New agents for gram-positive infections

April 2004

Due to the increased incidence of serious, multidrug-resistant bacterial infections, there has been renewed interest in the development of novel antibiotics to treat these infections. Methicillin-resistant Staphylococcus aureus (MRSA) now accounts for nearly 60% of staphylococcal infections in U.S. hospitals, and the incidence of community-acquired MRSA is an increasing concern.

Historically, vancomycin has been the treatment of choice for MRSA, although many clinicians agree that this therapy is suboptimal in its activity, particularly against severe infections and those in sequestered sites such as the central nervous system, lungs and bone. Additionally, vancomycin-resistant Enterococcus faecium (VREF) infections are now a clinical reality, and available therapeutic agents are limited.

Three new medications have been approved since 1999 that offer treatment options for infections caused by these resistant gram-positive pathogens. This article provides an overview of these new treatments, highlighting their role in the anti-infective armamentarium.

Quinupristin and dalfopristin

Synercid (Monarch Pharmaceuticals), a combination agent consisting of quinupristin and dalfopristin, is a streptogramin antibacterial approved by the FDA in September 1999. Its labeled indications include treatment of patients with serious or life-threatening infections associated with VREF bacteremia and complicated skin and skin-structure infections caused by methicillin-susceptible S. aureus (MSSA) or Streptococcus pyogenes.

Dalfopristin, comprising 70% of the combination, inhibits the early phase of protein synthesis by acting on the 50s ribosomal subunit, while quinupristin inhibits the late phase of protein synthesis. This synergistic combination provides bacteriostatic activity for E. faecium and bactericidal killing for strains of MSSA and MRSA. The agent demonstrates no activity against Enterococcus faecalis.

The main elimination route for both parent drugs and their metabolites is fecal excretion (75% to 77% of dose). Therefore, this agent can be used without concern or dosage adjustment in patients with renal impairment or hepatic insufficiency.

Regarding drug-drug interactions, in vitro studies have shown that quinupristin-dalfopristin significantly inhibits cytochrome P450 3A4. This results in increased concentrations, prolonged therapeutic effect and the potential for adverse reactions when administered with cyclosporine A, midazolam, nifedipine and terfenadine among others. Co-administration with any of these drugs requires caution and close monitoring.

The most common adverse events attributed to quinupristin-dalfopristin are localized infusion site reactions, gastrointestinal (GI) effects, myalgias and arthralgias. Therefore, it is recommended that quinupristin-dalfopristin only be administered through a central line. Muscle-related adverse events can be attenuated by lowering the administered dose to 5 mg/kg, although the efficacy of this regimen has not been evaluated in clinical trials. Of note, the most frequently observed abnormalities in laboratory studies are elevations in total and conjugated bilirubin. Increases greater than five times the upper limit of normal, irrespective of relationship to quinupristin-dalfopristin, were reported in more than 30% of patients who received the drug in clinical trials. Monitoring of the GI panel should be routinely performed in patients receiving prolonged therapy with this agent.

The clinical studies of quinupristin-dalfopristin for treating resistant infections were all noncomparative, as there were no available treatment options prior to approval of this agent. The patients in these studies were therefore likely to present with multiple comorbidities and/or physiologic impairments. Additionally, the patients were more likely to have been intolerant to or failed other antibacterial therapies. Despite these factors, quinupristin-dalfopristin had 90% efficacy in clearing the bloodstream of VREF within 72 hours of initiating therapy. Site-specific rates of cure ranged from 46% to 74% for other sites of infection including intra-abdominal, skin and skin structure, and urinary tract infections.

There have been two randomized, open-label, controlled clinical trials of quinupristin-dalfopristin (7.5 mg/kg q12h IV) in the treatment of complicated skin and skin structure infections. The comparator drug was oxacillin (2 g q6h IV) in the first study and cefazolin (1 g q8h IV) in the second. In both studies, vancomycin (1 g q12h IV) could be substituted for the specified comparator if the causative pathogen was suspected or confirmed MRSA or if the patient had an allergy to the comparator. Combined, the two studies enrolled nearly 900 patients and in both studies success rates were nearly equivalent for the two arms, between 66% to 68% for the quinupristin-dalfopristin group and 70% to 77% for comparators.

Quinupristin-dalfopristin has also been studied for empiric therapy of nosocomial pneumonia. When compared with vancomycin, clinical success rates were similar (45.3% and 43.3%). MRSA-specific cure rates were 58.6% and 64.3% for quinupristin-dalfopristin and vancomycin, respectively.

While quinupristin-dalfopristin was the first approved agent with specific activity against VREF, adverse events and the lack of an oral formulation have limited use. At most centers, this agent remains primarily a second-line agent for treating resistant gram-positive infections.

