A comparison of available and investigational antibiotics for complicated skin infections and treatment-resistant Staphylococcus aureus and enterococcus

This article compares vancomycin, teicoplanin, quinupristin-dalfopristin, linezolid, daptomycin, tigecyline, dalbavancin, telavancin, ceftobiprole, oritavancin, and ramoplanin for the treatment of complicated skin and skin structure infections (cSSSI), methicillin-resistant Staphylococcus aureus (MRSA), enterococcus, and vancomycin-resistant enterococcus. Vancomycin, a glycopeptide antibiotic, is administered intravenously, and is the mainstay of treatment for MRSA and cSSSI. While not available in the U.S., teicoplanin, another glycopeptide antibiotic, can be administered intramuscularly and has simpler dosing and monitoring requirements than vancomycin. Quinupristin/dalfopristin treats vancomycin-resistant Enterococcus faecium (VREF) infections but inhibits cytochrome P450 A3P4, and has only modest activity against MRSA pneumonia. Daptomycin effectively treats cSSSI but not pneumonia caused by MRSA, and is effective against all strains of Staphylococcus. Linezolid, available orally and intravenously, is approved to treat community-acquired and nosocomial pneumonia, cSSSI, and infections caused by MRSA and vancomycin-resistant enterococci including infections with concurrent bacteraemia and VREE Tigecycline, a glycylcycline derived from minocycline, has been approved by the FDA to treat cSSSI and complicated intraabdominal infections, and might be effective against Acinetobacter baumannii; its primary side effect is digestive upset. Dalbavancin, effective against MRSA and administered intravenously once weekly, possesses coverage similar to vancomycin. Telavancin deploys multiple mechanisms of action and is effective against MRSA and Gram-positive bacteria resistant to vancomycin. Ceftobiprole, a cephalosporin effective against MRSA, has few side effects. Oritavancin demonstrates similar activity to vancomycin but possesses extended activity against vancomycin-resistant Staphylococcus and enterococci. Ramoplanin, a macrocyclic depsipeptide, is unstable in the bloodstream but can be taken orally to treat Clostridium difficile colitis.     

The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract

Background:

The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug.     

Characteristics, control, and treatment of methicillin-resistant Staphylococcus aureus infections

The history, in vitro characteristics, epidemiology, clinical observations, control measures, and therapy of methicillin-resistant Staphylococcus aureus (MRSA) infections are reviewed. Strains of MRSA have been implicated in nosocomial infections, particularly in hospitals associated with medical schools. In vitro, MRSA cultures usually have only a small percentage of organisms that are resistant to methicillin. Patient-specific risk factors for acquiring MRSA infections have been identified in uncontrolled and controlled studies. Environmental culturing to identify sources of contamination has been nonproductive. Physical control measures such as good handwashing and proper isolation have produced variable results in dealing with MRSA. Other suggested measures for reducing the incidence of MRSA colonization include: increasing the nurse-to-patient ratio in intensive-care units; treatment of patients and hospital employees who are colonized with MRSA; and restriction of antibiotics. The drug of choice for treating MRSA infections is vancomycin given intravenously (peripherally or centrally) or by Ommaya reservoir (for CNS infections if bactericidical concentrations are not reached with i.v. doses). Vancomycin may be used empirically for patients at high risk for developing MRSA infections before culture-and-sensitivity reports are available.     

Linezolid: a pharmacoeconomic review of its use in serious Gram-positive infections

