Antibiotics Review _ __________________________________________________________________________
The Aminopenicillins The aminopenicillins have about the same activity as the natural penicillins against susceptible gram-positive organ- isms, plus improved coverage of selected gram-negative bacilli, including Enterobacteriaceae . Amoxicillin/clavulanic acid and ampicillin/sulbactam have better coverage against H. influen- zae and Klebsiella species than the natural penicillins and the aminopenicillins alone. The aminopenicillins include ampicillin and amoxicillin. Ampicillin can be given parenterally or orally. These agents are useful for the management of sinusitis/bronchitis, endo- carditis, meningitis, susceptible urinary tract infection, and salmonellosis [6]. Amoxicillin is the best absorbed of the oral penicillins. It is acid-stable and its absorption, unlike ampicil- lin, is not much affected by food. Improved absorption is also thought to provide an advantage over ampicillin in reducing the risk of antibiotic-associated diarrhea. Labeled uses include endocarditis prophylaxis and as a component of a multidrug H. pylori eradication regimen [6]. The Penicillinase-Resistant Penicillins The penicillinase-resistant penicillins were developed in response to the emergence of penicillinase-producing S. aureus . These penicillins are resistant to hydrolysis by the lactamase produced by the staphylococci, and they include nafcillin and oxacillin, which are parenteral formulations, and dicloxacillin, which is given orally. Methicillin and cloxacillin are no longer available in the United States [6]. Although penicillinase-resistant penicillins have the same spectrum of activity against many of the same gram-positive pathogens as the natural penicillins, they lack significant activ- ity against gram-negative or anaerobic organisms. They are, however, notable for their usefulness against penicillin-resistant (methicillin-sensitive) Staphylococcus species. The Antipseudomonal Penicillins The antipseudomonal penicillins are often also referred to as extended-spectrum penicillins; these include ticarcillin and piperacillin (both of which are parenteral). Mezlocillin, which was also parenteral, and carbenicillin, which could be adminis- tered orally, are no longer available in the United States [6; 17]. The extended-spectrum penicillins retain their activity against gram-positive bacteria and anaerobic gram-negative pathogens such as Bacteroides fragilis. However, these agents were devel- oped because of their excellent activity against Pseudomonas aeruginosa and other multidrug-resistant gram-negative patho- gens, including Klebsiella species and Serratia species. The antipseudomonal penicillins are effective for treatment of H. influenzae as well.
The Addition of Beta-Lactamase Inhibitors The addition of clavulanic acid, sulbactam, or tazobactam increases the spectrum of activity of the penicillin deriva- tive with which they are combined. They are generally active against the beta-lactamases produced by H. influenzae , Moraxella catarrhalis , and S. aureus . However, their activity is variable against some of the gram-negative bacteria, such as some species of Pseudomonas , Enterobacter , E. coli , Klebsiella , and Serratia , due to resistance to these beta-lactamase inhibitors [18]. ABSORPTION/ELIMINATION While most penicillins can be absorbed via the oral route, the bioavailability varies considerably, and food may interfere with absorption. Penicillin V, amoxicillin, ampicillin, and dicloxacillin can be given orally; the remaining penicillins are either too unstable in the acidic environment of the stomach or must be given intravenously in order to achieve sustained therapeutic levels. Amoxicillin is the best absorbed of the oral penicillins and the least affected by a recent meal. Following oral administration and GI absorption, these agents are widely distributed throughout the body. Therapeutic con- centrations of penicillins are readily achieved in tissues and secretions (e.g., joint fluid, pleural fluid, pericardial fluid, and bile). Low concentrations are found in prostatic secretions, brain tissue, intraocular fluid, and phagocytes. Cerebrospinal fluid (CSF) concentrations vary but are less than 1% of serum concentration when the meninges are normal. When the meninges are inflamed, CSF concentrations may rise to 5% and can be increased by co-administration of probenecid (500 mg 4 times daily) [6; 19]. Concentration in urine is high due to renal clearance mechanisms. Penicillins are excreted in the kidney by means of glomerular filtration and renal tubular secretion. Probenecid markedly reduces the tubular secretion of the penicillins and decreases the apparent volume of distribution, resulting in higher serum levels. All the penicillins are excreted to some degree in the bile, but biliary excretion is most important for antipseudomonal penicillins and nafcillin [20]. In patients with mild renal insufficiency, dosage adjustment is not needed, except with the use of ticarcillin [21]. If the creatinine clearance is less than 50 mL/min, then dosage adjustments of parenteral penicillins should be made to avoid excess serum levels. Nafcillin undergoes extensive hepatic metabolism, and the dosage must be adjusted for severe renal and hepatic insufficiency.
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