Temocillin

Temocillin is a derivative of ticarcillin that has been partly revived but is only available in Belgium, UK and Luxembourg (Eumedica SA). It is currently approved for treatment of septicaemia, urinary tract infection and lower respiratory tract infection due to Enterobacteriaceae.  Additionally, temocillin is designated Orphan Drug in Europe (EMA) and the United States (FDA) since 2004 for the treatment of Burkholderia cepacia infections in patients with cystic fibrosis.

When temocillin was first introduced in clinical practice in the 1980s it was commercially not viable as broad-spectrum antibiotics were favoured. The rise and spread of ß-lactamases revived the interest in temocillin. It is stable against hydrolysis by most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC-type β-lactamases, thus drawing attention as a potential alternative to carbapenems in treatment of infections caused by the Enterobactericeae producing these broad-spectrum β-lactamases.

In vitro activity of temocillin against extended spectrum β-lactamase-producing Escherichia coli (H. Rodriguez-Villalobos et al 2006):

TEmocillin ESBL

In a Belgian study, temocillin was active against more than 90% of the isolates including most AmpC- and ESBL-producing isolates (Y. Glupczynski et al 2007).

KPC producing enterobacteria are inhibited at MICs between 8 and 16 μg/ml for E.coli and between 16μg/ml and 64 μg/ml for K. pneumonia (J M Adams-Haduch et al 2009). Temocilliin is hydrolysed by OXA-48-like non-metalloenzymes or the metalloenzymes (N. Woodford et al 2013).

Currently there are no EUCAST breakpoints defined. The British Society for Antimicrobial Chemotherapy (BSAC) is the only organization that defines temocillin susceptibilities at ≤8 and ≤32 μg/ml in systemic and urinary tract infections, respectively.

The clinical evidence of temocillin’s effectiveness in ESBL-, AmpC-, or KPC-producing bacteria is meagre.  One clinical study examined the influence of the approved dosage (1-2 g every 12 hours) on outcome (I. Balakrishnan et al 2011).

Clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC β-lactamase-producing Enterobacteriaceae (I. Balakrishnan et al 2011):

Temocillin clinical

This figure illustrates the importance of using an optimal dosage of 2g twice daily vs a suboptimal dosage of 1g twice daily.

The clinical study confirms previous Monte Carlo simulation studies that showed that a daily dose of at least 4 g is necessary to attain the recommended pharmacokinetic/pharmacodynamic target for organisms with MICs of ≤8 mg/L (%fT>MIC ≥ 40%) (R. De Jongh et al 2007).

Probabilities of target attainment of temocillin (2 g every 12 h, using 25% average free drug) (R. De Jongh et al 2007):

Temocillin PTA

As the stability of temocillin largely exceeds the requirements of the European Pharmacopei a continuous infusion of 4g temocillin daily is a good alternative to manage patients with limited treatment options. The dosage should not be below the threshold of 4g daily in patients with normal renal function given as intermittent or continuous infusion.

Clinical studies with the aim to explore the safety of higher dosages might provide an alternative carbapenem-sparing treatment for patients with infections due to enterobacteriaceae, especially ESBL producing bacteria.

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