Linezolid (Zyvox), the first available oxazolidinone antibacterial agent, has good activity against Gram-positive pathogens, including multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Randomised multicentre trials in patients with various types of serious Gram-positive infections showed that clinical cure rates with linezolid were similar to those with vancomycin or teicoplanin. In some subgroup analyses, which must be interpreted with a degree of caution, clinical advantages were noted for linezolid (e.g. versus vancomycin in confirmed MRSA nosocomial pneumonia and MRSA-complicated skin and soft tissue infections). Although generally well tolerated, gastrointestinal adverse effects are relatively common with linezolid and it has been associated with thrombocytopenia and myelosuppression. The oral bioavailability of linezolid is approximately 100%, thus allowing sequential intravenous-to-oral administration without changing the drug or dosage regimen. Healthcare resource use data from various countries indicate that this practical advantage translates into at least a trend towards reduced length of hospital stay compared with vancomycin, which may offset its several-fold higher acquisition cost. Modelled analyses from the US, despite some limitations, indicate that, compared with vancomycin, linezolid is associated with lower total hospitalisation costs for the treatment of patients with cellulitis and has a favourable incremental cost-effectiveness ratio of approximately US30,000 dollars per QALY gained (2001 value) for patients with ventilator-associated pneumonia. Broadly similar results have also been reported in modelled analyses from other countries. In conclusion, for patients with serious Gram-positive infections, including those caused by suspected or proven multidrug-resistant pathogens such as MRSA, linezolid is an effective and generally well tolerated therapeutic option. Linezolid is currently the only antibacterial agent with good activity against MRSA that can be administered orally (as well as intravenously). It may be particularly useful as an alternative to vancomycin in patients who have impaired renal function, poor or no intravenous access, require outpatient therapy, or who have been unable to tolerate glycopeptides. Healthcare resource use studies and pharmacoeconomic analyses generally support the use of linezolid in some subgroups of patients, although results should be interpreted with due consideration of the study limitations.     

Antibiotics for treatment of infections caused by MRSA and elimination of MRSA carriage. What are the choices?

The widespread appearance of methicillin resistant Staphylococcus aureus (MRSA) has significantly undermined the efficacy of currently available antibiotic therapies as strains tend to be multi-resistant. Clinicians are therefore faced with a restricted choice in effective anti-MRSA therapies for infection or elimination of carriage. MRSA remain uniformly susceptible to glycopeptides vancomycin and teicoplanin which remain drugs of choice in treatment of infections. Centres with a high incidence of MRSA should use glycopeptides as empirical monotherapies against these organisms. The low toxicity of teicoplanin makes it an alternative for patients unable to tolerate vancomycin. Only mupirocin is truly effective for use as a topical agent in elimination of MRSA colonisation. For systemic use developmental glycopeptides such as daptomycin, MDL 63246, and LY191145 show better in vitro activity than vancomycin. New cephalosporins TOC-39 and FK-037 show promising anti-MRSA potential with low MICs, as does carbapenem BO-2727 which has a high in vitro activity. Whether the new cephalosporins and carbapenems with good in vitro and/or in vivo activities against MRSA will be clinically effective remains to be determined. New fluoroquinolones levofloxacin, temafloxacin and sparfloxacin have enhanced in vitro anti-MRSA activity, although the emergence of resistance, and subsequent cross resistance to related compounds during therapy is a problem. BAY 12-8039, DV-7751 and CS-940 are developmental fluoroquinolones with better in vitro activity and lower spontaneous mutation rates than related compounds. Co-trimoxazole shows good in vivo anti-MRSA activity, comparable to vancomycin, however, severe infections do not respond well and many strains are resistant to this drug. Rifampicin has excellent bactericidal activity but rapidly emerging resistance undermines its use as a monotherapy. Its use in a combination therapy offers limited potential as an alternative. Arbekacin shows good in vitro activity against many MRSA isolates, although resistance to related aminoglycosides is a problem. Streptogramins, virginiamicin and RP 59500 (dalfopristin/quinupristin), and the everninomicin SCH 27899, show excellent activity in vitro and in vivo activity against MRSA and real future potential as alternative agents to vancomycin. Azeleic acid and ramoplanin show future potential as agents for topical use against MRSA. In conclusion only vancomycin as a systemic agent and mupirocin as a topical agent, offer sufficient reliability for use against MSRA. Alternatives to glycopeptides and mupirocin rest with the development of new drugs from several classes of compounds.     

