JAC Advance Access originally published online on December 18, 2008
Journal of Antimicrobial Chemotherapy 2009 63(2):243-245; doi:10.1093/jac/dkn511
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Leading articles |
Temocillin revived
1 Antibiotic Resistance Monitoring and Reference Laboratory, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK 2 Unité de Pharmacologie Cellulaire et Moléculaire & Centre de Pharmacie Clinique, Université Catholique de Louvain, Bruxelles, Belgium
* Corresponding author. Tel: +44-20-8327-7223; Fax: +44-20-8327-6264; E-mail: david.livermore{at}hpa.org.uk
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Resistance in Gram-negative pathogens is an increasing concern, with carbapenems often appearing as the only acceptable treatment option in serious infections. Reviving older compounds that have fallen into disuse may help to alleviate this burden. Temocillin (6-
-methoxy-ticarcillin) is resistant to most if not all classical and extended-spectrum β-lactamases and to AmpC enzymes. It is also chemically stable, allowing administration by continuous infusion. Pharmacokinetic/pharmacodynamic analysis, aided by Monte-Carlo simulations, suggests a breakpoint of 8 mg/L for the registered maximum dosage of 4 g daily. Temocillin's weaknesses, explaining its limited previous use, are a lack of activity against Gram-positive organisms, anaerobes and Pseudomonas. In settings where these are unlikely or are covered by other agents, temocillin may be useful, potentially ‘sparing’ carbapenems and having little apparent potential to select for Clostridium difficile.
Keywords:
ESBLs
,
AmpC
,
-methoxy penicillins
Accumulating resistance among Gram-negative pathogens has spurred the search for novel targets, but the results are disappointing to date, with no anti-Gram-negative drug possessing a truly novel mode of action submitted for registration in more than 30 years.1 To meet present challenges, it is therefore important to re-examine older ‘forgotten’ compounds that may prove useful. Reviving temocillin is one example of this approach; others include renewed interest in polymyxins2 and intravenous fosfomycin.3
Developed and first marketed in the UK by Beecham Pharmaceuticals in the 1980s, temocillin was quickly abandoned because of what were then perceived as major drawbacks, namely a lack of activity against Gram-positive organisms, anaerobes and Pseudomonas aeruginosa.4,5 What was not taken into account—although appreciated at the time by clinical microbiologists—was temocillin's remarkable β-lactamase stability.5 Specifically, temocillin is resilient to all classical and extended-spectrum TEM, SHV and CTX-M enzymes and to AmpC β-lactamase.6–8 It is labile to the chromosomal metallo-β-lactamase of Chryseobacterium meningosepticum,9 but relatively stable to some (maybe not all) acquired metalloenzymes.10 Its stability to KPC and OXA carbapenemases remains to be assessed.
Temocillin is the 6--methoxy derivative of ticarcillin and so has the same relationship to its parent compound as cefoxitin does to cefalotin, although the modification is arguably more advantageous for temocillin. Molecular modelling and biochemical studies have elucidated the role played by this -methoxy moiety:11 specifically, it blocks the entry of a water molecule into the β-lactamase active site cavity, preventing activation of the serine and the chemical events leading to hydrolysis. The price is that temocillin's binding to many penicillin-binding proteins (PBPs) is also impaired, explaining its lack of activity against Gram-positive bacteria. Moreover, although PBP-3 remains temocillin's primary target in Escherichia coli—as revealed by low-temperature labelling studies and by the filamentation response of exposed cells—the PBP-3–antibiotic complex formed is unstable, a trait that leads to temocillin's affinity for this target being underestimated in conventional PBP competition experiments.12
The MICs of temocillin for Enterobacteriaceae are between 2 and 32 mg/L, with modes of 4–8 mg/L4,5,13 and with more than 90% of isolates susceptible at 16 mg/L.7,14 Some authors find MICs for Serratia spp. to be higher than those for other Enterobacteriaceae, but values are still mostly 
16 mg/L and the finding is not universal. Temocillin MICs are not significantly raised by the expression of common β-lactamases, including AmpC and extended-spectrum β-lactamase (ESBL) types.6–8,15 Moreover, unlike cephalosporins, temocillin does not select derepressed mutants of AmpC-inducible species.16 MICs for Bacteroides spp. are high: the reasons are unknown but probably relate to low PBP avidity as temocillin is stable to the chromosomal β-lactamases of these organisms.4 MICs for P. aeruginosa are high too, typically 128–256 mg/L,4,5 compared with ticarcillin MICs of 16–32 mg/L. Once again the reasons are unclear, but may relate to poor permeation, efficient efflux or reduced PBP binding. Paradoxically, Burkholderia cepacia is more susceptible to temocillin than to other β-lactams except meropenem and ceftazidime, with an MIC90 of 32 mg/L reported for isolates from cystic fibrosis patients.17
Longitudinal studies in Belgium, where temocillin has remained in use since the 1980s, indicate that MIC distributions for Enterobacteriaceae have remained stable, at least over the past 6 years.7,13,14
