Home
Up
Azlocillin
Mezlocillin
Piperacillin
Apalcillin

Ureidopenicillins

These semisynthetic penicillins are described together because they are often referred to as ‘‘newer antipseudomonal penicillins.’’ They are
all vulnerable to the action of many b-lactamases, but most of them are considerably more active in vitro than carbenicillin and ticarcillin against Pseudomonas aeruginosa, other Gram-negative bacteria, and some Gram-positive bacteria. These drugs are acylamino penicillins.
Because mezlocillin and azlocillin each contain a ureido group, they are called ureido-penicillins [1-2]. Piperacillin is now the key drug in this group that is commonly available, either alone or in the fixed combination of piperacillin / tazobactam.

Toxicity

Mezlocillin, azlocillin, and piperacillin may provoke any of the adverse reactions which occur with penicillin G. These drugs are contraindicated in patients with a history of penicillin hypersensitivity.

Among 63 patients whose chronic Pseudomonas osteomyelitis was treated with high doses of extended-spectrum penicillins for prolonged periods, side-effects such as rash, drug fever, and eosinophilia were more common in patients treated with ureido-penicillins than in those treated with carbenicillin [3].

Neurotoxicity

High doses of these drugs given i.v., similar to ‘‘massive’’ doses of penicillin G or carbenicillin, may have the propensity to cause neurotoxicity [4].

Bleeding disorders

Similar to carbenicillin and ticarcillin, mezlocillin, azlocillin, piperacillin, and apalcillin can cause a disturbance of platelet function [5-6]. Mezlocillin, piperacillin, and apalcillin have a lesser effect on platelet function than carbenicillin and ticarcillin at an equivalent dosage [6-9].

Neutropenia and thrombocytopenia

As with carbenicillin and ticarcillin and other b-lactam antibiotics, reversible neutropenia can occur during therapy with mezlocillin, azlocillin, and piperacillin [10-12]. This side-effect is more common with these penicillins than with carbenicillin. Thrombocytopenia can also rarely occur [13-15]. Piperacillin-induced neutropenia has been reviewed [16].

Hepatotoxicity

Reversible hepatotoxicity, mainly manifested by elevated enzymes, such as serum alkaline phosphatase, SGOT, and SGPT, has been noted
in 0.9% of mezlocillin-treated patients [12]. One patient with severe cholestatic jaundice caused by mezlocillin has been reported [17]. Elevations of hepatic enzymes and slight elevations of the serum bilirubin occurred in 3% of patients treated with piperacillin; one patient developed cholestatic hepatitis which reappeared with increased severity upon rechallenge with the drug [11].

Electrolyte and acid–base disturbance

An advantage of ureidopenicillins is that their sodium content per gram is less than half that of carbenicillin and ticarcillin, thus decreasing the risk of fluid overload and hypokalemia when high doses are used [18]. The sodium contents per gram of mezlocillin and piperacillin are 1.8 and 1.98 mEq, respectively, compared with a value of 4.7 mEq for carbenicillin.

Other side-effects

Some patients have developed nausea and diarrhea associated with parenteral use of these drugs.

Pharmacokinetic

None of these penicillins is absorbed from the gastrointestinal tract and they must be given parenterally (i.v. or i.m.).

The serum protein binding of these drugs depends on their serum concentration. At concentrations of 200 mg/ml, mezlocillin is 27% and azlocillin 30% protein bound. For piperacillin, the mean protein binding is 16% at concentrations in the range 200–300 mg/ml [19].

For all of these penicllins, the reason for the dose-dependent change in pharmacokinetics is that with larger doses there is saturation of the drugs’ biotransformation in the liver and biliary excretion.

Mezlocillin, azlocillin, piperacillin, and apalcillin are distributed in the body in a similar manner. Mezlocillin, azlocillin, and piperacillin penetrated well into interstitial and wound fluids, but after usual doses only low levels were reached in normal bone [19].

