IDCR - Infectious Diseases in Corrections Report

Newer Antibiotics for the Treatment of Infections Caused by Gram Positive Cocci

Todd Correll, PharmD
University of North Carolina Infectious Diseases Clinic

Disclosures: Speaker - Gilead Sciences

Introduction

Over the past several years a number of new antimicrobial agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of Gram positive infections, and additional drugs for such organisms are likely to be developed. Tigecycline, daptomycin, linezolid and quinupristin-dalfopristin are therapeutic alternatives to vancomycin when clinical failure to this drug occurs, in cases of infection with vancomycin resistant organisms or following intolerable side effects attributed to vancomycin. Although these newer agents provide alternative options to treat many Gram positive infections, vancomycin still remains the treatment of choice for many drug-resistant Gram positive organisms. In clinical trials, these newer agents have often been proven to be non-inferior to (that is, not significantly worse than) vancomycin, but these studies have rarely been powered sufficiently to demonstrate superiority over vancomycin. While the new antimicrobials have broadened the treatment options for a variety of difficult-to-treat infections, they are also are associated with an increase in drug acquisition costs and may cause significant adverse drug effects. Additionally, these drugs are not resistance-proof and reduced susceptibility to each has been documented. Below, we review the major new antimicrobials for Gram positive infections and highlight their relative strengths and limitations.

Tigecycline

Tigecycline is a glycylcycline antibiotic derived from the tetracyclines. Similar to the tetracyclines, tigecycline is a bacteriostatic agent and inhibits bacterial growth by binding to the 30S ribosomal subunit. Cross-resistance between tigecycline and the tetracyclines is not universal due to tigecycline's ability to overcome two key mechanisms of resistance: antibiotic efflux and ribosomal protection. Its spectrum of activity includes Gram positive, Gram negative and anaerobic organisms, including methicillin-sensitive and -resistant Staphylococcus species (i.e. MSSA and MRSA), vancomycin-sensitive (VSE) and -resistant Enterococcus species (VRE), Streptococcus species, E. coli, Acinetobacter species, Klebsiella species, Enterobacter species, S. maltophilia, Citrobacter species, and Serratia. The drug has excellent activity against anaerobic organisms including Bacteroides species.

Tigecycline also has in vitro activity against Mycobacterium species, but there are limited clinical data to support its use for these organisms. Importantly, tigecycline does not have anti-pseudomonal activity and has limited activity against Proteus species and Providencia species.

Tigecycline is only available as an injection and is administered parenterally as a 1-hour infusion. It has an extended half-life ranging from 37 to 67 hours and undergoes hepatic metabolism. Tigecycline produced high levels in tissues, including the lung, skin and gastrointestinal organs; however, levels do not routinely exceed the MIC of the organism in the serum or urine. Tigecycline also does not penetrate into the central nervous system (CNS) and is not eliminated through the kidneys. Thus, tigecycline should not routinely be used for catheter-related blood infections, bacteremias, endocarditis, brain abscesses, meningitis or urinary tract infections due to poor penetration to these sites of infection. Tigecycline requires a 100 mg IV loading dose followed 50 mg IV every 12 hours (See Table 2). Dose reduction is recommended for patients with moderate-to-severe liver dysfunction. The overall incidence of adverse events did not different between tigecycline and the comparator agents in randomized studies with the exception of nausea and vomiting, which occurred in 20-35% of patients.^1,2 The frequency and severity of these symptoms tend-to-be dose related and dissipate after the first 2-3 days of therapy in the majority of patients. Premedication with antiemetic agents (i.e. promethazine) 30 minutes prior to the tigecycline administration may decrease the incidence of nausea and vomiting. Other side effects included headache and pruritis.

Tigecycline is FDA-approved for the management of complicated skin and soft tissue infections and complicated intra-abdominal infections. A New Drug Application has been submitted to the FDA for the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia.

Daptomycin

Daptomycin is a cyclic lipopeptide antibiotic and the first member of the class to be FDA approved. Daptomycin is bactericidal, and its mechanism of action is through the insertion of the drug's lipophilic tail into the bacterial cell membrane causing cell wall depolarization. This allows for potassium efflux leading to inhibition of DNA, RNA and protein synthesis - ultimately resulting in cell death. Unlike vancomycin and beta-lactam agents such as penicillins, daptomycin does not cause bacterial cell lysis and thus, endotoxins from being released. This, theoretically, can be advantageous as some toxins released from infected cells can cause inflammatory reactions. Its spectrum of activity is limited to Gram positive organisms, including MRSA and MSSA, Glycopeptide-Intermediately Resistant Staphylococcus, vancomycin-sensitive and-resistant Enterococcus species and Streptococcus species. Like vancomycin and beta-lactams, daptomycin has been shown to have synergistic effects when used with aminoglycosides and rifampin.

Daptomycin is only available as an injection and is administered parenterally as a 30-minute infusion. Similar to aminoglycosides and fluorquinolones, daptomycin displays concentration-dependent-killing and a post-antibiotic effect. Its half-life is approximately 8 hours, allowing for once-daily dosing. Early studies demonstrated an increase risk of rhabdomyolysis when daptomycin was administered twice a day. However, the risk of rhabdomyolysis is low when administering daptomycin once-daily. Daptomycin obtains high -aconcentrations in the serum and in most tissue compartments. It undergoes renal elimination requiring dose reductions for patients with severe renal dysfunction. Daptomycin does not penetrate the cerebral spinal fluid (CSF) and should not be used for the management of meningitis or brain abscesses. Additionally, daptomycin is inactivated in the lung by surfactant and is not effective for the treatment of pneumonia.

