Staphylococcus Aureus
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REVIEWS New antimicrobial agents for methicillin-resistant Staphylococcus aureus Marin H Kollef In bacterial and fungal infections, optimal outcomes are ABSTRACT obtained through the timely provision of adequate antimi- crobial coverage in an initial anti-infective treatment regi- In bacterial and fungal infections, optimal outcomes are men.Crit However, Care Resusc selecting ISSN: 1441-2772 appropriate 7 Decem- antimicrobial obtained through the timely provision of adequate regimensber 2009 to treat11 4 282-286 infections in the intensive care unit can be antimicrobial coverage in an initial anti-infective treatment ©Crit Care Resusc 2009 challengingwww.jficm.anzca.edu. because of au/aaccm/journal/publi-the expansion of antibiotic resist- regimen. However, selecting appropriate antimicrobial ance.cations.htm Multidrug anti-infective regimens are typically needed regimens to treat infections in the intensive care unit is to adequatelyReviews cover the common important pathogens in challenging because of the expansion of antibiotic ICUs. The term “ESKAPE” has been coined for the group resistance. Multidrug anti-infective regimens are typically that causes most hospital-acquired infections able to needed to adequately cover common important pathogens “escape” our antibiotic arsenal in the United States: Entero- in ICUs. coccus faecium, Staphylococcus aureus, Klebsiella pneumo- Here, we describe novel antibacterial agents in the late niae, Acinetobacter baumannii, Pseudomonas aeruginosa, stages of clinical development that show potential for and Enterobacter spp. Their existence mandates the discov- treating methicillin-resistant Staphylococcus aureus (MRSA) ery of new antimicrobial agents. Here, we describe novel infections. antibacterial agents in the late stages of clinical develop- These include the fifth-generation cephalosporins, ment that show potential for treating methicillin-resistant ceftaroline and ceftobiprole; the glycopeptides, S. aureus (MRSA) infections. dalbavancin, oritavancin, and telavancin; and iclaprim. Crit Care Resusc 2009; 11: 282–286 Ceftaroline Ceftaroline fosamil is a fifth-generation cephalosporin pro- drug with activity against a broad range of gram-positive and Early-phase clinical trials established a dosing regimen for gram-negative bacteria. The active agent, ceftaroline, is ceftaroline of 600 mg intravenously (IV) every 12 hours (as a active against MRSA and has a minimum inhibitory concen- 1-hour infusion) as the preferred regimen for future study. μ tration for 90% of organisms (MIC90) of 1–2 g/mL because Less than 20% of the drug is protein bound in serum, and it of its enhanced binding to penicillin-binding protein 2a has a volume of distribution similar to the extracellular fluid (PBP2a), as compared with other β-lactam antibiotics.1 The volume at around 16–17 L. Ceftaroline is primarily elimi- drug is also active against penicillin- and cephalosporin- nated by renal excretion, and multiple-dose pharmaco- resistant Streptococcus pneumoniae and β-haemolytic strep- kinetic studies have shown the half-life is around 2.5–3 tococci, and has variable activity against Enterococcus faeca- hours. It does exhibit an extended half-life or area under the lis but little or no activity against vancomycin-resistant plasma concentration time curve under conditions of mild- Enterococcus faecium. Against relevant gram-negative path- to-moderate renal impairment, and would be expected to ogens, it has broad-spectrum activity similar to that of require dose adjustment in these populations. No data are ceftriaxone. However, its MICs are generally higher than currently available on ceftaroline clearance in dialysis. Its those of cefepime against most non-fermenting gram-nega- potential for use in pneumonia is supported by the finding tive bacteria and Enterobacteriaceae, and it is expected to be that lung tissue penetration in rabbits at the end of inactive against Pseudomonas spp. and Acinetobacter spp. ceftaroline infusion was 42% of serum concentrations.2 Ceftaroline appears to be a weak inducer of AmpC β- A phase II clinical trial has compared ceftaroline (preferred lactamases, and, like other clinically available cephalosporins regimen for 7–14 days) with vancomycin (1 g IV every 12 (besides cefepime), is labile to AmpC and expected to be hours, with or without aztreonam (1 g IV every 8 hours) for clinically ineffective against AmpC isolates. Like other the treatment of complicated skin and skin structure infec- advanced-generation cephalosporins, ceftaroline is not relia- tion (cSSSI).3 Clinical cure rates were similar for the ceftaro- bly active against strains of Enterobacteriaceae that produce line (96.7%) and standard therapy (88.9%) groups. Phase