These semisynthetic penicillins are
described together because they are often referred to as ‘‘newer antipseudomonal
penicillins.’’ They are
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 .
High doses of these drugs given i.v., similar to ‘‘massive’’ doses of penicillin G or carbenicillin, may have the propensity to cause neurotoxicity .
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 .
Reversible hepatotoxicity, mainly
manifested by elevated enzymes, such as serum alkaline phosphatase, SGOT, and
SGPT, has been noted
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 . 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.
Some patients have developed nausea and diarrhea associated with parenteral use of these drugs.
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 .
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 .
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 .
Mezlocillin, azlocillin, and
piperacillin are excreted unchanged in the urine by both glomerular ﬁltration
and tubular secretion. Approximately
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 .
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.
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.
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