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Temocillin

 Temocillin is a b-lactamase resistant penicillin [1-2] belonging to the class of carboxypenicillins primarily used for the treatment of multiresistant Gram-negative bacteria.

Therapeutic use

Temocillin is not active against Gram positive bacteria or bacteria with altered penicillin-binding proteins. It is normally active against Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium and Yersinia enterocolitica. It is also active against some Enterobacter species, Morganella morganii, and Serratia species. Temocillin has no useful activity against Gram positive organisms, Acinetobacter species, or Pseudomonas aeruginosa. Its primary use is against Enterobacteriaceae, and in particular against strains producing extended spectrum b-lactamase or AmpC b-lactamase [3].

Respiratory tract infections

38 episodes of Burkholderia cepacia infections in 23 patients were treated with temocillin and reported favorable outcome [4].

Other infections

Clinical cure was achieved in 21 of 22 patients with acute peritonitis [5]. Of 25 patients who had had biliary tract surgery and developed infections, 23 were cured, one developed a staphylococcal pneumonia, and one had defective wound healing [6]. In a group of 22 patients with culture-positive septicemia, clinical cure was reported in 15, improvement in four, and failure in three [7]. Among patients with acute gonorrhoea, temocillin given as a single intramuscular dose of 0.5 or 1 g resulted microbiologic cure in 248 of 267 patients (93%) [8].

Dosage

The common dosage is 2g i.v. bid. There are good theoretical reasons for giving Temocillin as a continuous intravenous infusion in severe disease. Temocillin may be used in patients with impaired renal function. No adjustment needs to be made to the dose in mild to moderate renal impairment (creatinine clearance greater than 30ml/min). In severe renal impairment with creatinine clearance between  10 and 30ml/min, the dose is 1g in 24 hours; when less than 10, the dose is 1g every 48 hours.

Adults

Temocillin is administered parenterally at doses of 1 or 2 g intramuscularly or intravenously twice or three times daily or up to
6 g per day as continuous infusion [9]. Temocillin for intravenous injection is diluted in 20ml of sterile water and is diluted in less than 2.7ml of sterile water when being prepared for intramuscular injection.  Temocillin is stable for 24 hours in an 8% solution. With a 4 g per day dose given as continuous infusion, concentrations >16 mg/ml are maintained [10].

Newborn infants and children

No official information is available. In one trial of the use of temocillin for the treatment of pyelonephritis in children, a dose of 25 mg/kg. twice-daily was given to 22 children aged three months to 13 years [11].

Altered dosages

The manufacturer recommends no dose reduction in patients with a creatinine clearance >30 ml/min. In patients with creatinine
clearance between 10 and 30 ml/min, it is recommended to administer temocillin doses at 24-hour intervals, and in those with creatinine clearance <10 ml/min, every 48 hours [12]. In patients on hemodialysis, it is recommended to give one dose of temocillin after each dialysis [12].

Toxicology

The undesirable effects of temocillin are those characteristic of b-lactam antibiotics. In particular, Temocillin has been associated with angioedema and anaphylaxis in penicillin allergic patients. Animal studies have not shown any induction of Clostridium difficile infection [13]. As with any other penicillin, convulsions can occur if very high doses are given.

The animal toxicology studies showed a high degree of safety [14]. Since temocillin is rather highly protein bound, displacement of bilirubin from cord serum was studied [15]. Displacement was found only at concentrations far higher than those achieved clinically.

Since biliary concentrations of temocillin are very high, a hamster model of antibiotic-associated colitis was used to test the potential of temocillin to cause colitis [16]. It was reported that temocillin did not cause antibiotic-associated colitis, whereas that was the case when cefoxitin or clindamycin was administered as positive controls.

Pharmacokinetic data

The volume of distribution increases disproportionately with increasing temocillin doses, as does extrarenal clearance (from 6 ml/min at 0.5 g to 14 ml/min at 2 g). These findings could be due to a high and dose-dependent binding of temocillin to plasma proteins. In a study the protein binding was 88% , 83%, and 63% at concentrations of 50, 100, and 200 mg/ml [17]. Similar results were reported by other authors [18-19].