Clinical relevance of increasing glycopeptide MICs against Staphylococcus aureus

Glycopeptides are among the most widely used agents for the treatment of serious infections caused by Gram-positive bacteria, with vancomycin recommended for the treatment of infections caused by beta-lactam-resistant Staphylococcus aureus (MRSA). However, the utility of glycopeptides against MRSA has come into question owing to their poor tissue penetration, slow bactericidal activity and the emergence of strains with reduced susceptibility. A number of single-centre studies have demonstrated incremental increases in glycopeptide MICs for S. aureus strains over time - a phenomenon known as glycopeptide creep. High MICs have long been known to correlate with poorer clinical outcomes, but recent studies have shown that even small increases in MIC below the susceptibility breakpoint can affect the clinical efficacy of glycopeptides. The accurate measurement and ongoing surveillance of glycopeptide MICs at individual sites is therefore recommended to assist clinicians in their choice of empiric therapy for suspected serious S. aureus infections.     

Linezolid - the first oxazolidinone in the treatment of nosocomial MRSA pneumonia

The incidence of nosocomial pneumonia involving multi-drug resistant Staphylococcus aureus strains (MRSA) in particular is on the rise worldwide. For years, vancomycin has been used as the drug of choice in the treatment of MRSA infections and was recommended as such by clinical guidelines. Inadequate drug levels in pulmonary compartments due to large molecular size may be the cause of the comparatively low survival rates of patients with MRSA pneumonia treated with vancomycin, despite in vitro susceptibility of the bacterial isolates. Several trials demonstrated the clinical effectiveness of the novel oxazolidinone linezolid in nosocomial MRSA pneumonia. Linezolid achieves higher pulmonary concentrations than vancomycin which may be the cause of superior survival rates observed with linezolid in nosocomial MRSA pneumonia. Staphylococcus aureus strains with reduced susceptibility to vancomycin (VISA) are encountered with increasing frequency and may contribute to clinical failures of vancomycin. To date, linezolid-resistance appears to be rare and predominantly affects Enterococci, while very few linezolid-resistant S. aureus isolates were reported. Reduced susceptibility to linezolid is caused by point mutations in the 23S ribosomal RNA genes, which may be selected for by long-term therapy. The future development of linezolid resistance is hard to predict since the drug has been in use only for a limited period of time. This article describes the drug profile, patents and current data on the clinical efficacy of linezolid and reviews its role in treatment of MRSA pneumonia.     

Linezolid: a review of its use in the management of serious gram-positive infections

Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroidesfragilis. In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with community-acquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia. Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug. CONCLUSIONS: Linezolid has good activity against gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillin-resistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious gram-positive infections.     

Benefit-risk assessment of linezolid for serious gram-positive bacterial infections

Linezolid is an oxazolidinone, a new class of antibacterial with a unique mechanism of action, namely inhibition of the formation of a functional 70S initiation complex in the 50S bacterial ribosomal subunit. Linezolid is highly active against multidrug-resistant Gram-positive cocci, including meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate and vancomycin-resistant S. aureus, and vancomycin-resistant enterococci; its spectrum of activity also includes some anaerobic bacteria.Linezolid has been studied in several randomized controlled trials for the treatment of patients with community-acquired and nosocomial pneumonia, skin and soft tissue infections (SSTIs), urinary tract infections and bacteraemia. The available evidence suggests that linezolid is at least as effective as vancomycin for patients with nosocomial pneumonia, and there are some retrospective analyses supporting its superiority in comparison with vancomycin for MRSA nosocomial pneumonia, including ventilator-associated pneumonia. Linezolid is more effective than glycopeptides, macrolides and beta-lactams for SSTIs. The limited available data for the treatment of patients with bacteraemia suggest that it may be a better treatment option than vancomycin and beta-lactams for these patients, but questions have arisen regarding patients with catheter-related bacteraemias.Compared with other antibacterials, linezolid is associated with a greater frequency of adverse events, mainly nausea, vomiting, diarrhoea and headaches. Thrombocytopenia also occurs more frequently in patients taking linezolid but there is no increased frequency of anaemia. Other adverse events potentially related to linezolid therapy include fungal infections (moniliasis), hypertension and serotonin-like syndrome, tongue discolouration and taste alterations, dizziness, insomnia, rash and Clostridium difficile-related diarrhoea. The majority of adverse events develop after prolonged administration (i.e. >2 weeks) and subside shortly after discontinuation of linezolid. Peripheral or optic neuropathy, another possible adverse effect, is associated with an even longer duration of treatment (3-6 months).In conclusion, linezolid is an important treatment option for the treatment of patients with multidrug-resistant, Gram-positive bacterial infections. However, in order to reduce the possibility of development of resistance and preserve its activity, the use of linezolid should be restricted to treatment of patients with infections associated with high morbidity and mortality, particularly those caused by multidrug-resistant bacteria.     

