinetobacter spp. are another group of multiresistant pathogens where tigecycline's activity is exciting much interest, especially as growing numbers of isolates of the genus are resistant even to carbapenems owing to production of OXA carbapenemase or, more rarely, metallo-ß-lactamases.27 Currently, three carbapenemase-producing A. baumannii strains are prevalent in multiple hospitals in and around London,28 two with both OXA-23 and OXA-51-like carbapenemases and the third with only an OXA-51-like enzyme. Producers of these and other OXA carbapenemases are being widely reported elsewhere in Europe, South America and East Asia, with OXA-24 enzyme prevalent in Iberia and metallo-carbapenemases more frequent in the Far East.27 In the USA, the proportion of Acinetobacter isolates resistant or intermediately resistant to imipenem rose from 6.3% in 1999 to 11.4% in 2001,27 though the prevalent mechanisms remain undefined. Many carbapenemase-producing A. baumannii isolates are resistant to all available agents except polymyxins, drugs with significant toxicity and poor penetration to respiratory secretions (though this might be overcome with nebulized colistin). Tigecycline, which is active against most carbapenemase-producing strains at 2 mg/L,4 may be a useful alternative to polymyxins. A few positive case reports have begun to appear29 and there is also a report of successful use of doxycycline and minocycline in six of seven cases of ventilator-associated Acinetobacter pneumonia, supporting the concept of using tetracyclines in this setting.30 Nevertheless, systematic study is needed to assess the relative merits of tigecycline versus polymyxins in infections due to multiresistant acinetobacters.
Last, tigecycline will certainly be used as microbiologically-directed therapy of infections due to multiresistant Gram-positive pathogens, including MRSA and vancomycin-resistant enterococci, and a key challenge is to determine when to prefer tigecycline as against old and new glycopeptides, linezolid, daptomycin, and (in the future) ceftobiprole. There is growing evidence that linezolid is superior to vancomycin versus MRSA31,32 but, as yet, there is no comparison among the various new agents, including tigecycline.
In short, tigecycline is among the more unique recent additions to the armamentarium and its achievements in clinical trials should lead us to rethink the status of tetracycline derivatives. Aside from empirical usage in wound infections where either or both MRSA and Enterobacteriaceae are likely, tigecycline should have a role in directed treatment of infections due to ESBL producers, pan-resistant Acinetobacter spp. and multiresistant Gram-positive cocci. Needless to say, its propensity to select resistance needs to be monitored closely and it is disturbing that in vitro-selected mutations of tet(A), enabled efflux of glycylcyclines;33 also that there were five instances of emerging resistance during the Phase III trials, two with K. pneumoniae and one each with Enterobacter cloacae, Morganella morganii and A. baumannii, all apparently associated with up-regulation of chromosomally-mediated efflux pumps (Wyeth, data on file). Moreover, this reference laboratory is also investigating several tigecycline non-susceptible (MIC, 416 mg/L) A. baumannii from London, and particular attention needs to be addressed to any potential for selection of resistance in this notoriously adaptable species. Whether or not significant resistance threats ultimately do emerge (and experience shows that they usually do!), it is excellent news to have a new agent with increased activity againstGram-negative as well as Gram-positive bacteria. Few others will come this decade.
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