___________________________________________________________________________ Antibiotics Review
leakage of cell contents, and disruption of the architecture of the cell membrane [175]. Following clinical trials to assess efficacy and the parameters of safe dosage, daptomycin was approved by the FDA in 2006 for parenteral treatment (4 mg once daily) of complicated bacterial skin and soft tissue infections. Subsequent experience and formal clinical trials have demonstrated that daptomycin efficacy is comparable to standard therapy for treatment of MRSA bacteremia and endocarditis, especially when administered at the higher dose of 6–10 mg daily. Daptomycin is an option for salvage and first-line treatment of bacteremia, endocarditis, and osteo- myelitis caused by MRSA and Enterococcus isolates showing resistance to vancomycin (minimal inhibitory concentration >2 mg/L) [176]. Adverse effects of daptomycin are rare with once daily dos- ing. Skeletal myopathy has been reported, mostly prior to 2006 when daptomycin was administered in multiple daily doses. When high dosage or prolonged daptomycin regimens are employed, coadministration with other drugs associated with myopathy, such as hydroxymethylglutaryl CoA reductase inhibitors (statins), should be avoided, and patients should be monitored for muscle pain or weakness [177]. Eosinophilic pneumonia has been reported in association with prolonged treatment of osteomyelitis. In a cohort study involving 1,021 patients who received daptomycin for bone and joint infec- tions, 17 (1.7%) were diagnosed with daptomycin-induced eosinophilic pneumonia [178]. All patients recovered upon discontinuation of daptomycin. LYPOGLYCOPEPTIDES Lipoglycopeptides are semisynthetic derivatives of glycopep- tides, akin to vancomycin and developed for treatment of multidrug-resistant staphylococcal and enterococcal infections. These newer agents have enhanced activity and favorable pharmacokinetics—in some cases, permitting administered at weekly intervals. In comparison to vancomycin, lipoglyco- peptides have greater potency against gram-positive bacteria, including vancomycin-resistant strains, and appear less likely to lead to emergence of resistant organisms [161; 162; 179]. As with vancomycin, lipoglycopeptides must be administered intravenously. The lipophilic side chain prolongs plasma half- life and helps anchor these agents to the outer structure of the bacterial cell, inhibiting cell wall synthesis and disrupting cell membrane integrity [163]. In animal studies, lipoglyco- peptides have proven effective in treating a variety of serious gram-positive infections, including bacteremia, pneumonia, and endocarditis [161; 162]. Clinical studies of efficacy in humans have been limited to date. At present, three lipoglycopeptides, telavancin, dalbavancin, and oritavancin, are approved by the FDA for the treatment of acute bacterial skin and soft-tissue infection. Clinical tri- als show equivalent or superior efficacy against MRSA skin infection when compared with vancomycin [7; 162; 164].
Telavancin is also approved for treatment of hospital-acquired and ventilator-associated S. aureus pneumonia. A phase III clinical trial is ongoing to assess telavancin efficacy and safety for treatment of complicated S. aureus bacteremia and right- sided endocarditis [179]. The side effect profile of these agents is mild and comparable to other effective regimens. Reported adverse effects include headache, nausea, pruritus, pain at injection site, and fever. Taste disturbance (i.e., metallic taste), nausea and vomiting, and foamy urine have been reported with telavancin [6; 163]. Of note, a risk/benefit analysis should be conducted when using telavancin in patients with pre-existing moderate-to- severe renal impairment treated for hospital-acquired or ventilator-associated bacterial pneumonia, as mortality is increased compared with administration of vancomycin [6]. Dalbavancin has the advantage of a prolonged plasma half-life (6 to 10 days), allowing for weekly administration and perhaps obviating the need for an indwelling central line. In adults and children 12 to 17 years of age, the best-studied treatment protocol is 1 g IV, followed by 500 mg weekly [164; 165]. In a randomized trial comparing dalbavancin (1 g IV on days 1 and 8) with vancomycin (IV for 3 days followed by the option of oral linezolid to complete 10 to 14 days) for treatment of skin infection, the clinical response outcomes were similar in both treatment arms. For patients with S. aureus infection, including MRSA, clinical success was observed in 90.6% of patients treated with dalbavancin and 93.8% of those who received vancomycin-linezolid [164]. The lipoglycopeptides have had some adverse effects on fetal development in animals; safety data in pregnant women are limited. These agents should be used during pregnancy only when the benefit outweighs the risk [163]. PLEUROMUTILINS Pleuromutilins were discovered as natural-product antibiotics in 1950. However, their use was limited to veterinary medicine until 2007, when the first agent (retapamulin) was approved for use in humans [166]. Retapamulin was only approved for topical application. In 2019, lefamulin was approved for human use via oral and intravenous delivery [6]. Pleuromutilin derivatives are designed primarily through modifications at the C(14) side chain [166]. These agents inhibit bacterial protein synthesis through interactions (hydrogen bonds, hydrophobic interactions, and Van der Waals forces) with the A- and P-sites of the peptidyl transferase center in domain V of the 23s ribosomal RNA of the 50S subunit [6]. The binding pocket of the bacterial ribo- some closes around the mutilin core for an induced fit that prevents correct positioning of transfer RNA [6].
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