Novel Antibiotics for the Treatment of Staphylococcus aureus

Knut Ohlsen

Expert Rev Clin Pharmacol. 2009;2(6):661-672.

Abstract and Introduction

Abstract

Staphylococcus aureus is a leading cause of nosocomial and community-acquired infection associated with significant morbidity and mortality. Antibiotic treatment of infections owing to S. aureus have become increasingly challenging as the pathogen has acquired a broad spectrum of antibiotic resistance mechanisms. In particular, emergence and spread of methicillin-resistant S. aureus (MRSA) progressed to a global health threat. The glycopeptides antibiotics vancomycin and teicoplanin have remained as the drugs of last resort for more than 20 years. Fortunately, in addition to the glycopeptides, several novel antibiotics including linezolid, daptomycin, tigecycline, quinupristin/dalfopristin and ceftobiprole acting against MRSA have been recently introduced into clinical practice broadening therapeutic options. Although the arsenal of antistaphylococcal drugs has filled up in recent years, the rate of MRSA infection continues to be high in most countries. This demands an ongoing search for new antibacterials and lead compounds as well as development of alternative therapies and faster diagnostics to ensure effective anti-staphylococcal therapy in the future.

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Table 1. *In vitro* susceptibilities of methicillin-resistant *Staphylococcus aureus* to novel antibiotics.
Drug	Class	Sensitivity breakpoint (mg/l)*	Range (mg/l)	MIC₉₀ (mg/l)	Ref.
Quinupristin/dalfopristin	Streptogramine	≤1	0.03-0.1	1	^[73]
Linezolid	Oxazolidinone	≤4	0.5-8	4	^[82]
Tigecycline	Glycylcycline	≤0.5	0.06-0.5	0.5	^[71]
Daptomycin	Cyclic lipopeptide	≤1	0.125-0.5	0.5	^[92,93]
Ceftobiprole	Cephalosporin	≤4^‡	0.5-2	2	^[92]
Oritavancin (LY333328)	Glycopeptide	≤4^‡	0.5-1 1-4	1 4	^[94,95]
Dalbavancin	Glycopeptide	≤0.5^‡	0.016-0.25	0.25	^[78]
Telavancin (TD-6424)	Glycopeptide	≤2^‡	0.03-1	0.25-0.5	^[82]
Radezolid (RX-1741)	Oxazolidinone	≤4^‡	0.025-8	2-4	^[91]
Iclaprim (AR-100)	DHFR inhibitors	≤1^‡	0.015-2	0.06	^[88]
Delafloxacin (RX-3341)	Fluoroquinolone	≤1^‡	0.008-1	0.5	^[101]

*According to European committee on antimicrobial susceptibility testing (EUCAST).^[103]
^‡No official breakpoint defined yet, values have been proposed on the basis of MIC testings.

Table 2. Characteristics of newer (approved) agents against resistant *Staphylococcus aureus*.
Drug	Approved indication	Comments
Linezolid	Nosocomial pneumonia, cSSSI	Oral and intravenous form available, bacteriostatic, not approved for catheter-related bloodstream infections, side effects include myelosuppression, thrombocytopenia, anemia and neutropenia, which occur mostly with prolonged use
Daptomycin	Bacteremia, right-sided endocarditis, cSSSI (MRSA, MSSA)	Administered intravenously, once-daily dose, rapidly bactericidal, not active against VISA, no efficacy in pneumonia, potential muscle toxicity
Tigecycline	cSSSI (MRSA, MSSA), complicated intra-abdominal infections (MSSA)	Administered intravenously, broad spectrum (Gram-positive and Gram-negative), bacteriostatic, limited clinical data
Quinupristin/dalfopristin	cSSSI (MSSA), not approved for MRSA by the US FDA	Administered intravenously, side effects, poor tolerability, drug-drug interactions
Ceftobiprole*	cSSSI (MRSA, MSSA)	Administered intravenously, not approved for children, broad-spectrum activity includes AmpC-producing Pseudomonas aeruginosa and Escherichia coli, not active against ESBL-producing strains, limited clinical data

*Approved in Canada and Switzerland, under review in the USA and EU.
cSSSI: Complicated skin and skin-structure infection; ESBL: Extended spectrum β lactamase; MRSA: Methicillin-resistant Staphylococcus aureus; MSSA: Methicillin-susceptible Staphylococcus aureus.