Meeting the Unmet Need in the Management of MDR Gram-Positive Infections with Oral Bactericidal Agent Levonadifloxacin

Table 1

Common limitations of the currently available anti-MRSA agents.

Antibiotic	Mechanism of action	Limitations
Vancomycin	(i) Inhibits cell wall (peptidoglycan) synthesis; (ii) Bactericidal activity (variable)	(i) MIC creep, hVISA development; (ii) Variable tissue penetration; (iii) Potential for nephrotoxicity at higher concentrations and in combination with other nephrotoxic agents; (iv) Need for TDM
Daptomycin	(i) Disrupts cell membrane potential through rapid depolarization; (ii) Bactericidal activity	(i) Inactivated by pulmonary surfactant, not effective treatment of MRSA pneumonia; (ii) Potential for decreased susceptibility with increased vancomycin MIC and hVISA
Linezolid	(i) Inhibits protein synthesis through binding of 50S ribosomal subunit; (ii) Bacteriostatic activity	(i) Multiple potentially serious side effects (marrow suppression, lactic acidosis, peripheral and optic neuropathy, serotonin syndrome), especially with prolonged use
Trimethoprim/sulfamethoxazole	(i) Inhibits multiple stages in bacterial folate and thymidine synthesis; (ii) Bactericidal activity	(i) May be ineffective in infections involving undrained pus due to thymidine scavenging; (ii) Limited data supporting use in bacteremia and endocarditis
Clindamycin	(i) Inhibits protein synthesis through binding of 50S ribosomal subunit; (ii) Bacteriostatic activity	(i) Largely unproven for treatment of invasive infections in adults; (ii) Inducible resistance can be missed if D-testing is not performed on clinical isolates; (iii) Association with antibiotic-associated diarrhea and Clostridium difficile colitis
Tetracyclines	(i) Inhibit protein synthesis through binding of 30S ribosomal subunit; (ii) Bacteriostatic activity	(i) Unproven for treatment of invasive infections
Tigecycline	(i) Inhibits protein synthesis through binding of 30S ribosomal subunit; (ii) Bacteriostatic activity	(i) Low serum levels; (ii) Probably not effective in treatment of HA-MRSA pneumonia
Quinupristin/dalfopristin	(i) Synergistic combination of two streptogramin compounds that inhibit protein synthesis; (ii) Bactericidal activity in the absence of MLSB resistance	(i) Frequent side effects (arthralgias, myalgias, venous intolerance); (ii) Multiple drug-drug interactions; (iii) Limited data supporting use in invasive disease
Rifampicin	(i) Inhibits bacterial transcription; (ii) Bactericidal activity	(i) Rapid development of resistance; cannot be used as monotherapy; (ii) Multiple drug-drug interactions; (iii) Potential hepatotoxicity
Teicoplanin	(i) Inhibits cell wall synthesis	(i) Nephrotoxicity; (ii) MIC creep; (iii) 2-3 days required to reach therapeutic levels, even with loading dose; (iv) Variable tissue penetration; (v) Dose adjustment required in renal patients; (vi) TDM is recommended
Ceftaroline	(i) Binds to penicillin binding protein (PBP2a) and inhibits the synthesis of the peptidoglycan layer of bacterial cell walls	(i) Poor intracellular concentration; (ii) Dose adjustment in renal patients; (iii) Cannot be used as monotherapy in CABP; (iv) Clostridium difficile-associated diarrhea

CABP: community-acquired bacterial pneumonia; HA-MRSA: hospital-associated MRSA; hVISA: heteroresistant vancomycin-intermediate Staphylococcus aureus; MIC: minimum inhibitory concentration; MLS_B: macrolide-lincosamide-streptogramin B; MRSA: methicillin-resistant Staphylococcus aureus; TDM: therapeutic drug monitoring.