Antimicrobial activity of phenothiazines

Multidrug-resistant Mycobacterium tuberculosis (MDRTB) and antibiotic-resistant Plasmodium falciparum are the major global lethal infections accounting for over 4 million deaths per year. Methicillin-resistant Staphylococcus aureus (MRSA) is the major global nosocomial infection and resistance to vancomycin is evident and may become common. This review provides the scientific and medical basis that support the use of one particular group of compounds, the phenothiazines, and in particular thioridazine, for the management of the above antibiotic-resistant infections. Because thioridazine, a relatively mild neuroleptic as compared to its parental compound chlorpromazine, kills intracellular MDRTB and MRSA at clinical concentrations, its use for the management of these infections may be considered. The review also discusses the activity of phenothiazines against protozoa and parasites, the mechanisms by which phenothiazines promote their antimicrobial effects, their potential for regulating efflux pumps that are a cause for mono or multidrug resistance, as well as their potential for the therapy of problematic infections caused by bacteria that have acquired plasmid-antibiotic-resistant genes.     

Treatment strategies for methicillin-resistant Staphylococcus aureus infections in pediatrics

Staphylococcus aureus is an important pathogen that frequently causes clinical disease in children. A wide array of illnesses can be caused by this common pathogen ranging from non-invasive skin infections to severe, life-threatening sepsis. Additionally, as antibacterials have been used to eradicate S. aureus, it has developed resistance to these important therapeutic agents. Methicillin-resistant S. aureus (MRSA) has become an increasing problem in pediatric patients over the past decade. In this review, we discuss the epidemiology, pathogenesis, and treatment options available in treating MRSA infections in children. Specifically, we address the importance of abscess drainage in the treatment of skin and soft tissue infections, the most common clinical manifestation of MRSA infections, and highlight the various agents that are available for treating this common infection. In severe, life-threatening invasive MRSA infections the primary therapeutic option is vancomycin. In cases of MRSA toxic shock syndrome the addition of clindamycin is necessary. In other invasive MRSA infections, such as pneumonia and musculoskeletal infections, the empiric treatment of choice is clindamycin. Finally, newer agents and additional treatment options are discussed.     

Linezolid: an oxazolidinone antimicrobial agent.

The pharmacology, antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effects of linezolid are reviewed. Linezolid, the only oxazolidinone antimicrobial approved for use in the United States, has significant activity against gram-positive bacteria, including penicillin-, cephalosporin-, and vancomycin-resistant species. Linezolid inhibits bacterial protein synthesis via binding to the 50S ribosomal subunit to prevent translation. The drug lacks cross-resistance with other antimicrobials. Linezolid is primarily excreted renally as unchanged drug. The measured plasma half-life of four to five hours permits twice-daily administration for all indicated infections. Virtually complete oral bioavailability allows for 1:1 conversion between the intravenous and oral dosage forms. Controlled comparative clinical trials demonstrate that linezolid is effective in the treatment of vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus (MRSA) infections, nosocomial and community-acquired pneumonia, and skin and skin-structure infections due to susceptible organisms. The recommended dosage is 600 mg i.v. or p.o. twice daily for all indications except uncomplicated skin and skin-structure infections (400 mg twice daily); adjustments for mild to moderate renal or hepatic impairment are not necessary. Clinically important interactions with monoamine oxidase inhibitors have not been observed. Reversible myelosuppression has been observed in a few patients. Linezolid has gram-positive activity comparable to that of vancomycin, is effective in a variety of infections, and is well tolerated, with diarrhea, headache, and nausea being the most frequently reported adverse effects. Linezolid provides a reasonable therapeutic alternative for patients with vancomycin-resistant E. faecium infections and patients infected with MRSA who cannot tolerate vancomycin.     