The MICs of an antibiotic must, of course, be viewed together with its pharmacokinetics and safety profile. Temocillin is from a chemical class well known for its excellent tolerability, except among patients with specific allergy, and there is no evidence that it behaves differently from other widely used penicillins in this context. Its pharmacokinetics are also straightforward, with a V of 
0.2 L/kg,18 similar to most other β-lactams, but with relatively slower clearance (40–45 mL/min)19,20 related to strong protein binding (70% to 85%).21–23 Based on the maximum registered dosage of 2 g twice daily, the peak and trough total concentrations are 150–200 and 15–30 mg/L, respectively,19,22,23 with free concentrations at 15% to 30% of these values. Like all β-lactams, temocillin has ‘time-dependent’ microbiological activity, related to the fraction of the dosage interval during which the free concentration exceeds the MIC (fT > MIC). In discontinuous administration, an fT > MIC of 29% to 34% achieves bacteriostasis for penicillins against Gram-negative target organisms.24 Taking a value of 40%, for the sake of caution, along with median pharmacokinetic values, Monte-Carlo simulations for intensive care patients suggest a clinical breakpoint of 16 mg/L, as originally proposed as epidemiological cut-off,25 whereas a breakpoint of 8 mg/L allows for 95% confidence intervals of the pharmacodynamic parameters.23 The latter value was adopted for systemic infections by the BSAC Working Party on Susceptibility Testing, with a 32 mg/L breakpoint for lower urinary tract infection (UTI), to allow for the high concentrations reached in urine.26
An improved pharmacokinetic/pharmacodynamic profile is obtained by administering temocillin as a continuous infusion. The compound remains un-degraded for several days in aqueous solution, facilitating this approach and permitting stable free-drug concentrations above 16 mg/L.23 Based on general experience with penicillins, these levels should achieve stasis against organisms with MICs of 16 mg/L and maximal cidality rates against those with MICs of 4 mg/L.27 Recent investigators have used larger dosages (2 g thrice daily, or 6 g/day by continuous infusion) without adverse effect,28 implying that there may be scope to increase both the dose and the breakpoint.
Registered indications of temocillin in the UK and in Belgium as noted in the Specification of Product Characteristics are septicaemia, UTIs and lower respiratory tract infections, ‘where susceptible Gram-negative bacteria are suspected or confirmed’. Based on temocillin's relatively narrow spectrum, we view it as potentially most appropriate as microbiologically directed therapy, particularly for the UTIs due to confirmed ESBL producers. The spread of E. coli with ESBLs, principally CTX-M types, is a growing problem in both Europe and Asia, especially among ‘complicated’ patients with recent antibiotics and healthcare exposure.29 Empirical use in urinary infection might be considered if the local epidemiology and the patient's risk factors suggest that ESBL-producing Enterobacteriaceae are likely. In this setting, temocillin might be an alternative to carbapenems, which are the only other β-lactams with comparable β-lactamase stability. It is understood that the manufacturer is undertaking an outcome analysis for temocillin in complicated UTIs due to ESBL producers in the UK, and we welcome this. It is plausible that, as a narrow-spectrum antibiotic, temocillin may be ecologically benign: certainly, old studies suggest little or no propensity to select for resistant pathogens or for overgrowth by Clostridium difficile.30,31
Published clinical data on temocillin's use in severe sepsis or nosocomial pneumonia remain scanty and date from nearly a quarter of a century ago.23,28,32–34 Allowing for the complexity of many of the patients who have non-urinary infections with ESBL producers, meaningful comparative trials will be difficult to initiate in these settings. Nevertheless, Belgian experience suggests that temocillin is safe and effective in, for example, ventilator-associated pneumonia so long as the organism appears susceptible in vitro or, in empirical use, so long as anti-Gram-positive agents are also given and Pseudomonas is considered unlikely.
Temocillin is likely to remain a niche product, yet its prudent use, along the lines suggested here, may help clinicians to cope with difficult situations while sparing other agents.
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No funding was used for the production of this article. The laboratory work and pharmacokinetic/pharmacodynamic investigations of P. M. T. on β-lactams, including temocillin, are supported by the Belgian Programme of Interuniversity Poles of Attraction initiated by the Federal Office for Scientific Technical and Cultural Affairs (research projects IAP5/33 and IAP6/19), the Belgian Fonds de la Recherche Scientifique Médicale (grant numbers 3.4549.00 and 3.4542.02) and the Direction générale de la recherche et des technologies of the Région Wallonne (FIRST-Entreprise Programme).
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None to declare.
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