Optimizing therapy for MRSA pneumonia

Optimizing therapy for MRSA pneumonia

Semin Respir Crit Care Med. 2007 Dec

Skrupky LP, Micek ST, Kollef MH.
Department of Pharmacy, Barnes-Jewish Hospital. St. Louis, Missouri.

With its remarkable armamentarium of resistance and virulence factors, STAPHYLOCOCCUS AUREUS has emerged as a dominant pathogen causing pneumonia of all classifications. Rates of methicillin resistance are increasing as clinicians struggle to find ways to prevent the acquisition of methicillin-resistant STAPHYLOCOCCUS AUREUS (MRSA) and to effectively treat MRSA pneumonia. Community-associated MRSA has been identified as an important subset of MRSA with unique characteristics. Vancomycin remains a recommended first-line therapy for MRSA pneumonia, but resistance and therapeutic failures with vancomycin are being increasingly reported. Factors associated with vancomycin success or failure have been identified, including the genetics of the MRSA isolate, vancomycin lung penetration, minimum inhibitory concentration, and pharmacokinetic and pharmacodynamic variables. Retrospective analyses suggest that linezolid may provide improved outcomes compared with vancomycin for MRSA pneumonia, but validation in a prospective trial is currently lacking. Other treatment options are limited, but new prospects are being investigated. This paper reviews the epidemiology and pharmacotherapy of MRSA pneumonia.

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The Increasing Problem of Wound Bacterial Burden and Infection in Acute and Chronic Soft-Tissue Wounds Caused by Methicillin-Resistant Staphylococcus

The Increasing Problem of Wound Bacterial Burden and Infection in Acute and Chronic Soft-Tissue Wounds Caused by Methicillin-Resistant Staphylococcus aureus.

J Burns Wounds. 2007

Demling RH, Waterhouse B.
Brigham and Women's Hospital, Burn and Trauma Center, Boston, MA.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of colonization and infection in both acute and chronic soft-tissue wounds. Objective: Our objective is to define this current epidemic problem caused by both community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA), focusing on the similarities and differences between these 2 isolates as well as the impact on wound management decisions. Methods: Methods used include a literature review on the growth of the current MRSA problem and its International scope. In addition, a current up-to-date assessment had been made of the problem and the current approach to management of MRSA in acute soft-tissue and chronic wounds. Burns are not discussed because this injury usually does not fit either categories and is managed quite uniquely. Results: Results included the following: (1) There are very distinct properties of CA-MRSA and HA-MRSA, which must be considered for acute and chronic wound care. Management of both requires rigorous barrier precaution techniques to avoid cross-contamination. The presence of MRSA as a carrier state increases the risk of both a systemic and local wound infection in the carrier. There are large and increasing reservoirs of CA-MRSA and HA-MRSA worldwide leading to more bacteremias and wound problems. Topical antimicrobial therapy has not been addressed in managing MRSA in acute and chronic wounds. Conclusion: Conclusions include the fact that both HA-MRSA and CA-MRSA wound infections are rapidly increasing, especially with CA-MRSA. This high incidence requires appropriate wound prediction and management decisions as well as attempts to avoid further cross-contamination and reservoir growth. Topical antimicrobial therapy would seem to be an important component in controlling this tremendous problem. Yet this topic has yet to be adequately addressed.

PMID: 18091985 [PubMed - in process]

Pharmacokinetics and Pharmacodynamics of Ceftobiprole, an Anti-MRSA Cephalosporin with Broad-Spectrum Activity

Pharmacokinetics and Pharmacodynamics of Ceftobiprole, an Anti-MRSA Cephalosporin with Broad-Spectrum Activity
Clin Pharmacokinet. 2008

Murthy B, Schmitt-Hoffmann A.
Clinical Pharmacology and Experimental Medicine, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey, USA.

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.

PMID: 18076216 [PubMed - in process]