Penicillinase-Resistant Penicillins

Penicillinase resistant penicillins include isoxazolyl penicillins: Oxacillin, Cloxacillin, Dicloxacillin and Flucloxacillin. Isoxazolyl penicillins combine resistance to staphylococcal b-lactamase with resistance to gastric acidity. Similar to methicillin and nafcillin, they are effective antistaphylococcal agents, but they can be administered orally. Four such penicillins are available as described below (see Figure 1).

Figure 1. Chemical structure of isoxazolyl penicillins.

The antibacterial spectrum of the isoxazolyl penicillins is similar to that of methicillin and nafcillin. Isoxazolyl penicillins are active against Gram-positive cocci, such as wild-type Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, viridans streptococci, and many species of Gram-positive bacteria, but Enterococcus species and Bacillus cereus are resistant. The Neisseria species are the only Gram-negative bacteria susceptible to these drugs.

S. aureus and Staphylococcus epidermidis

The isoxazolyl penicillins are primarily of interest because, being resistant to staphylococcal b-lactamase (penicillinase), they are active against staphylococci resistant to penicillin G. Resistance to this enzyme varies, some b-lactamase-resistant penicillins are more resistant than others [1-3]. The clinical significance of this is not known, but is generally considered to be of little importance. The less common human pathogen, S. lugdunensis, may be penicillin G susceptible as many strains do not produce penicillinase. Penicillinase producing strains are susceptible to isoxazolyl penicillins [4-5].

Synergy between one of the isoxazolyl penicillins or nafcillin and an aminoglycoside, such as gentamicin, against sensitive S. aureus strains can often be demonstrated in vitro and in animal experiments. Clinically, it is still uncertain whether this combination has any major advantages compared with single-drug therapy with an appropriate penicillinase-resistant penicillin [6-7]. The isoxazolyl penicillins are considerably less active than penicillin G against bacteria which are susceptible to penicillin G. However, they are 4- to 8-fold more active than methicillin against S. aureus.


1. Frimodt-Møller N., Rosdahl V.T., Sorensen G. et al. "Relationship between penicillinase production and the in vitro activity of methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, and cephalothin against strains of Staphylococcus aureus of different phage patterns and penicillinase activity". J. Antimicrob. Chemother. 18: 27, (1986).

2. Jarløv J.O., Rosdahl V.T., Mortensen I., Bentzon M.W. "In vitro activity and beta-lactamase stability of methicillin, isoxazolyl penicillins and cephalothin against coagulase-negative staphylococci". J. Antimicrob. Chemother. 22: 119, (1988).

3. Rennenberg J., Forsgren A. "The activity of isoxazolyl penicillins in experimental staphylococcal infection". J. Infect. Dis. 159: 1128,  (1989).

4. Herchline T.E., Barnishan J., Ayers L.W., Fass R.J. "Penicillinase production and in vitro susceptibilities of Staphylococcus lugdunensis". Antimicrob. Agents Chemother. 34: 2434, (1990).

5. Vandenesch F., Etienne J., Reverdy E., Eykyn S.J. "Endocarditis due to Staphylococcus lugdunensis: report of 11 cases and review". Clin. Infect. Dis. 17:
871, (1993).

6. Abrams B., Sklaver A., Hoffman T., Greenman R. "Single or combination therapy of staphylococcal endocarditis in intravenous drug abusers". Ann. Intern. Med. 90: 789, (1979).

7. Kaplan M.H., Tenenbaum M.J. "Staphylococcus aureus: cellular biology and clinical application". Am. J. Med. 72: 248, (1982).




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