Linezolid

Linezolid (Zyvox, Pfizer), a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, was approved for use by the FDA in April 2000 and is indicated for use in VREF infections, complicated and uncomplicated skin and skin structure infections and nosocomial and community-acquired pneumonia. Linezolid has clinical utility in the treatment of infections caused by aerobic gram-positive bacteria. Specifically, linezolid is effective against E. faecium, S. aureus (including methicillin-resistant strains), Streptococcus agalactiae, Streptococcus pneumoniae and S. pyogenes. Additionally, the in vitro spectrum of activity of linezolid includes certain gram-negative and anaerobic bacteria.

Linezolid is neither a substrate nor inhibitor of the CYP-450 enzyme system; therefore, there are no reported drug-drug interactions through this route. Linezolid is a reversible, nonselective inhibitor of monoamine oxidase and could potentially react with serotonergic agents resulting in serotonin syndrome. There has recently been a series of case reports documenting this reaction in patients on concomitant selective serotonin reuptake inhibitors (SSRIs). Caution should also be used when linezolid is dosed with myelosuppressive medications, concurrent use may increase the risk of myelosuppression, a major side effect of this antibacterial. Studies also found concurrent use with tramadol may increase the risk of seizures.

Most linezolid-associated adverse events are mild and reversible. Associated marrow toxicity, however, occurs with prolonged durations of therapy and can be severe. Thrombocytopenia is reported in 2.4% of patients and typically occurs when the duration of therapy exceeds 10 to 14 days. In most patients, platelet counts will return to baseline after discontinuation of the drug; however, careful monitoring of this parameter is warranted particularly in patients requiring prolonged treatment courses with linezolid.

There have been several clinical trials evaluating the use of linezolid in a variety of treatment settings. Linezolid has been shown effective in treating infections cause by VRE (both E. faecium and E. faecalis) with a success rate ranging from 52% to 67% among patients receiving low and high-dose linezolid therapy, respectively. Patients with bacteremia, skin and skin structure infections, pneumonia and urinary tract infections were included in this study. In addition, linezolid is approved for treatment of skin and skin structure infections caused by other gram-positive organisms, including MRSA. Cure rates for microbiologically evaluable patients with MRSA skin and skin structure infection were 79% and 73% for linezolid- and vancomycin-treated patients, respectively. The indication for nosocomial pneumonia was based on comparative studies against vancomycin. Overall success rates were similar between groups at 57% and 60% for linezolid and vancomycin, respectively.

Linezolid therapy has also been evaluated in treatment of diabetic foot infections compared with a ß-lactam/ß-lactamase inhibitor combination. Linezolid performed well in this setting, which included 57 patients with osteomyelitis. Overall response was 81% for linezolid compared with 71% for comparators, although this did not reach statistical significance. Linezolid was preferred, however, in patients with infected foot ulcers (81% vs. 68%, P = .018). Clinical outcomes were also improved in patients without osteomyelitis (87% vs. 72%, P = .003).

Experience regarding linezolid use in more difficult to treat infections has been published. This includes data on 55 patients who received linezolid for treatment of osteomyelitis. An overall success rate of 82% was reported for this noncontrolled data generated from the linezolid compassionate use program. Case reports have also shown isolated instances where linezolid effectively treated resistant infections, including endocarditis in a pediatric patient.

More recently, the data from the two multicenter studies used to approve linezolid for treatment of nosocomial pneumonia have been reanalyzed to specifically evaluate use in treatment on MRSA pneumonia. These two publications have focused on all patients with documented MRSA pneumonia, which accounted for 160 of the more than 1,000 subjects in the two studies. There was a significant difference in favor of linezolid for survival (80% vs. 63.5%, P = .03).

Other investigators used the data from the subset of patients with ventilator-associated pneumonia (VAP) to determine the cost-effectiveness of an empiric treatment approach with linezolid. The more expensive linezolid was shown to be cost-effective when compared with vancomycin when these results were extrapolated to a hypothetical cohort of 1,000 patients with VAP. It is important to note that these data should be considered hypothesis-generating until further documented in controlled clinical trials and that these data specifically address the agent used as initial empiric therapy and not a change in therapy based on documented culture results.

Pharmacokinetic data do provide evidence supporting the efficacy of linezolid for pneumonia due to MRSA.

Epithelial lining fluid concentrations of linezolid are greater than those in serum and in all cases exceed minimum inhibitory concentrations (MICs) of linezolid against common gram-positive pathogens. This, in combination with the data from previous nosocomial pneumonia studies, has generated increased clinical interest in linezolid for treating nosocomial pneumonia where MRSA is suspected. Clinical trials are being performed to document this finding in a prospective, randomized fashion.

To date, linezolid use has primarily been reserved for treatment of patients with resistant infections where therapeutic options are limited. The excellent oral bioavailability of this agent makes it attractive for outpatient management of MRSA infections, which historically have been limited to home antibiotic therapy with vancomycin.