Bioavailability  
Protein binding 88%
Metabolism  
Half-life (hrs) 5.2 (0.5g); 5.0 (1g); 5.0 (2g)
Cmax (mg/ml) 78 (0.5g); 161 (1g); 236 (2g)
tmax (hrs) 0.08
AUC (mg/ml/h) 344 (0.5g); 573 (1g); 785 (2g)
Distribution volume Vdss (l/kg) 0.15 (0.5g); 0.17 (1g); 0.24 (2g)
Clearance ml/min 19 (0.5g); 19 (1g); 30 (2g)
Excretion 74% (0.5g); 66% (1g); 68% (2g) urinary

Absorption

Temocillin is not orally available.

Distribution

The penetration of temocillin into various tissues has been assayed and the tissue concentrations varied between 9% and 39% of concurrent serum concentrations [20-21]. In peripheral lymph, the maximal concentrations and areas under the serum concentration curve were reported to be approximately 50% of those in serum [22]. In bile, very high temocillin concentrations have been reported by several groups [23-25]. The cerebrospinal fluid penetration of temocillin was was found to be highly variable [26].

Excretion

Temocillin is primarily excreted by renal mechanisms. Urinary excretion accounted for 38% of the total dose given after 6 hours in six healthy volunteers, and total biliary excretion was recorded as 2.2% of the given dose (0.5 or 1 g) [23]. Seventy-one percent of the administered dose is excreted by 12 hours [27]. The mean concentration of temocillin in gallbladder bile was 314.7 (273.2) mg/ml after the 0.5-g dose and 474.5 (307.3) mg/ml after the 1-g dose. Thus, temocillin is highly concentrated in the normal gallbladder in man [23].

Metabolism

Mechanism of Action

Similar to other b-lactam antibiotics, temocillin acts by inhibiting penicillin-binding proteins (PBPs). A higher affinity of PBP 3 and 1 for temocillin than for ticarcillin and cefoxitin was observed. The affinity for PBP 2 of temocillin was low.

Antibacterial activity

Routine susceptibility

The antibacterial spectrum of temocillin is shown in Table 1 [28]. Similar results were reported by other authors [2, 18, 29-30]. Temocillin lacks activity against Gram-positive organisms and against Pseudomonas spp. Against B. cepacia, temocillin displays relatively high activity, with 82% of strains from patients with cystic fibrosis being susceptible if a breakpoint for susceptibility of 16 mg/ml was used [31]. Temocillin has a high activity against Neisseria gonorrhoeae, Branhamella catarrhalis, and Haemophilus influenzae irrespective of pencillinase production [32-33].

Emerging resistance and cross-resistance

Temocillin has a high degree of stability to b-lactamases, including extended-spectrum b-lactamases [3, 28, 34]. Temocillin has therefore kept most of its activity over the years [35]. 

Table 1. In vitro activity of temocillin.

Organism (n. of isolates) MIC range (mg/ml) MIC50 (mg/ml) MIC90 (mg/ml)
Gram-negative bacteria      
Acinetobacter spp. (32) 2->256 >256 >256
Aeromonas spp. (5) 2-8 4 8
Bacteroides spp. 8->256 32 256
Bordetella bronchiseptica (1) >256    
Burkholderia cepacia (3) 8-256 8 256
Citrobacter freundi (17) 4-64 4 16
Enterobacter aerogenes (25) 2->256 8 32
Enterobacter agglomerans (6) 2->256 8 16
Enterobacter cloacae (20) 2-128 4 128
Escherichia coli (29) 2-32 4 8
Haemophilus influenzae (10) 0.1-1 0.25 0.5
Klebsiella oxytoca (12) ≤1-16 4 16
Morganella morganii (18) 2-8 2 4
Neisseria gonorrhoeae (10) 0.05-1 0.2 1
Pasteurella multocida (1) 1    
Proteus mirabilis (23) 2-8 8 8
Proteus vulgaris (9) 2-4 2 4
Providencia rettgeri (22) ≤1-≥256 2 16
Providencia stuartii (31) ≤1-26 ≤1 4
Pseudomonas aeruginosa (32) 128->256 256 >256
Pseudomonas diminuta (1) 256    
Pseudomonas fluorescens (2) 16-256    
Pseudomonas stutzeri (2) 32-256    
Salmonella spp. (27) 2-32 8 32
Shigella spp. (27) 2-32 8 16
Serratia liquifaciens (3) <1-256 8 16
Serratia marcescens (29) 4-256 32 >256
Stenotrophomonas maltophilia (12) 8->256 128 >256
Gram-positive bacteria      
Bacillus subtilis (1) >256    
Clostridium difficile (1) >256    
Clostridium perfringens (1) >256    
Listeria monocytogenes (5) >256    
Staphylococcus aureus (7) >256    
Staphylococcus epidermidis (7) >256    
Streptococcus agalactiae (5) >256    
Streptococcus bovis (1) >256    
Streptococcus durans (1) >256    
Streptococcus pneumoniae (5) >256    
Streptococcus pneumoniae (9) 64->256 256 >256