In animals, these penicillins penetrate poorly into normal cerebrospinal fluid (CSF). Mezlocillin and azlocillin penetrate much better when bacterial meningitis is induced, when CSF concentrations of 13.5% and 13.3% of steady-state serum concentrations, respectively, can be attained [20].

Mezlocillin, azlocillin, and piperacillin are excreted unchanged in the urine by both glomerular filtration and tubular secretion. Approximately
50–80% of an i.v. dose of these drugs is eliminated via the kidneys in an unchanged form [21-23]. With dose increments, an increasing proportion of all these drugs is recovered unchanged in the urine; for instance, with azlocillin 61% is recovered in the urine after a 1-g dose compared with 69% after a 5-g dose [19]. This is because with higher doses nonrenal mechanisms for drug elimination become saturated. Probenecid decreases renal excretion of these penicillins by partial blockage of renal tubular secretion. High concentrations of the active form of all these drugs are attained in the urine after usual i.m. or i.v. doses.

Significant amounts of mezlocillin, azlocillin, piperacillin, and apalcillin are eliminated via the bile. The percentage of these drugs eliminated via bile may increase in patients with impaired hepatic function; this is probably because there is less biotransformation in the liver [19].

Antibacterial activity

The antibacterial spectra of ureidopenicillins are similar to those of carbenicillin and ticarcillin, but there are differences between their degree of activity against various bacterial species. All of these antibiotics have lost much of their activity owing to emergence of resistance. To some extent, that problem has been reduced for mezlocillin and piperacillin, which are available in fixed combinations with sulbactam and tazobactam, respectively. The comparative in vitro susceptibility data for these agents against common pathogens are shown in Table 1.

Table 1. In vitro susceptibility of common pathogens to mezlocillin, azlocillin, piperacillin, and apalcillin in comparison with ticarcillin.

Organism

MIC (mg/ml)

Ticarcillin Mezlocillin Azlocillin Piperacillin Apalcillin
Gram-positive          
Staphylococcus aureus, non penicillinase producer 1.25 0.2 0.2 0.78 0.39
Staphylococcus pyogenes 0.5 0.025 <0.1 0.1 0.1
Streptococcus pneumoniae 1.25 0.025 0.1 0.01 0.05
Enterococcus faecalis 125 1 0.5 0.4-1.6 12.5
Clostridium perfringens 0.5 0.07 0.04 0.06-4 1.56
Gram-negative          
Escherichia coli 5 1-2 1-8 0.8 0.39
Enterobacter spp. 5 2-8 12.5-100 1.6 3.1
Klebsiella spp. 500 12.5-100 12.5->100 3.1 6.3
Serratia marcescens 12.5 12.5 12.5 0.8->100 25
Proteus mirabilis 1.25 1.56 1.56 0.2 0.76
Proteus vulgaris 2.5 1.56 12.5 0.78 12.5
Morganella morganii 2.5 1.56 12.5 0.78 3.1
Salmonella typhi 2.5 2 8 0.39 3.1
Neisseria gonorrheae 0.02 0.005 0.005 0.015-0.03 0.1
Haemophilus influenzae 0.25 0.15-0.25 0.06 0.015-0.03 -
Pseudomonas aeruginosa 25 25-50 12.5 6.5 6.3
Prevotella melaninogenica 0.1-4 0.5-4 - - -
Bacteroides fragilis 4-128 1-128 1-128 25 25

In vitro synergy and antagonism

In combination with an aminoglycoside (such as gentamicin, tobramycin, amikacin, or netilmicin), ureidopenicillins act synergistically against many strains of Gram-negative bacilli, such as P. aeruginosa, E. coli, P. vulgaris, P. rettgeri, Morganella morganii, and Klebsiella, Citrobacter, Enterobacter, and Serratia spp.
 


 


1. Lang R., Lishner M., Ravid M. "Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins". Rev. Infect. Dis. 13: 68, (1991).

2. Malanga C.J., Kokontis L., Mauzy S., Bodensteiner J.B. "A Piperacillin-induced seizures". Clin. Pediatr. 36: 475, (1997).