The dose of daptomycin is 4-6 mg/kg IV daily depending on the site of infection (See Table 2). Elevated creatine phophokinase (CPK) may occur with daptomycin therapy. Baseline CPK level and follow-up levels should be monitored. If elevations occur, daptomycin should be discontinued in patients who are asymptomatic with CPK levels 10 times the upper limit of normal or in patients who are symptomatic with CPK levels 5 times the upper limit of normal.

Daptomycin is FDA-approved for the management of complicated skin and soft tissue infections and Staphylococcus bacteremias with or without right-sided, native valve endocarditis.

Linezolid

Linezolid is the first antimicrobial agent in the oxazolidinone class and exerts its antibacterial effect by binding to the 50S subunit of the ribosome, preventing 70S formation and resulting in inhibition of bacterial synthesis. Its spectrum of activity consists of Gram positive organisms, including methicillin-sensitive and -resistant Staphylococcus species, vancomycin-sensitive and -resistant Enterococcus species, Streptococcus species.

Linezolid is available in oral and injectable formulations. Due to high bioavailability, linezolid can be converted from the intravenous formulation to the oral formulation at the same dose. Linezolid achieves high concentrations in the lung, liver, spleen, skin and vascular system. Linezolid concentrations 30-60% of plasma levels have been identified in the CSF in case reports. Approximately 60-70% of the drug is eliminated via the biliary system with remaining drug elimination via the kidney. The standard dose is 600 mg IV or PO every 12 hours (See Table 2). Dose reductions are not required for patients with renal or hepatic dysfunction.

Long-term use of linezolid has been associated with optic neuritis, peripheral neuropathy and bone marrow suppression. The most commonly reported hematologic side effect attributed to linezolid is thrombocytopenia - occurring in up to 30% of recipients. However, more recent data has demonstrated the risk of linezolid-induced thrombocytopenia is similar to vancomycin when administered for less than 14 days.³ Linezolid is a weak MOA-I type B inhibitor and has been associated with serotonin syndrome when used concomitant serotonergic agents. Serotonin syndrome secondary to linezolid is uncommon and does not preclude the use of linezolid with serotonergic agents. However, patients should be carefully monitored for clinical signs and symptoms of serotonin syndrome when initiating these agents together. ^4-6

Linezolid is FDA-approved for the treatment of vancomycin-resistant Enterococcus faecium infections (VRE), nosocomial pneumonia, complicated and uncomplicated skin and soft tissue infections and community acquired pneumonia.

Quinupristin-dalfopristin

Quinupristin-dalfopristin is a 30:70 mixture of a streptogramin B and A. Quinupristin-dalfopristin inhibits bacterial synthesis by binding to the 50S ribosomal subunit. When administered individually, quinupristin and dalfopristin exert modest antimicrobial activity and are usually bacteriostatic. When administered concomitantly, quinupristin and dalfopristin are more potent and able to overcome antimicrobial resistance. The spectrum of activity of this drug is limited to Gram positive organisms, including methicillin-sensitive and -resistant Staphylococcus spp and Streptococcus spp. Of note, Quinupristin-dalfpristin is only active against Enterococcus faecium, including vancomycin-resistant strains, and is not active against Enterococcus faecalis.

Quinupristin-dalfopristin is only available as an injection and is preferably administered through a central venous catheter as it is often causes thrombophlebitis. The recommended quinupristin-dalfopristin dose is 7.5 mg/kg IV every 8 to 12 hours (See Table 2). It undergoes extensive hepatic metabolism and is not renally eliminated. Quinupristin-dalfopristin inhibits CYP450 3A4, which may result in increased drug concentrations for agents metabolized by this hepatic process. Due to its hepatic metabolism, quinupristin-dalfopristin may cause elevations of AST and/or ALT as well as elevations in total bilirubin. Approximately 10% of patients will develop severe arthralgias and myalgias during quinupristin-dalfopristin therapy. Due to alternative agents with more extensive clinical data and more tolerable side effect profiles, quinupristin-dalfopristin should be reserved for treatment failures or when alternate agents cannot be administered.

Quinupristin-dalfopristin is FDA-approved for the management of vancomcyin Resistant Enterococcus faecium infections, including bacteremia and complicated skin and soft tissue infections.

Gram positive agents in drug development

Several pharmaceutical companies have Gram positive agents in clinical trials. Oritavancin, dalbavancin and televancin are members of a new antibiotic class called the lipoglycopeptides. Lipoglycopeptides possess Gram positive antibacterial activity including organisms with decreased vancomycin susceptibilities. Dalbavancin and televancin have received Fast Track status from the FDA for approval consideration and may be available by the middle of 2007 to early 2008. Another agent which has received Fast Track status is ceftobiprole, a cephalosporin with broad Gram negative and Gram positive antimicrobial activity, including Pseudomonas and methicillin-resistant Staphylococcus spp. Similar to other cephalosporins, ceftobiprole is not effective against Enterococcus spp.

Conclusion

As Gram positive infections - including antimicrobial resistant strains - continue to emerge as a major cause of community, institutional and hospital acquired infections, development of new agents to treat these infections is critical. Newer agents for infections caused by Gram positive organisms have a number of strengths and limitations compared to older agents such as vancomycin. Clinicians need to become familiar with these drugs in order to prescribe them safely and appropriately.

References
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^2. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The Efficacy and Safety of Tigecycline for the Treatment of Skin and Skin-Structure Infections: Results of 2 Double-Blind Phase 3 Comparison Studies with Vancomycin-Aztreonam. Clinical Infectious Diseases 2005;41:S341-53.
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