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Susceptibility of "enterobacteria" to penicillins, cephalosporins, lincomycins, erythromycin, and rifampin.

Agar dilution tests for susceptibility of gram-negative rods and enterococci were done with a number of penicillins, cephalosporins, lincomycin analogues, erythromycin, and rifampin. Many in the first three categories were investigational drugs. All were generally less active than aminoglycoside and tetracycline antibiotics against gram-negative rods and more active against enterococci. Cephalosporins as a group were more active than penicillins against Klebsiella pneumoniae and Escherichia coli and less active enterococci. Both groups were equally active against Enterobacter, Proteus, and Providencia but inactive against most strains of Serratia and all strains of Pseudomonas; however, ticarcillin, carbenicillin, and BL-1654 were active against most strains of Pseudomonas. Penicillins and cephalosporins were more active against Proteus mirabilis than against indole-positive Proteus. Lincomycins had little or no activity against gram-negative rods but were moderately active against enterococci. Erythromycin was more active than the lincomycins, but rifampin was much more active than either of these types of drug. Of the penicillins, ticarcillin, carbenicillin, and BL-P1654 were the most active against gram-negative rods, whereas BL-P1654, amoxicillin, and ampicillin were the most active against enterococci. The penicillinase-resistant penicillins, cyclacillin, and penicillin V were essentially inactive against gram-negative rods. Of the cephalosporins tested, cephanone and cefamandole were the most active against most gram-negative rods, whereas cephaloridine and cephacetrile were the most active against enterococci. The least active of the cephalosporins against most species were cephradine, cephalexin, and cephapirin, but cefoxitin was the least active against enterococci.

Acinetobacter↗

Drug-acetaldehyde interactions during ethanol metabolism in vitro.

Acetaldehyde, at concentrations occurring in vivo was found to avidly react in vitro with several clinically relevant drugs. The greatest reactivity was observed for the hydrazine and hydrazide-containing drugs, hydralazine and isoniazid, respectively. Substantial reactivity was also evidenced for the amine-containing penicillins cyclacillin and ampicillin and for the cephalosporins cephalexin, cephradroxyl and cephradine. However, the virtual lack of reactivity of the amine-containing penicillanic and cephalosporanic acids reveals a major role of the acyl groups of these antibiotics in their reactivity towards acetaldehyde. The presence of moieties which increase the electron density of the amine group appears to favour the molecule reactivity. Amongst several phenylethylamines tested, dopamine and noradrenaline were the most active in forming adducts with acetaldehyde. It is suggested that in vitro binding of acetaldehyde to the above-mentioned drugs could lead in vivo to decreased drug bioavailability, and conceivably the adducts formed may mediate some of the side effects associated with simultaneous drug and alcohol ingestion.

Acetaldehyde↗

Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives.

Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.

Amino Acids↗

Susceptibility of anaerobic bacteria in vitro to 23 antimicrobial agents.

589 isolates of anaerobic bacteria, including 127 isolates of Bacterioides fracilis, were tested against 23 antimicrobial agents. At their usually achievable serum levels, carbenicillin, ticarcillin, mezlocillin and piperacillin; cefoxitin, minocycline, doxycycline, clindamycin, chloramphenicol and rifampin were effective against more than 80% of B. fragilis isolates. At usual therapeutic doses, penicillin (PEN), ampicillin (AMP), cyclacillin (CYC), cephalothin (CT), cefazolin (CZ), cephradine (CPD), cefamandole (CMD), cefaclor (CCL), cefuroxime (CRX), spectinomycin (SPT), tetracycline (TET), ethambutol (EMB) and isoniazid (INH) were ineffective against B. Fragilis. However, high and clinically tolerated doses of PEN, CMD and SPT inhibited more than 80% of B. fragilis isolates, but AMP, CYC, CT, CZ, CPD, CCL and CRX, TET, EMB and INH remained totally ineffective against B. fragilis. The therapeutic merits of these antibiotics are discussed.

Anaerobiosis↗

Mutual effects of amino-beta-lactam antibiotics and glycylglycine on the transmural potential difference in the small intestinal epithelium of rats.

The transport mechanism of amino-beta-lactam antibiotics across in vitro rat ileum was examined using the electrophysiological technique in comparison with that of dipeptides. The changes in the transmural potential difference (PDt) induced by a series of amino-beta-lactam antibiotics were correlated with the absorption percentage of these antibiotics from the in situ rat intestinal loops. On the contrary, beta-lactam antibiotics without alpha-amino group such as dicloxacillin, methicillin and cefazolin did not induce such a stable change of PDt. The changes in PDt induced by cyclacillin (ACPC), cefadroxil (CDX) and glycylglycine (Gly-Gly) became saturable when the concentration of the substances increased. The half saturation concentration for ACPC, CDX, and Gly-Gly estimated from the changes in PDt was nearly identical with that determined from influx of the substrates in the everted intestinal sacs. The mutual inhibition between amino-beta-lactam antibiotics and Gly-Gly was observed in their induced PDts. The changes in PDt induced by amino-beta-lactam antibiotics were independent of those of glucose, glycine, and cefazolin. By the removal of Na+ from the mucosal solution, the PDt decreased one-fifth of the PDt induced in the presence of Na+. These results suggest that amino-beta-lactam antibiotic-induced PDt relates to the Na+ ion fluxes as reported for dipeptides.