III extended spectrum β-lactamases (ESBLs). clinical trials for this indication are now complete, but data 282 Critical Care and Resuscitation • Volume 11 Number 4 • December 2009 REVIEWS had not been published at the time of writing. Perhaps diabetic foot and mixed bacterial cSSSI infections and more interesting for ICU practitioners, phase III trials are compared ceftobiprole (500 mg IV every 8 hours) with currently ongoing to compare 5–7 days of ceftaroline vancomycin (1 g IV every 12 hours) plus ceftazidime (1 g IV therapy with ceftriaxone (1 g IV daily) for treatment of every 8 hours) for 7–14 days. Clinical cure rates were also community-acquired pneumonia. similar for the ceftobiprole (90.5%) and standard therapy (90.2%) groups. Ceftobiprole (500 mg IV every 8 hours) was also compared with a combination of ceftazidime and Ceftobiprole linezolid for treatment of nosocomial pneumonia.7 Ceftobiprole medocaril is another fifth-generation cepha- Although the study showed ceftobiprole was non-inferior losporin pro-drug, with a broad spectrum of activity similar versus the combination regimen, it was unexpectedly asso- to that of ceftaroline. Like ceftaroline, ceftobiprole was ciated with lower cure rates in patients with ventilator- designed to maximise binding to PBP2a and yield potent associated pneumonia, particularly those younger than 45 μ 4 anti-MRSA activity, with an MIC90 of 2 g/mL. Ceftobiprole years and those with high creatinine clearance. is active against cephalosporin-resistant S. pneumoniae and ampicillin-susceptible E. faecalis, but not E. faecium. Cefto- biprole has broader gram-negative activity than ceftaroline; Dalbavancin it appears to have a gram-negative spectrum of activity Dalbavancin is a lipoglycopeptide currently under investiga- intermediate between that of ceftriaxone and cefepime, tion. It has a bacteriocidal mechanism of action similar to largely because of its greater stability to AmpC β-lactam- that of other glycopeptides in that it complexes with the D- ases than ceftriaxone and ceftaroline. Ceftobiprole also has alanyl-D-alanine (D-Ala-D-Ala) terminal of peptidoglycan and activity against P. aeruginosa, and MICs against this patho- inhibits transglycosylation and transpeptidation.8 Like teico- gen are generally similar to those of cefepime and ceftazi- planin, dalbavancin possesses a lipophilic side chain that dime. Activity against Acinetobacter spp. appears to be leads to both high protein-binding and an extended half- highly variable. As with other advanced-generation cepha- life, which allows once-weekly dosing. losporins, ceftobiprole is not reliably active against ESBL- Dalbavancin is more potent than vancomycin against producing bacteria. staphylococci, and is highly active against both methicillin- The volume of distribution is similar to the extracellular susceptible S. aureus (MSSA) and MRSA, with MIC90 values fluid volume, at about 18 L, although this may be doubled of < 0.13 mg/L and 0.25 mg/L, respectively. Dalbavancin is in patients with ventilator-associated pneumonia. There are also active against vancomycin-intermediate S. aureus μ currently no data on the epithelial lining fluid penetration of (VISA), although MIC90 ranges are higher, at 1–2 g/mL. It ceftobiprole, but a pharmacokinetic study is ongoing to inhibits streptococci, including penicillin-resistant S. pneu- evaluate concentrations of ceftobiprole in bronchoalveolar moniae, and enterococci with the VanB or VanC phenotype, lavage fluid after IV infusion. The drug is 16% bound to but is not active against enterococci with the VanA pheno- plasma proteins, is primarily eliminated in the urine, and has type. a half-life of around 3–4 hours. Because of its extensive Dalbavancin is administered intravenously, and the most renal clearance, dose adjustments have been proposed for commonly used dose in clinical trials has been 1000 mg on patients with mild-to-moderate renal impairment. Ceftobi- Day 1, followed by 500 mg weekly thereafter. This dose prole appears to be removed effectively by some haemodi- achieves a maximum serum concentration of 312 μg/mL, alysis modalities. with mean serum concentrations > 35 μg/mL maintained for Results of early phase clinical trials and Monte Carlo a 7-day dosing period. The drug has a volume of distribu- simulations suggested two dosing regimens for ceftobip- tion of 0.11 L/kg and a half-life of 147–258 hours, support- role: 500 mg IV as a 1-hour infusion every 12 hours for ing once-weekly dosing. Only 40% is eliminated by the treatment of gram-positive infections, and 500 mg IV as a kidneys, with no apparent need for dose adjustments in the 2-hour infusion every 8 hours for empirical treatment of setting of either moderate renal or hepatic impairment. It mixed gram-positive and gram-negative infections. Two