Emerging options for treatment of invasive, multidrug-resistant Staphylococcus aureus infections

Limited established treatment options exist for the treatment of serious, invasive infections caused by multidrug-resistant Staphylococcus aureus, most notably nosocomially acquired methicillin-resistant S. aureus (MRSA). Although vancomycin represents the gold standard for therapy of such invasive infections, reports of increasing in vitro resistance to vancomycin, combined with reports of clinical failures (with this and other antistaphylococcal agents), underscore the need for alternative therapies. Older agents with favorable in vitro activity available in both oral and intravenous dose forms include trimethoprim-sulfamethoxazole and clindamycin. Limited clinical data exist to support their routine use as initial therapy in the treatment of invasive disease. However, these and other options (e.g., tetracyclines) are being reexplored in the setting of increasing concern over MRSA acquired in the community setting. Newer treatment options for MRSA include linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline. With the exception of linezolid, these newer agents require intravenous administration. Combination therapy may be considered in select invasive diseases refractory to standard monotherapies. These diseases include infections such as endocarditis, meningitis, and prosthetic device infections. Additional alternatives to vancomycin are under clinical investigation. Those in later stages of development include oritavancin, dalbavancin, telavancin, and ceftobiprole.     

Community-acquired methicillin-resistant Staphylococcus aureus infections

Methicillin-resistant Staphylococcus aureus (MRSA) should no longer be regarded as a strictly nosocomial pathogen. During the past decade, community-acquired MRSA (CA-MRSA) infections among young persons without healthcare-associated (HCA) risk factors have emerged in several areas worldwide. These infections are caused by strains that almost exclusively carry the staphylococcal cassette chromosome mec type IV element and the Panton-Valentine leukocidin genes and, unlike HCA-MRSA strains, are not multiresistant. Although the majority of CA-MRSA infections are mild skin and soft tissue infections, severe life-threatening cases of necrotizing pneumonia, necrotizing fasciitis, myonecrosis and sepsis have been reported. Clindamycin is an effective agent for skin and soft tissue infections, however attention should be paid to the possibility of the emergence of resistance during treatment in strains with the macrolide, lincosamide and group B streptogramin (MLS(B))-inducible resistance phenotype. For patients with invasive infections that may be caused be CA-MRSA, vancomycin, teicoplanin and linezolid represent appropriate empirical therapeutic options.     

Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections

Ceftaroline fosamil is a cephalosporin antibacterial approved by the US Food and Drug Administration (FDA) for use in the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). After intravenous administration, ceftaroline fosamil is rapidly converted to its bioactive metabolite, ceftaroline. Ceftaroline has broad-spectrum in vitro activity against Gram-positive and Gram-negative bacteria, including contemporary resistant Gram-positive phenotypes, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae. Because of its unique spectrum of activity, the Clinical and Laboratory Standards Institute (CLSI) designated ceftaroline as a member of a new subclass of β-lactam antimicrobials, cephalosporins with anti-MRSA activity. The activity of ceftaroline against S. aureus extends to heteroresistant vancomycin-intermediate, vancomycin-intermediate, vancomycin-resistant and daptomycin-nonsusceptible isolates. Ceftaroline has low minimum inhibitory concentrations (MICs) for all tested species of streptococci, and has potent activity against S. pneumoniae isolates with varying degrees of penicillin resistance. The activity of ceftaroline is limited against Enterococcus faecalis and Enterococcus faecium and against anaerobes such as Bacteroides fragilis. The in vitro activity of ceftaroline includes many Gram-negative pathogens, but does not extend to bacteria that produce extended-spectrum β-lactamases, class B metallo-β-lactamases or AmpC cephalosporinases, or to most nonfermentative Gram-negative bacilli. Ceftaroline fosamil has been studied for the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired pneumonia (CAP) in phase III randomized, double-blind, international, multicentre noninferiority clinical trials. Two identical trials (CANVAS 1 and CANVAS 2) compared the efficacy of ceftaroline fosamil with that of vancomycin plus aztreonam in 1378 adults with cSSSI. Results demonstrated that ceftaroline was noninferior to vancomycin plus aztreonam, with 91.6% in the ceftaroline fosamil group (pooled analysis) achieving clinical response compared with 92.7% in the vancomycin plus aztreonam group (difference -1.1%, 95% CI -4.2, 2.0). An additional analysis evaluated clinical cure in a subgroup of patients who met the FDA guidance definition of ABSSSI at treatment day 3. Clinical response, defined as cessation of lesion spread and absence of fever, was 74.0% in the ceftaroline fosamil group compared with 66.2% in the vancomycin plus aztreonam group (treatment difference 7.8%, 95% CI 1.3, 14.0). Clinical efficacy of ceftaroline fosamil in 1240 hospitalized adults with CAP was compared with that of ceftriaxone in two additional phase III trials (FOCUS 1 and FOCUS 2). Of note, because ceftriaxone does not have activity against MRSA, patients with confirmed or suspected MRSA CAP were excluded from the FOCUS trials. Results demonstrated that ceftaroline was noninferior to ceftriaxone, with 84.3% in the ceftaroline fosamil group achieving clinical cure compared with 77.7% in the ceftriaxone group (difference 6.7%, 95% CI 1.6, 11.8). An additional analysis of the trials was conducted in patients with moderate to severe CAP and at least one proven typical bacterial pathogen at baseline (i.e. CABP). Day 4 clinical response rates were 69.5% for ceftaroline and 59.4% for ceftriaxone (difference 10.1%, 95% CI -0.6, 20.6). In the phase III trials, adverse event rates were similar between groups. Overall, ceftaroline is well tolerated, which is consistent with the good safety and tolerability profile of the cephalosporin class. In summary, ceftaroline fosamil is a broad-spectrum parenteral cephalosporin with excellent in vitro activity against resistant Gram-positive pathogens, including MRSA, as well as many common Gram-negative organisms. It is a welcome treatment option for ABSSSI and CABP.     

Telavancin: a novel lipoglycopeptide for serious gram-positive infections

Telavancin, a once-daily dosing lipoglycopeptide derived from vancomycin, has a broad-spectrum microbiologic activity against gram-positive bacteria, including vancomycin-resistant staphylococci. Telavancin displays a dual mode of action and a rapid bactericidal killing. The in vitro activity of telavancin is superior to vancomycin and comparable with, or greater than, linezolid, daptomycin and other novel lipoglycopeptides. Telavancin is effective against gram-positive pathogens in animal models of soft tissue infections and deep-seated infections including endocarditis, pneumonia and bacteremia. Clinical experience with telavancin in Phase II and III studies for complicated skin and skin structure infections have demonstrated similar efficacy and tolerability compared with standard anti-staphylococcal beta-lactams and vancomycin. Telavancin is in Phase III studies for nosocomial pneumonia. Telavancin seems to be promising as a novel agent for empiric therapy or as an alternative agent in serious infections caused by clinically important resistant gram-positive pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin intermediate-susceptible S. aureus, vancomycin-resistant S. aureus and vancomycin-resistant enterococci.     

In vitro exposure of community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains to vancomycin: does vancomycin resistance occur?

Vancomycin is the preferred parenteral antibiotic for the treatment of all methicillin-resistant Staphylococcus aureus (MRSA) infections, including the newly emerging community-associated MRSA (CA-MRSA) infections. Vancomycin-intermediate nosocomial MRSA strains have developed in vitro and in vivo after exposure to vancomycin. The aim of this study was to determine whether daily serial passage of CA-MRSA strains onto vancomycin-supplemented agar selects for the development of vancomycin resistance. Twelve clinical isolates of the six commonest Australian and US strains of CA-MRSA were serially passaged daily for 25 days onto brain-heart infusion agar plates supplemented with 4 microg/mL vancomycin and then subcultured for a further 15 days onto antibiotic-free agar to assess the stability of the resistance phenotype. Minimum inhibitory concentrations (MICs) were determined by standard Etest every 5 days from day 0 to day 40. Serial passaging resulted in increased MICs in all strains but the rises were modest, with an increase of < 2 doubling dilutions. All strains remained vancomycin susceptible throughout the experiment according to Clinical Laboratory Standards Institute criteria.     