While this is certainly one method to decrease costs associated with therapy, clinicians should be careful to consider the impact of increased antimicrobial resistance that may occur from use of this approach. Cases of linezolid-resistant enteroroccus have been reported and associated with oral linezolid use.

Daptomycin

Daptomycin (Cubicin, Cubist Pharmaceuticals), the first cyclic lipopeptide, was approved by the FDA in September 2003 for the treatment of complicated skin and skin-structure infections caused by aerobic gram-positive bacteria, including MRSA and methicillin-susceptible Staphylococcus epidermidus (MSSE). Daptomycin also has activity against enterococcal species, and although only FDA-approved for vancomycin-susceptible strains, it is also effective for resistant infections.

In vitro, daptomycin exhibits rapid, concentration-dependent bactericidal activity against gram-positive organisms. Daptomycin inhibits bacterial growth by binding to bacterial membranes and causing a rapid depolarization of membrane potential. This leads to the inhibition of protein, and DNA and RNA synthesis, which results in bacterial cell death.

Daptomycin is only available in an IV formulation; however, a once-a-day dosing regimen makes this an agent easily administered in the inpatient as well as outpatient setting. Muscle pain and weakness are the major drug-related toxicities associated with daptomycin. In clinical trials, 0.2% of patients had symptoms including elevated creatine phosphokinase (CPK) values greater than four times the upper limit of normal. The symptoms resolved within three days, and CPK returned to normal within seven to 10 days after discontinuing treatment. Therefore, daptomycin should be used cautiously or discontinued in patients with muscle pain or weakness, and CPK monitoring should routinely be performed.

This reaction has also led to concerns over co-administration of daptomycin with other drugs associated with rhabdomyolysis, such as the HMG-CoA reductase inhibitors, including lovastatin, atorvastatin and pravastatin. In clinical trials, concomitant administration of daptomycin and simvastatin was not associated with any additional toxicity, although clinicians should still exercise caution when giving these agents together as use of the statin class of anti-hyperlipidemic medication was not allowed in most clinical trials of daptomycin.

Phase-3 studies of daptomycin have been conducted for complicated skin and skin-structure infections, community-acquired pneumonia, urinary tract infections and infections due to VREF.

More than 1,000 patients were enrolled in clinical trials for skin and skin-structure infections comparing daptomycin to either vancomycin (1 g IV q12h) or a semisynthetic penicillin (ie, nafcillin, oxacillin, cloxacillin or flucloxacillin; 4 to 12 g IV per day). Both studies were similar in design, but differed in patient characteristics, including history of diabetes and peripheral vascular disease. Most patients (89.7%) received IV medication exclusively, although step-down oral antibiotics were allowed. Clinical success rates were similar between the groups (81.1% vs. 73.5%, 95% CI, -15.5, 2.0) for daptomycin and comparator, respectively.

Daptomycin was also studied for treatment of community-acquired pneumonia in two separate trials. Daptomycin was shown to be statistically less effective than ceftriaxone in this study and therefore should not be used to treat pneumonia. Studies of resistant enterococcal and urinary tract infections were both terminated early due to poor enrollment and results have not been released. Ongoing clinical trials are investigating use of this agent for more severe infections, including bacteremia and endocarditis. Of note, doses being studied for these indications are higher than those for the approved indication (6 mg/kg/day vs. 4 mg/kg/day).

Conclusion

These three relatively new agents each represent unique additions to the antibacterial armamentarium and are invaluable in treating resistant gram-positive infections. Newer data are also emerging to establish their role in a greater variety of infections caused by both resistant and susceptible pathogens. None of them, however, provide a significant cost advantage over the standard of therapy, vancomycin, a factor that will likely limit their use.

While clinicians are now faced with multiple effective agents, judicious use of these drugs is required to maintain efficacy and prevent further resistance. The landscape of therapy for gram-positive infection has changed in the past decade and will continue to grow as new agents in the pipeline define their roles.

For more information:

• Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38:994-1000.
• Eliopoulos GM. Quinupristin-dalfopristin and linezolid: evidence and opinion. Clin Infect Dis. 2003;36:473-481.
• Lipsky BA, Itani K, Norden C, et al. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis. 2004;38:17-24.
• Rayner CR, Baddour LM, Birmingham MC, et al. Linezolid in the treatment of osteomyelitis: results of compassionate use experience. Infection. 2004;32:8-14.
• Shorr AF, Sulsa GM, Kollef MH. Linezolid for treatment of ventilator-associated pneumonia: a cost-effective alternative to vancomycin. Crit Care Med. 2004;32:137-143.
• Wunderink RC, Rello J, Cammarata SK, et al. Analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003;124:1789-1797.

• Elizabeth Dodds Ashley, PharmD, BCPS, is from the Division of Infectious Diseases, Duke University Medical Center.
• Peter Brunner is a PharmD Candidate at Duke University Medical Center.