Penicillin isoxazolyl

The pharmacology of penicillins differs markedly from compound to compound but has been well reviewed (57). The majority of derivatives, including penicillin G and the antipseudomonal penicillins, ate unstable in gastric acid and ate not available orally. The isoxazolyl penicillins ate relatively acid stable but not consistendy well absorbed by the oral route. Nafcillin and oxacillin ate poody absorbed orally cloxacillin, dicloxacillin, and ducloxacillin ate more teUable. Penicillin V, ampicillin, and patticulady amoxicillin ate relatively well absorbed orally. Esters of ampicillin such as bacampicillin, pivampicillin, and talampicillin improve the level of oral absorption of ampicillin to that achieved by amoxicillin. Absorption can be diminished by food after oral adruinistration, however, and peak blood levels, usually achieved after 1 to 2 h, ate somewhat delayed after ingestion of food. 

Cloxacillin sodium salt (sodium 3-o-chlorophenyl-5-methyl-4-isoxazolyl penicillin monohydrate) [642-78-4] M 457.9, m 170°, [a]J, +163° (HjO pH 6.0-7.5), pKe, 2.8 (COOH). Purified by dissolving in isoPrOH containing 20% of H2O, and diluting with isoPrOH to a water content of 5% and chilled, and recrystd again in this manner. The sodium salt is collected and dried at 40° in air to give the colourless monohydrate. It is soluble in H2O (5%), MeOH, EtOH, pyridine and ethylene glycol. [Doyle et al. J Chem Soc 5838 I 963 Naylor et al. Nature 195 1264 1962.]... 

Class D enzymes (Mr of about 27,000) exhibit a high activity versus isoxazolyl penicillins, such as oxacillin and are referred to as the OXA-family. Surprisingly, the amino group of the SXXK lysine residues is carboxylated in the most active forms of the enzymes. Penicillins are generally better substrates than cephalosporins but mutations have been found which confer extended activity spectra to these enzymes. 

An immunoassay was developed to determine the penicillinase stable isoxazolyl penicillins cloxacillin and dicloxacillin in milk by Usleber et alJ The assay detected lOpgkg" of cloxacillin and 30pgkg of dicloxacillin with recoveries of 102% and 84%, respectively. The calibration curve was prepared by fortifying skimmed milk powder (lOOgL ) with standards. Fortified samples were prepared in pasteurized milk and analyzed directly after decreaming by centrifugation. This immunoassay was performed with minimal sample preparation, probably because the extensive water solubility of the penicillins prevents problems associated with more lipid-soluble analytes. 

Penicillins. This group includes penicillin G (benzyl-penicillin), penicillin VK (phenoxymethyl-penicillin), the isoxazolyl penicillins oxacillin, cloxacillin, dicloxacillin and nafcillin, the amino-penicillins ampicillin, hetacillin and amoxycillin, the carboxy-penicil-lin carbenicillin, and the thienyl-penicillin ticarcillin. 

Similar to isoxazolyl penicillins, Less strongly protein-bound (90%), Resistant to staphylococcal f lactamase. 

PENICILLINS RESISTANT TO STAPHYLOCOCCAL BETA LACTAMASE (METHICILLIN, NAFCILLIN, AND ISOXAZOLYL PENICILLINS)... 

An isoxazolyl penicillin such as oxacillin, cloxacillin, or dicloxacillin, 0.25-0.5 g orally every 4-6 hours (15-25 mg/kg/d for children), is suitable for treatment of mild to moderate localized staphylococcal infections. All are relatively acid-stable and have reasonable bioavailability. However, food interferes with absorption, and the drugs should be administered 1 hour before or after meals. 

Oxacillin, cloxacillin, and dicloxacillin are all semisynthetic isoxazolyl penicillins suitably modified to be relatively resistant to hydrolysis by staphylococcal -lactamase. They have the additional advantage of being stable in the presence of gastric acid, so they can be administered orally as well as parenterally. 

Dicloxacillin is absorbed well from the gastrointestinal tract but the presence of food in the stomach reduces resorption. Although cloxacillin differs chemically from oxacillin only in the presence of a chlorine atom, their absorption profile after oral administration is not similar. Cloxacillin is more rapidly and effectively absorbed than oxacillin. However, absorption of all isoxazolyl penicillins is better when given by intramuscular injection. These agents can be also administered by intravenous, intrauterine, intra-articular, intrapleural, and intramammary injections. 

Following absorption, all isoxazolyl penicillins are bound to plasma proteins in the circulation and are partly metabolized in the body. They cross the placenta and are found in breast milk. Parent drugs and their metabolites are principally excreted in the urine, whereas small amounts are also found in bile. 

Oxacillin and cloxacillin are the most widely used isoxazolyl penicillins, the latter being particularly appropriate for treatment or prevention of bovine staphylococcal mastitis. Following intramammary treatment of a lactating cow with three successive infusions of 200 mg/48 h each of sodium cloxacillin, residues were present in milk (detection limit equal to 3 ppb) from the treated quarter for 60 h after the last infusion crossover from treated to untreated quarter was also observed (59). When cloxacillin benzathine was administered by the intramammary route to dairy cows in the dry period at a dosage of 500 mg/quarter, cloxacillin residues were present neither in serum ( 25 ppb) sampled after 5 days of drug administration nor in milk ( 5 ppb), including the milk collected... 

