ABSTRACT
A topoisomerase was identified as the bacterial target site for quinolone action in the late 1970s. Since that time, further study identified two bacterial topoisomerases, DNA gyrase and topoisomerase IV, as sites of antibacterial activity DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms, but this varies with the drug. Three mechanisms of resistance against quinolones are mutations of topoisomerases, decreased membrane permeability, and active drug efflux. Although these mechanisms occur singly, several resistance factors are often required to produce clinically applicable increases in minimum inhibitory concentrations. Appropriate drug selection and dosage and prudent human and veterinary interventions are important factors in controlling the emergence of resistance.
Subject(s)
Anti-Infective Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Drug Resistance, Bacterial/genetics , Topoisomerase II Inhibitors , 4-Quinolones , Animals , Anti-Infective Agents/metabolism , DNA Gyrase/genetics , DNA Topoisomerase IV/genetics , Enzyme Inhibitors/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/enzymology , Gram-Negative Bacteria/genetics , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/enzymology , Gram-Positive Bacteria/genetics , Humans , Mutation , Veterinary MedicineABSTRACT
The ketolides represent a new subclass of antibiotics among the macrolide-lincosamide-streptogramin group. Telithromycin, the first ketolide to be awarded approvable status for clinical use, demonstrates in vitro activity against community-acquired respiratory pathogens including penicillin- and erythromycin-resistant Streptococcus pneumoniae. An extended half-life permits once-daily oral administration. Telithromycin is a substrate for cytochrome P450 (CYP) 3A4 and also inhibits drugs metabolized by CYP3A4. A relatively high frequency of mild-to-moderate gastrointestinal adverse effects has been reported. Similar clinical and microbiologic efficacy has been demonstrated with oral dosing in comparative clinical trials for community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, and pharyngitis. Although limited data on penicillin-resistant S. pneumoniae and erythromycin-resistant Streptococcus pyogenes are available from clinical trials, this drug appears promising for respiratory infections caused by these pathogens.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Ketolides , Macrolides , Respiratory Tract Infections/drug therapy , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/economics , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Bacteria/drug effects , Clinical Trials as Topic , Drug Interactions , Drug Resistance , Humans , Respiratory Tract Infections/microbiologyABSTRACT
Amiloride was administered to 19 oncology patients exhibiting marked amphotericin B-induced electrolyte wasting. Mean serum potassium concentrations increased in the 5 days preceding and following administration (3.4 +/- 0.5 versus 3.9 +/- 0.8 mmol/L, P = 0.002). A trend towards decreased potassium supplementation was also observed (48.0 +/- 66.5 versus 29.4 +/- 43.2 mmol/day, P = 0.12). Amiloride is a therapeutic option to decrease potassium wasting in patients being treated with amphotericin B.
Subject(s)
Amiloride/therapeutic use , Amphotericin B/adverse effects , Antifungal Agents/adverse effects , Hypokalemia/drug therapy , Adult , Aged , Humans , Hypokalemia/chemically induced , Magnesium/blood , Middle Aged , Potassium/administration & dosageABSTRACT
Synercid (RP 59500), the first injectable streptogramin antibiotic, is composed of two semisynthetic pristinamycin derivatives, quinupristin and dalfopristin. Individually, each component has bacteriostatic activity against staphylococci and streptococci, but together, the agents exhibit synergy, leading to bactericidal activity. The combination drug, however, is bacteriostatic against Enterococcus faecium and has poor activity against Enterococcus faecalis. Despite a short half-life, an extended postantibiotic effect allows the agent to be dosed every 8-12 hours. Both drugs are largely hepatically metabolized and excreted in bile. Although not metabolized by cytochrome P450 3A4, quinupristin-dalfopristin can inhibit agents that are metabolized through this pathway. Dosage adjustments may be necessary in patients with hepatic dysfunction. Alterations in renal function have minimal effects on the agent's pharmacokinetics. Adverse events include arthralgia, myalgias, and infusion-related pain. Based on available data, quinupristin-dalfopristin appears to have a role in treating severely ill patients with infections due to multiresistant gram-positive pathogens.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Drug Therapy, Combination/therapeutic use , Virginiamycin/therapeutic use , Animals , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacology , Bacteremia/drug therapy , Clinical Trials as Topic , Drug Resistance, Microbial , Drug Synergism , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/pharmacology , Gram-Negative Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Humans , Microbial Sensitivity Tests , Virginiamycin/adverse effects , Virginiamycin/pharmacologyABSTRACT
Obesity is associated with physiological changes that can alter the pharmacokinetic parameters of many drugs. Vancomycin and the aminoglycosides are the only antibacterials that have been extensively investigated in the obese population. The apparent volume of distribution (Vd) and total body clearance of vancomycin are increased in obese patients and have a better correlation with total bodyweight (TBW) than with ideal bodyweight (IBW). The Vd of aminoglycosides is increased in obesity and can be estimated from an adjusted bodyweight that accounts for a fraction of the excess bodyweight (TBW - IBW). These observed changes in pharmacokinetic parameters of vancomycin and aminoglycosides in obese patients may necessitate a deviation from the commonly recommended dosages administered to non-obese individuals. There are limited data regarding the pharmacokinetics of other antibacterial classes in obese patients. The available information for cephalosporins suggests that dosages may need to be increased in obese patients in order to obtain similar serum and tissue concentrations as in non-obese patients. Additional pharmacokinetic studies of other antibacterial classes are required in this special patient population.