Animals↗

Determination of beta-lactam antibiotics in water by fluorescence quenching of mercurochrome, and application for simple investigation of potency.

The fluorescence quenching reaction between fluorescein mercury or halogeno-fluorescein mercury compounds (fl. Hg, 2,7- or 2,4-dichloro-fl.Hg, 3',4',5',6'-tetrachloro-fl.Hg, mercurochrome) and beta-lactam antibiotics (ampicillin (AB-PC) and cephalexin (CEX] was investigated, and mercurochrome was selected for the detection of beta-lactam antibiotics; the detection limit was about 0.8 micrograms/ml. A fluorimetric assay of beta-lactam antibiotics was established by measuring the fluorescence of mercurochrome and mercurochrome-beta-lactam antibiotics solutions in weakly basic media to determine the degree of fluorescence quenching. The maximum emission wavelength of mercurochrome solution was at 544 nm with excitation at 470 nm. The calibration graphs were linear over the ranges of about 0-6 micrograms/ml beta-lactam antibiotics penicillins (AB-PC, penicillin G, sulbenicillin, amoxicillin, cyclacillin, oxacillin, hetacillin and piperacillin) and cepham antibiotics (CEX, cefazolin, cephaloglycin, cephaloridine and cefpyramide), and the relative standard deviation was 2.7% for 1.4 micrograms/ml of AB-PC (n = 5). This fluorescence quenching reaction between mercurochrome and beta-lactam antibiotics was applied in a survey of decomposition and remaining potency of beta-lactam antibiotics.

Anti-Bacterial Agents↗

Effect of sex hormones on the disposition in rats of 1-aminocyclohexane carboxylic acid, a metabolite of semisynthetic penicillin.

The renal clearance of 1-aminocyclohexanecarboxylic acid (ACHC), a metabolite of the semisynthetic penicillin, cyclacillin, is about 10 times faster in female than in male rats. The slower clearance in males is attributed to a higher net rate of reabsorption of the compound from the tubule of the kidney. Because ACHC is not metabolized, it is apparently continuously recirculated through the kidney of the male, resulting in the longer half-life. The sex-related disposition of the metabolite can be modified by gonadectomy and/or treatment with sex hormones. Castrated males show increased urinary excretion and decreased plasma half-life of ACHC relative to intact males. In ovariectomized females, less ACHC is excreted and the half-life is longer than in intact females. Thus, in both sexes, gonadectomy shifts the excretion and the residence time in plasma toward the values of these parameters for the opposite sex. Treatment of castrated males with estradiol markedly enhances the effect of castration, but treatment of ovariectomized females with testosterone propionate has little or no additional effect over ovariectomy. Treatment of intact males with estradiol modifies both excretion and residence time in plasma to a great extent, but treatment of intact females with testosterone has a lesser effect on the disposition of ACHC. These results indicate that excretion and residence time of ACHC in both male and female rats are influenced by sex hormones. The described effect is an example of the action of sex hormones on the transport of foreign compounds in this species. Its mechanism is quite different from the well known influence of sex hormones on the microsomal metabolism of foreign compounds in rats.

Animals↗

Therapy of otitis media.

The epidemiology, pathogenesis, diagnosis, complications and sequelae, and therapy of otitis media are reviewed. Otitis media is one of the most common infections in infants and children. Epidemiologic studies have identified season of the year, bottle versus breast feeding, socioeconomic status, race, sex, and daycare attendance as factors associated with the occurrence of otitis media. The condition is believed to arise secondary to eustachian tube dysfunction in the presence of viral or bacterial invasion of the nasopharynx. Diagnosis is often made by direct observation of the tympanic membrane with an otoscope. If untreated, the infection can spread to other structures in the aural cavity or even to the brain and meninges. The most frequent complication of otitis media is hearing loss, which may result in speech and learning difficulties. Oral antimicrobial agents--notably ampicillin, amoxicillin, amoxicillin-clavulanate, cefaclor, cefuroxime axetil, bacampicillin, cyclacillin, erythromycin ethylsuccinate-sulfisoxazole, cefixime, and trimethoprim-sulfamethoxazole--are the mainstay of treatment. Selection of the agent should be based primarily on its spectrum of activity against Streptococcus pneumoniae and Haemophilus influenzae. Other considerations include the presence of beta-lactamase-producing strains of H. influenzae and Branhamella catarrhalis, adverse effects, cost, and compliance. In cases of recurrent otitis media, antimicrobial prophylaxis or surgery may be indicated. Chronic otitis media with effusion may be treated with oral antimicrobials, but surgery may also be necessary. Chronic suppurative otitis media often requires hospitalization and intravenous antimicrobial therapy with agents effective against Pseudomonas aeruginosa. Oral antimicrobial agents represent the treatment of choice for otitis media, but such therapy addresses only one of the several etiologic factors identified.