The stability of several -lactam antibiotic in aqueous solutions is pH dependent. Optimum stability for monobasic penicillins in general is exhibited at pH 6-7, while for the amphoteric penicillins this coincides with the isoelectric point (18). A fast degradation occurs at both acidic and basic conditions. At pH 2.6, acid-labile -lactams such as penicillin G, methicillin, and nafcillin disappear almost completely while acid-resistant compounds like penicillin V and isoxazolyl penicillins survive (19). 

Sometimes the easiest way to destroy drug-protein binding is to dilute the sample with a physiological saline solution. For instance, for isoxazolyl penicillins with a binding percentage of over 95%, dilution with 9 volumes of 0.9% sodium chloride solution can be sufficient (9). Alternative widely used techniques are based on either protein denaturation or enzymatic/chemical hydrolysis of the drug-protein complexes (10-12). 

Beyond polyclonal antibodies, monoclonal antibodies to isoxazolyl penicillins were recently produced by immunization of mice with a cloxacillin-human serum albumin conjugate prepared by a mixed anhydride procedure (35). Sensitivity and specificity of these antibodies were tested in an indirect ELISA in which a cloxacillin-glucose oxidase conjugate prepared by an activated ester procedure served as a coating agent. It was found diat die prepared antibodies could be... 

The pharmacology of penicillins differs markedly from compound to compound. The majority of derivatives, including penicillin (j and the antipseudomonal penicillins, are unstable in gastric acid and are not available orally. The isoxazolyl penicillins are relatively acid-stable but... 

The generic nature of the antiserum was shown by good relative cross-reactivities with penicillin type (3-lactam antibiotics such as amoxicillin (50%), ampicillin (47%), and penicillin V (145%), and a lower response to the isoxazolyl penicillins such as oxacillin, cloxacillin, and dicloxacillin. No cross-reactivity was obtained for cephalosporin type p-lactam antibiotics (cephapirin), cloramphenicol, or fluoroquinolones (enrofloxacin and ciprofloxacin). 

Common Name [3-(o-Chlorophenyl)-5-methyl-4-isoxazolyl]penicillin Structural Formula ... 

The most evident design would appear to be a three-level factorial design. An example of a three-level factorial design is shown in Fig. 6.1.. A full three-level factorial design, 3, can be used to obtain quadratic models. However, unless / is small (/ = 2) the design requires a number of experiments (= V) that is not often feasible. An example of the use of a 3" design can be found in Ref. 51]. The two factors, the pH and the percentage acetonitrile were examined to evaluate their influence on the retention and resolution of three isoxazolyl penicillin antibiotics. The centre point experiment was triplicated to evaluate experimental error. 

One approach has been to modify the structure of the yS-lactam antibiotic so as to increase its stability and thus confer resistance to yS-lactamases, whilst retaining its inhibitory activity against transpeptidases. This was achieved by introducing sterically crowded 6-acyl substituents, as in methicillin (1) and the isoxazolyl penicillins (2) and (3) [20], or by the introduction of a methoxy substituent to the a-face of the -lactam, as in cefoxitin (9) [21] and temocillin (11) [22]. The two latter compounds were a direct result of the discovery of the y5-lactamase stable cephamycins (10), isolated by fermentation of Streptomyces in 1970 by Merck and Lilly [23]. 

More severe liver disease, presenting as hepatitis and/ or intrahepatic cholestasis, has been seen with beta-lactam antibiotics of various classes, the isoxazolyl penicillins being most frequently involved. Co-amoxiclav has repeatedly been associated with cholestatic hepatitis. 

The other isoxazolyl penicillins, that is cloxacUUn, dicloxacilUn, and oxacillin, can cause similar hepatotoxicity (77-82). However, it is not known whether the incidence is as high as with flucloxaciUin. Nor is it known whether the clearly dose-dependent oxacillin hepatitis (83-85) is an identical reaction. 

In isolated cases, glucocorticoids (77) and nrsodeoxy-choUc acid (86) apparently improved the ontcome of hepatitis related to isoxazolyl penicillins. 

After the influx of several a-amino penicillins such as ampicillin (Table 1) and related analogues, and the p-lactamase stable isoxazolyl penicillins in the 1950s and early 1960s, attention turned to identifying derivatives having a broader spectrum of activity. Carbenicillin and later, ticarcillin, reached the marketplace by the early 1970s. Effort then focused on the acyl and ureido ampicillin derivatives and culminated in the commercialization first of azlocillin and mezlocillin, then of piperacillin. Many thousands of derivatives were synthesized and some of the more active examples that have made tittle or no commercial impact are shown in Tables 2 and 3. 

The isoxazolyl penicillins are potent inhibitors of the growth of most penicillinase-producing staphylococci Slightly more active than oxacilUn against penicillin G-resistant S. aureus... 

Nafcillin and the isoxazolyl penicillins (oxacillin, cloxacillin, dicloxacillin). 

The isoxazolyl penicillins potently inhibit the growth of most penicillinase-producing staphylococci. Dicloxacillin is the most active. They are less effective against microorganisms susceptible to penicillin G and are not useful against gram-negative bacteria. 

The isoxazolyl penicillins are excreted rapidly by the kidney. Normally, -50% of these drugs are excreted in the urine within 6 hours of an oral dose. They also are eliminated in the bile. Their half-lives are between 30 and 60 minutes. Intervals between doses are unchanged for patients with renal failure. 

Acid-resistant, orally absorbed, broad spectnim isoxazolyl penicillin highly resistant to p-lacia-mases. 

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