 


Medicinal Chemistry

CAS number: 66148-78-5 EINECS: 266-184-1

Molecular Formula: C16H18N2O7S2
Average mass: 414.453308 Da
Monoisotopic mass:  414.055542 Da


Systematic name: (2S,5R,6S)-6-[(Carboxy-3-thienylacetyl)amino]- 6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid


SMILES: CC1([C@@H](N2[C@H](S1)[C@@](C2=O)(NC(=O)C(C3=CSC=C3)C(=O)O)OC)C(=O)O)C
Std. InChI: InChI=1S/C16H18N2O7S2/c1-15(2)9(12(22)23)18-13(24)16(25-3,14(18)27-15)17-10(19)8(11(20)21)7-4-5-26-6-7/h4-6,8-9,14H,1-3H3,(H,17,19)(H,20,21)(H,22,23)/t8?,9-,14+,16-/m0/s1

Properties

Melting Point:

 

ACD/LogP: 2.040.90 # of Rule of 5 Violations: 0
ACD/LogD (pH 5.5): -2.68 ACD/LogD (pH 7.4): -2.71
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 9 #H bond donors: 3
#Freely Rotating Bonds: 6 Polar Surface Area: 186.78 2
Index of Refraction: 1.675 Molar Refractivity: 97.10.4 cm3
Molar Volume: 258.55.0 cm3 Polarizability: 38.50.5 10-24cm3
Surface Tension: 82.55.0 dyne/cm Density: 1.60.1 g/cm3
Flash Point: 414.632.9 C Enthalpy of Vaporization: 116.43.0 kJ/mol
Boiling Point: 761.960.0 C at 760 mmHg Vapour Pressure: 0.02.7 mmHg at 25C

 


1. Andrews JM, Jevons G, Walker R, Ashby J, Fraise AP, "Temocillin susceptibility by BSAC methodology". J. Antimicrob. Chemother. 2007, 60, (1), 1857.

2. Van Landuyt HW, Pyckavet M, Lambert A, Boelaert J,  "In vitro activity of temocillin (BRL 17421), a novel beta-lactam antibiotic". Antimicrob. Agents Chemother. 1982, 22, (4), 53540.

3. Livermore D.M. et al. "Activity of temocillin vs. prevalent ESBL- and AmpC-producing Enterobacteriaceae from SE England". J. Antimicrob. Chemother. 57(5), 1012-4,(2006).

4.Lekkas A., Gyi K.M., Hodson M.E. "Temocillin in the treatment of Burkholderia cepacia infection in cystic fibrosis". J. Cyst. Fibros. 5: 121, (2006).

5. Pfeiffer M., Fock R.R.E. "Therapeutic experience with temocillin in peritonitis". Drugs 29, (Suppl 5): 194,  (1985).

6. Wittke R.R., Adam D., Klein H.E. "Therapeutic results and tissue concentrations of temocillin in surgical patients". Drugs 29, (Suppl 5): 221, (1985).

7. Van Lanuyt H.W., Lambert A., Van Couter A., Boelart J. "Temocillin in the treatment of Gram-negative septicaemia". Drugs 29, (Suppl 5): 182, (1985).

8. Reimer G., Milbradt R., Hulla F.W., Kammacher D. "Single dose therapy with temocillin in acute gonorrhoea". Drugs 29 (Suppl 5): 210, (1985).

9. De Jongh R. et al. "Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection". J. Antimicrob. Chemother. 61(2), 382-8, (2008).

10. De Jongh R., Hens R., Basma V. et al. "Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: Stability comparability, population pharmacokinetic studies and breakpoint selection". J. Antimicrob. Chemother. 61: 382, (2008).

11. Verboven M., Lauwers S., Pintens H. "Temocillin in the treatment of pyelonephritis in children". Drug Exp. Clin. Res. 13: 171, (1987).

12. Boelart J., Daneels R., Schurgers M. et al. "Effect of renal function and dialysis on temocillin pharmaciokinetics". Drugs 29, (Suppl 5): 109, (1985).