3. Slack M.P.E. "Antipseudomonal beta-lactams". J. Antimicrob. Chemother. 8: 165, (1981).

4. Selwyn S. "The evolution of the broad-spectrum penicillins". J. Antimicrob. Chemother. Suppl. B 1, (1982).

5. Dijkmans B.A.C., Van der Meer J.W.M., Boekhout-Mussert M.J. et al. "Prolonged bleeding time during azlocillin therapy. J. Antimicrob. Chemother. 6: 554,  (1980).

6. Gentry L.O., Jamsek J.G., Natelson E.A. "Effect of sodium piperacillin on platelet function in normal volunteers". Antimicrob. Agents Chemother. 19: 532, (1981).

7. Copelan E.A., Kusumi R.K., Miller L., Fass R.J. "A comparison of the effects of mezlocillin and carbenicillin on haemostasis in volunteers". J. Antimicrob. Chemother. 11 Suppl. C: 43, (1983).

8. Ballard J.O., Barnes S.G., Sattler F.R. "Comparison of the effects of mezlocillin, carbenicillin, and placebo on normal hemostasis". Antimicrob. Agents Chemother. 25: 153, (1984).

9. Gentry L.O., Wood B.A., Natelson E.A. "Effects of apalcillin on platelet function in normal volunteers". Antimicrob. Agents Chemother. 27: 683, (1985).

10. Eykyn S.J. "Azlocillin in the treatment of serious infection with Pseudomonas aeruginosa". J. Antimicrob. Chemother.9: 395, (1982).

11. Gooding P.G., Clark B.J., Sathe S.S. "Piperacillin: a review of clinical experience". J. Antimicrob. Chemother. 9 Suppl.: 93, (1982).

12. Parry M.F., Neu H.C. "The safety and tolerance of mezlocillin". J. Antimicrob. Chemother. 9 (Suppl A): 273, (1982).

13. Lang R., Lishner M., Ravid M. "Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins". Rev. Infect. Dis. 13: 68, (1991).

14. Olivera E., Lakhani P., Watanakunakorn C. "Isolated severe thrombocytopenia and bleeding caused by piperacillin". Scand. J. Infect. Dis. 24: 815, (1992).

15. Gharpure V., O’Connell B., Schiffer C.A. "Mezlocillin-induced thrombocytopenia". Ann. Intern. Med. 119: 862, (1993).

16. Scheetz M.H., McKoy J.M., Parada J.P. et al. "Systematic review of piperacillin-induced neutropenia". Drug Safety 30: 295, (2007).

17. Hargreaves J.E., Herchline T.E. "Severe cholestatic jaundice caused by mezlocillin". Clin. Infect. Dis. 15: 179, (1992).

18. Eliopoulos G.M., Moellering Jr R.C. "Azlocillin, mezlocillin, and piperacillin: new broad-spectrum penicillins". Ann. Intern. Med. 97: 755, (1982).

19. Bergan T. "Overview of acylureidopenicillin pharmacokinetics". Scand. J. Infect. Dis. 29 (Suppl): 33, (1981).

20. Hodges G.R., Worley S.E. "Comparative penetration of azlocillin and mezlocillin into cerebrospinal fluid of normal rabbits and rabbits with experimentally induced Pseudomonas aeruginosa meningitis". Antimicrob. Agents Chemother. 22: 909, (1982).

21. Bergan T. "Pharmacokinetics of mezlocillin in healthy volunteers". Antimicrob. Agents Chemother. 14: 801, (1978).

22. Fiegel P., Becker K. "Pharmacokinetics of azlocillin in persons with normal and impaired renal functions!. Antimicrob. Agents Chemother. 14: 288, (1978).

23. Meyers B.R., Hirschman S.Z., Strougo L., Srulevitch E. "Comparative study of piperacillin, ticarcillin, and carbenicillin pharmacokinetics". Antimicrob. Agents Chemother. 17: 608, (1980).

 

 

 

     Hit Counter

 

Send mail to stefano.biondi@innovativesolution.it with questions or comments about this web site.
Copyright © 2010 Innovative Solution di Biondi Stefano