(2S,5R,6S)-6-[(3-Hydroxy-3-oxo-2-thiophen-3-ylpropanoyl)amino]-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Uses

Antibacterial.

Definition

ChEBI: Temocillin is a penicillin compound having a 6alpha-methoxy and 6beta-[2-carboxy(thiophen-3-yl)acetamido side-groups. It is a conjugate acid of a temocillin(2-).

Antimicrobial activity

The introduction of the 6-α-methoxy group has resulted in loss of activity against Gram-positive cocci and anaerobic Gram-negative bacilli, but it is active against enterobacteria (MIC 1–8 mg/L), H. influenzae and Mor. catarrhalis, with somewhat elevated MICs against carbapenemase- producing isolates of K. pneumoniae (MIC 16–64 mg/L) and Esch. coli (modal MICs 8–16 mg/L). In most cases, β-lactamase-positive and negative strains are equally susceptible. In contrast to the structurally related ticarcillin, it is inactive against Ps. aeruginosa, but Burkholderia cepacia, Ps. acidovorans and Aeromonas spp. are susceptible (MIC 4 mg/L). Most Acinetobacter spp. are resistant, and Ser. marcescens exhibits variable susceptibility.
It is bactericidal at concentrations 2–4 times the MIC; filaments formed at lower concentrations slowly lyse at higher drug levels. Temocillin consists of diastereoisomers. The naturally predominant R epimer is more rapidly bactericidal than the S epimer. It is highly resistant to most bacterial β-lactamases, including those that confer resistance to extended-spectrum cephalosporins. It is hydrolyzed by β-lactamases produced by Flavobacterium spp. and by those of Bacteroides spp.

Pharmacokinetics

Oral absorption: Negligible
C_max 1 g intramuscular injection: 70 mg/L
1 g rapid intravenous infusion: 172 mg/L after 5 min
Plasma half-life: 4.3–5.4 h
Plasma protein binding: 85%
Absorption and distribution
It is not absorbed when given orally and must be administered parenterally. Relatively high protein binding, together with its distribution in a volume less than the extracellular fluid, accounts for its relatively low renal clearance and subsequent high urinary concentrations that may be effective against some Enterobacteriaceae resistant to other β-lactam antibiotics. In artificial blister fluid and peritoneal fluid, concentrations reach 50% of the peak plasma level; in lymph, concentrations reach 25–60% of the simultaneous plasma level, with a similar half-life. The R epimer differs from the S epimer in lower protein binding, a 25% greater volume of distribution and a 60% shorter half-life.
Metabolism and excretion
Elimination is principally in the glomerular filtrate, with 80% of the dose appearing in the urine in the first 24 h. A small amount is disposed of in the bile and by degradation. Elimination declines in parallel with renal function, the half-life reaching 30 h in patients with creatinine clearance below 5%.

Clinical Use

Severe infection with susceptible bacteria, including urinary and respiratory tract infections, peritonitis and septicemia.

Side effects

As with all penicillins, hypersensitivity reactions, including serious anaphylactic responses, may occur. It is generally well tolerated and administration of 4 g intravenously every 12 h produced no significant effect on template bleeding time, prothrombin time or ADP-induced platelet aggregation.

Drug interactions

Potentially hazardous interactions with other drugs
Temocillin can reduce the excretion of methotrexate (increased risk of toxicity).

Metabolism

Temocillin is excreted unchanged mainly in the kidney.