13. Boon R.J. et al., "Studies with temocillin in a hamster model of antibiotic-associated colitis". Antimicrob. Agents Chemother.  27 (6), 9801, (1985).

14. Cockburn A., Mellows G., Jackson D., White D.J. "Temocillin. Summary of safety studies". Drugs 29, (Suppl 5): 103, (1985).

15. Davies B.E. "Displacement of bilirubin from cord serum by sulphadimethoxine, amocycillin, clavulanic acid, temocillin and cloxacillin". Br. J. Clin. Pharmacol. 20: 345, (1985).

16. Boon R.J., Beale A.S. "Studies with temocillin in a hamster model of antibiotic-associated colitis". Antimicrob. Agents Chemother. 27: 980, (1985).

17. Hampel B., Feike M., Koeppe P., Lode H. "Pharmacokinetics of temocillin in volunteers". Drugs 29, (Suppl 5): 99, (1985).

18. Slocombe B., Basker M.J., Bentley P.H. et al. "BRL 17421, a novel b-lactam antibiotic highly resistant to b-lactamases, giving high and prolonged serum levels in humans". Antimicrob. Agents Chemother. 20: 38, (1981).

19. Overbosch D., van Gulpen C., Mattie H. "Renal clearance of temocillin in volunteers". Drugs 5, (Suppl 5): 128, (1985).

20. Cowan W., Baird A., Sleigh J.D. et al. "Lung tissue penetration of temocillin". Drugs 29, (Suppl 5): 151, (1985).

21. Gould J.G., Meikle G., Cooper D.L., Horton R. "Temocillin concentrations in human tissues". Drugs 29, (Suppl 5): 167, (1985).

22. Bergan T., Olszewski W.L., Engeset A. "Temocillin penetration of peripheral lymph". Drugs 29, (Suppl 5): 114, (1985).

23. Maudgal D.P., Lanzini A., Northfield T.C. et al. "Quantification of temocillin biliary excretion and gallbladder bile concentration". Drugs 29, (Suppl 5): 146, (1985).

24. Poston G.J., Greengrass A., Moryson C.J. "Biliary concentrations of temocillin". Drugs 29, (Suppl 5): 140, (1985).

25. Spelsberg F., Bauernfeind A., Wiest W., Hanser P. "Biliary concentrations of temocillin". Drugs 29, (Suppl 5): 122, (1985).

26. Brckner O., Trautmann M., Borner K. "A study of the penetration of temocillin in the cerebrospinal fluid". Drugs 29, (Suppl 5): 162, (1985).

27. Modr Z., Morvek J., Dvorcek K. et al. "Pharmacokinetics of temocillin after intravenous and intramuscular administration". Czech. Med. 9: 181, (1986).

28. Jules K., Neu H.C. "Antibacterial activity and b-lactamase stability of temocillin". Antimicrob. Agents Chemother. 22: 453, (1982).

29. Greenwood D., Cowlishaw A., Eley A. "In vitro activity of temocillin, a new b-lactamase-stable penicillin active against enterobacteria". Antimicrob. Agents Chemother. 22: 198, (1982).

30. Verbist L. "In vitro activity of temocillin (BRL 17421). A novel beta-lactamase-stable penicillin". Antimicrob. Agents Chemother. 22: 157, (1982).

31. Bonacorsi S., Fitoussi F., Lhopital S., Bingen E. "Comparative in vitro activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime in combination with tobramycin, rifampin, or ciprofloxacin against Burkholderia cepacia isolates from patients with cystic fibrosis". Antimicrob. Agents Chemother. 43: 213, (1999).

32. Piot P., van Dyck E. "In vitro activity of BRL 17421 against Haemophilus influenzae, Neisseria gonorrhoeae, and Branhamella catarrhalis. Antimicrob. Agents Chemother. 21: 166, (1982).

33. Jephcott A.E., Egglestone S.I. "In vitro activity of temocillin against Neisseria gonorrhroea, including penicillinase-producing strains". Drugs 5, (Suppl 5): 18, (1985).

34. Rodriguez-Villalobos H., Malaviolle V., Frankard J. et al. "In vitro activity of temocillin against extended spectrum b-lactamase-producing Escherichia coli". J. Antimicrob. Chemother. 57: 771, (2006).

35. Livermore D.M., Tulkens P.M. "Temocillin revived". J. Antimcrob. Chemother. 63: 243,  (2009).

 

 

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