Activity of pulmonary vancomycin exposures versus planktonic and biofilm isolates of methicillin-resistant Staphylococcus aureus from cystic fibrosis sputum

Vancomycin is commonly used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with cystic fibrosis (CF) lung disease. However, there are limited data to support the in vitro activity of this agent against MRSA isolated from CF sputum. The primary objective of this study was to evaluate the activity of vancomycin at pulmonary concentrations (intravenous and inhaled) against four clinical MRSA CF sputum isolates in planktonic and biofilm time–kill (TK) experiments. Vancomycin minimum inhibitory concentrations (MICs) were determined for these isolates at standard inoculum (SI) (~10⁶ CFU/mL) and high inoculum (HI) (~10⁸ CFU/mL) as well as in biofilms cultivated using physiological medium representing the microenvironment of the CF lung. Vancomycin concentrations of 10, 25, 100 and 275 µg/mL were evaluated in TK experiments against planktonic MRSA at varying inocula and versus biofilm MRSA. Vancomycin MICs increased from 0.5 µg/mL when tested at SI to 8–16 µg/mL at HI. Vancomycin MICs were further increased to 16–32 µg/mL in biofilm studies. In TK experiments, vancomycin displayed bactericidal activity (≥3 log₁₀ killing at 24 h) against 1/4 and 0/4 planktonic MRSA isolates at SI and HI, respectively, whereas vancomycin was bactericidal against 0/4 isolates against MRSA biofilms. Based on these findings, vancomycin monotherapy appears unlikely to eradicate MRSA from the respiratory tract of patients with CF, even at high concentrations similar to those observed with inhaled therapy. Novel vancomycin formulations with enhanced biofilm penetration or combination therapy with other potentially synergistic agents should be explored.     

抗菌药物联用对耐甲氧西林金黄色葡萄球菌体外抗菌活性研究

目的了解万古霉素与头孢哌酮/舒巴坦、亚胺培南、左氧氟沙星联用对MRSA的体外抗菌活性,指导临床合理用药。方法常规方法培养分离细菌,用VITEK微生物自动分析仪或API系统鉴定到种。MRSA鉴定应用乳胶凝集试剂盒,药敏试验采用肉汤倍比稀释法和琼脂平板稀释法。结果万古霉素对40株MRSA的MIC90为4mg/L,而与头孢哌酮/舒巴坦、亚胺培南、左氧氟沙星联用MIC90降为0.25～1mg/L。结论万古霉素与上述三种药物联用以协同作用为主,抗菌活性提高4倍以上。临床上治疗由MRSA引起的重症感染应根据药敏试验结果采用万古霉素与亚胺培南或头孢哌酮/舒巴坦或其它抗菌药物联合应用。     

蒙特卡洛模拟评价鞘内注射万古霉素治疗耐甲氧西林金黄色葡萄球菌颅内感染的给药方案

目的 应用蒙特卡洛模拟评价万古霉素鞘内注射治疗成人开颅术后耐甲氧西林金黄色葡萄球菌(MRSA)颅内感染的给药方案.方法 查阅有关成都地区万古霉素对MRSA菌株的最低抑菌浓度值(MIC)及其分布频率与中国成人开颅术后脑膜炎感染患者的群体药动学资料,Crystal Ball软件模拟5 000例次后得到相应目标获得概率(PTA)和累计反应分数(CFR).结果 当MIC值分别为0.03、0.06、0.12、0.25、0.50、1、2 mg·L-1时,万古霉素对MRSA的MIC分布频率分别为12.79％、12.79％、12.79％、12.79％、12.79％、29.07％和6.98％.当MIC分别为≤0.25、0.05、1、2mg·L-1时,分别予2.5、5、10、20 mg·d-1即可达到满意的抗菌活性(PTA=100％);鞘内注射10 mg·d-1的给药方案,其CFR大于90％.结论 结合各MIC分布频率与达满意抗菌活性的最低剂量可知,大多数成人开颅术后MRSA颅内感染的患者鞘内注射万古霉素10 mg·d-1时均可达到满意的治疗效果,经验性鞘内注射万古霉素时可考虑10 mg·d-1的给药剂量方案.