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Question
Does piperacillin/tazobactam (Tazocin) cover methicillin-sensitive Staphylococcus aureus (MSSA) infection? Or should we add a penicillinase-resistant penicillin to that treatment regimen?

Response from Ben M. Lomaestro, BS, PharmD
Senior Clinical Pharmacy Specialist in Infectious Diseases, Department of Pharmacy, Albany Medical Center Hospital, Albany, New York

The resistance of Staphylococcus aureus to beta-lactams is complex but primarily attributable to the blaZ and mecA genes. BlaZ encodes for beta-lactamase, an enzyme that destroys susceptible beta-lactam antibiotics; mecA encodes for penicillin-binding protein 2a (PBP2a), which is not well inhibited by beta-lactams, making cell wall cross-linking possible despite the presence of antibiotics.^[1] These genes are regulated by beta-lactam sensor/signal transducer proteins BlaR1 and MecR1 and repressor genes blaI and mecI.^[1]

The vast majority of S aureus strains produce beta-lactamase. This Ambler class A beta-lactamase was reported in the literature before the widespread clinical use of penicillin. The organism responded to the introduction of beta-lactamase-resistant semisynthetic beta-lactams (such as methicillin and oxacillin) by acquiring the mecA gene, and this marked the emergence of methicillin-resistant S aureus (MRSA).^[1]

Resistance in S aureus can also be caused by the presence of small colony variants (SCVs) that are naturally occurring subpopulations with increased beta-lactam resistance associated with persistent or recurrent infection. SCV resistance is due to differences in growth rate, atypical colony morphology, ability to survive intracellularly, and unusual biochemical characteristics rather than unique beta-lactamase production.^[2]

There are also "borderline methicillin-susceptible" strains of S aureus for which minimum inhibitory concentrations (MICs) of penicillinase-stable penicillins are at or just above the susceptibility breakpoint. Here, the possible mechanisms may include the presence of mecAand consequently altered PBPs, or hyperproduction of beta-lactamases. Sufficient doses of beta-lactamase inhibitors (such as tazobactam) will restore susceptibility in hyperproducing isolates.^[3,4] It has also been suggested that PBP2a alone is insufficient for high-level or homogeneous resistance expression of MRSA, and some other factor besides the mecA gene (referred to as chr*) is involved.^[5] Still other genes, designated as fem or aux, may contribute to high-level MRSA resistance by their involvement in cell wall synthesis.^[4,6]

S aureus beta-lactamase will retain susceptibility to piperacillin/tazobactam, whereas those strains producing an altered target site will not. Investigation of the activity of piperacillin/tazobactam against 51 strains of MSSA confirm continuing high potency with 100% piperacillin susceptibility and MIC₅₀ of 0.5, MIC₉₀ of 2, and an MIC range of 0.12-2.0 mcg/mL.^[7]Older regulatory trials also demonstrated clinical and microbiologic activity equal to comparators for several organisms including S aureus.^[8,9]

In summary, for strains in which the mechanism of resistance to S aureus is beta-lactamase production, piperacillin/tazobactam retains activity. There is no need to add a semisynthetic penicillin such as oxacillin.

References

1. Cha J, Vakulenko SB, Mobashery S. Characterization of the B-lactam antibiotic sensor domain of the MecR1 signal sensor/transducer protein from methicillin-resistant Staphylococcus aureus. Biochem. 2007;46:7822-7831.
2. Vaudaux P, Kelley WL, Lew DP. Staphylococcus aureus small colony variants: difficult to diagnose and difficult to treat. Clin Infect Dis. 2006;43:968-970. Abstract
3. Massidda O, Mingoia M, Fadda D, Whalen MB, Montanari MP, Varaldo PE. Analysis of the beta-lactamase plasmid of borderline methicillin-susceptible Staphylococcus aureus: focus on bla complex genes and cadmium resistance determinants cadD and cadX. Plasmid. 2006;55:114-127. Abstract
4. Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. 1997;10:781-791. Abstract
5. Kondo N, Kuwahara-Arai K, Kuroda-Murakami H, Tateda-Suzuki E, Hiramatsu K. Eagle-type methicillin resistance: new phenotype of high methicillin resistance under mec regulator gene control. Antimicrob Agents Chemother. 2001;45:815-824. Abstract
6. Berger-Bachi B. Genetic basis of methicillin resistance in Staphylococcus aureus. Cell Mol Life Sci. 1999;56:764-770. Abstract
7. Johnson DM, Biedenbach DJ, Jones RN. Potency and antimicrobial spectrum update for piperacillin/tazobactam (2000): emphasis on its activity against resistant organism populations and generally untested species causing community-acquired respiratory tract infections. Diag Microbiol Infect Dis. 2002;43:49-60.
8. Daniel KP, Krop LC. Piperacillin-tazobactam: a new beta-lactam-beta-lactamase inhibitor combination. Pharmacother. 1996;16:149-162.
9. Schoonover LL, Occhipinti DJ, Rodvold KA, Danziger LH. Piperacillin-tazobactam: a new beta-lactam/beta-lactamase inhibitor combination. Ann Pharmacother. 1995;29:501-514.