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The simultaneous determination of nafcillin and methicillin was accomplished by constant wavelength synchronous fluorimetry, in combination with partial least-squares multivariate calibration. The total luminescence information of the compounds was used to optimize the spectral data set to perform the calibration. A calibration set of standard samples was designed by combination of a factorial design, with three levels for each factor, and a central composite design. A comparative study of the results obtained using the excitation, the emission, the constant wavelength synchronous and the constant energy synchronous spectral data as analytical signals was performed. The data, set composed of the constant wavelength synchronous spectra, was selected as the analytical signal. The method was successfully applied to the determination of nafcillin and methicillin in mixtures.

A method for the spectrofluorimetric determination of methicillin is proposed (lambda ex = 279 nm, lambda em = 379 nm), for concentrations between 0.030 and 10.0 micrograms ml-1. The method was performed in water, at pH 6.20 provided by addition of phosphate buffer solution. The values obtained for detection and determination limits were 0.0188 and 0.063 micrograms ml-1, respectively. The method was successfully applied to assay a commercial injection containing methicillin sodium monohydrate.

The effect of intramuscular chimotripsin on the levels of methicillin and tetracycline administered respectively intramuscularly and orally was studied in patients with chronic pneumonia and in experimental rats. It was found that the dose of chimotripsin providing higher methicillin blood levels was many times lower than the enzyme doses providing analogous indices for the blood serum and organs of the rats. When the patients were treated with tetracycline and chimotripsin, increased blood levels of the antibiotic were observed. Administration of chimotripsin to the rats had no effect on tetracycline pharmacokinetics in the animals.

To determine the penetration of the antistaphylococcal antibiotics, nafcillin, methicillin, and cefazolin, into brain tissue, we gave to each of 27 patients undergoing craniotomy and brain biopsy one of the antibiotics in a 2-g intravenous infusion just before operation. At the time of brain tissue removal (30 to 225 minutes after the start of the infusion), a serum specimen was obtained, and tissue and serum were assayed for antibiotic concentration. Eleven of 13 brain specimens contained detectable nafcillin concentrations between 0.36 and 11 micrograms/g of tissue (mean, 2.7 micrograms/g for all 13 specimens). Fourteen of 18 brain tissue specimens contained detectable methicillin concentrations between 0.56 and 5.0 micrograms/g of tissue (mean, 2.0 micrograms/g for all 18 specimens). Ten of 11 brain tissue specimens contained detectable cefazolin concentrations between 2.0 and 40 micrograms/g of tissue (mean, 10.6 micrograms/g for all 11 specimens). Each antibiotic penetrated "abnormal" brain tissue better than "relatively normal" brain tissue. Because nafcillin is more active against Staphylococcus aureus, we conclude that nafcillin is preferable to methicillin for the therapy of central nervous system staphylococcal infections. Cefazolin achieves higher brain tissue concentrations than the penicillins, but has not been clinically evaluated for the therapy of central nervous system infections.

Probenecid was given intravenously to rabbits in an effort to extend the intraocular longevity of intravitreal methicillin. With relatively high levels of probenecid, an insignificant elevation of half-life was obtained. Aqueous levels of methicillin were measured after intravitreal injection and were found to be adequate to inhibit penicillinase-producing S. aureus for approximately 20 hours.

Tamethicillin (TAM) is a basic ester pro-drug of methicillin (MET) which is converted in the body by non-specific esterases to MET. Equal doses of MET and TAM were administered intramuscularly in a crossover trial involving four dairy cows. Acute mastitis was induced in each cow by infusing two quarters of the udder with Escherichia coli endotoxin 3 h before antibiotic administration. Peak serum MET concentrations after MET injection were significantly (P less than 0.001) higher than peak serum drug concentrations after TAM injection. The t1/2 of MET in serum after MET and TAM treatments were 18 min and 2 h, respectively. Normal milk MET concentrations during the first 8 h after TAM administration were significantly (P less than 0.05) higher than after MET treatment. Mastitic milk MET concentrations during the period 2-6 after MET injection were significantly (P less than 0.01) higher than after TAM administration. However, MET concentrations which were equal to or higher than the minimal inhibitory concentrations for penicillin G-resistant staphylococci were maintained in the mastitic milk for 8 h after treatment with MET and TAM.

The combination of the subconjunctival injection of lidocaine HCl or procaine HCl with the subconjunctival injection of penicillin G, methicillin, cephaloridine, or gentamicin did not influence their intraocular penetration or subsequent antibiotic activity in aqueous humor of experimental animals.

Large glass plates are used for this modified agar-well diffusion assay method, allowing up to 81 replications on a single plate. With a specially designed agar punch, it is possible to prepare the small agar wells very quickly. The saving in serum resulting from fewer replications of standards with the large plates, and the small volume of the agar wells, makes it economically feasible to use pooled human serum for the standard antibiotic solutions. Methods are described for preparing the standard solutions, and for providing controls for the deterioration of standards and unknowns. Procedures for preparing and maintaining the commonly used assay organisms are presented. Serum specimens are tested directly rather than diluting them to a narrow range of antibiotic concentrations. This is possible because of a procedure for calculations that recognizes the curvilinear relationship between zone sizes and antibiotic concentrations. Adaptation of this method to a number of the commonly used antibiotics is described. With this method, it has been possible to test large numbers of clinical specimens in a minimal time, and with accuracy consistently better than 10%.

A simplified method of assaying mixtures of ampicillin and cloxacillin is presented. The method consists of cylinder-plate assays of appropriately diluted samples in three assay systems in which: (i) cloxacillin is measured, utilizing agar seeded with a penicillinase-producing Staphylococcus aureus; (ii) ampicillin is measured after the greatest dilution practicable, by use of agar seeded with Sarcina lutea; and (iii) the proportion of activity found in the second assay that remains after treatment with staphylococcal penicillinase is determined on agar seeded with S. lutea. The error was 4% or less when each system was run in quadruplicate, except when there was 10 or more times as much cloxacillin as ampicillin, in which case the greatest error was 12%. Mixtures of methicillin with benzylpenicillin or with ampicillin can also be quantitated by this method.

An experimental model was designed to study the ability of antibiotics to enter the pericardial compartment. Noninfected and infected pericardial fluid and serum antibiotic activities were determined in adult mongrel dogs before and at intervals after antibiotic administration. After the administration of penicillin G, methicillin, cephaloridine, streptomycin, or gentamicin, clinically adequate antibiotic levels in the noninfected pericardial fluid were obtained within 1 h, and these levels approached or exceeded the serum levels within 2-4 h. Antibiotic levels obtained from infected dog pericardial fluids were higher than those from noninfected animals. Patients' serum and pericardial fluid antibiotic levels were measured after penicillin G, penicillin V, cephalothin, and gentamicin administration. We have found, both in the canine and human studies, that pericardial antibiotic levels taken at least 2 h after antibiotic administration are almost identical to those in the blood.