Humans↗

In vivo sensitivity test in otitis media: efficacy of antibiotics.

During a 10-year period, antibiotics were assigned in random, double-blind fashion in six combinations to treat 948 episodes of otitis media in children. Exudate from the middle ear of all patients was cultured before treatment. Three follow-up visits were conducted; the first follow-up visit was three to five days after the start of therapy, and the second and third visits were 14 and 31 days after onset of treatment. Exudates were recultured for 75% of the patients on the first follow-up visit. Comparison of treatment results showed that triple sulfonamide combined with either phenoxymethyl penicillin, or benzathine and procaine penicillin G given intramuscularly (IM) was as effective as was ampicillin or amoxicillin. Phenoxymethyl penicillin and cyclacillin alone were usually effective against pneumococci but relatively ineffective against Haemophilus influenzae. Cefaclor and trimethoprim-sulfamethoxazole produced unsatisfactory results in about half the cases caused by pneumococci or H influenzae. Although production of beta-lactamase by some otitis-causing Haemophilus and Staphylococcus species may explain the ineffectiveness of some treatments, the percentage of organisms positive for beta-lactamase was too small to be responsible for the poor results with certain drugs.

Anti-Bacterial Agents↗

In vitro effect of new penicillins and aminoglycosides on tests for glycosuria.

The effect of newer penicillins (azlocillin, mezlocillin, cyclacillin, and piperacillin) a 6 beta-amidinopenicillanic acid derivative (amdinocillin), and newer aminoglycosides (netilmicin and sisomicin) on the accuracy of tests for glycosuria was studied. Solutions of each of the drugs were prepared in urine in a range of clinically obtainable drug concentrations. In addition, urine solutions were prepared that contained the same drug concentrations and 0.5, 1, and 2% glucose. All solutions were tested in triplicate using the five-drop Clinitest method and two glucose oxidase methods (Diastix and Tes-Tape). Falsely elevated Clinitest readings of approximately 0.25% were obtained with the penicillins. These readings were influenced by the concentration of the penicillins and of glucose. Neither amdinocillin nor the aminoglycosides had an effect on Clinitest determinations. None of the drugs interfered with Diastix or Tes-Tape readings. Because the Clinitest-penicillin interaction is unpredictable, Clinitest results should be rechecked using one of the qualitative glucose oxidase tests when Clinitest is used as a quantitative test for glycosuria in patients receiving penicillins. All three tests studied can be used to test for glycosuria in patients receiving amdinocillin or one of the aminoglycosides.

Aminoglycosides↗

Efflux properties of basolateral peptide transporter in human intestinal cell line Caco-2.

Small peptides and some pharmacologically active compounds are absorbed from the small intestine by the apical H(+)-coupled peptide transporter 1 (PEPT1) and the basolateral peptide transporter. Here we investigated the efflux properties of the basolateral peptide transporter in Caco-2 cells using two strategies, efflux measurements and a kinetic analysis of transepithelial transport of glycylsarcosine (Gly-Sar). [(14)C]Gly-Sar efflux through the basolateral membrane was not affected significantly by the external pH. Both approaches revealed that the basolateral peptide transporter was saturable in the efflux direction, and that the affinity was lower than that in the influx direction. For two peptide-like drugs, there was no difference in substrate recognition by the basolateral peptide transporter between the two sides of the membrane. Using the kinetic parameters of PEPT1 and the basolateral peptide transporter, a computational model of Gly-Sar transport in Caco-2 cells was constructed. The simulation fitted the experimental data well. Our findings suggested that substrate affinity of the basolateral peptide transporter is apparently asymmetric, but pH-dependence and substrate specificity are symmetric for the two directions of transport. The behaviour of Gly-Sar in Caco-2 cells could be predicted by a mathematical model describing the peptide transporters.

Anti-Bacterial Agents↗

[Serum and tissue levels of ciclacillin].

The level of Ciclacillin in serum, bone, and muscle was determined in 58 patients, subjected to bone surgery. 50 to 120 minutes after application, the drug concentration in bone was many times higher than in serum.

Adolescent↗

Comparative studies of the activity of ciclacillin and dicloxacillin.

The penicillins ciclacillin and dicloxacillin demonstrate marked similarities in biological activity but, as far as can be determined, differ substantially in respect to the degree of protein binding, which is relatively low for ciclacillin and relatively high for dicloxacillin. In mice infected with Staphylococcus aureus Smith, ciclacillin is considerably more active than dicloxacillin, although both drugs are similarly effective in vitro and similarly absorbed and eliminated in vivo. The high degree of protein binding exhibited by dicloxacillin could therefore very probably explain its relatively low chemotherapeutic activity. Moreover, the in vitro and in vivo findings of the study are inconsistent with the tenets of the tau/2 thesis.

Animals↗