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Cyclacillin-induced potentiation of Escherichia coli immunogenicity in vivo and in vitro.

The efficacy of cyclacillin as an antimicrobial agent against Escherichia coli was assessed in vivo in mice infected with low numbers of bacteria and compared to the relative effectiveness of the antibiotic against the same organisms in vitro. Treatment of mice with cyclacillin resulted in a rapid clearance of E. coli from the blood and their greater killing in the spleen and liver. Furthermore, a significantly higher antibody plaque response against E. coli developed in cyclacillin-treated mice than in untreated mice or in those given ampicillin. The increased immunogenicity of the E. coli in the antibiotic-treated mice appeared to be due to high levels of cyclacillin in the animals and rapid killing of the bacteria in vivo. In vitro experiments showed that injection of normal mouse peritoneal exudate macrophages which had been incubated with E. coli together with cyclacillin resulted in a greater immunogenicity of the bacteria than when the injection mixture was composed of E. coli which had been incubated alone or only with macrophages. These results suggest that the in vivo effectiveness of an antibiotic such as cyclacillin against a gram-negative organism such as E. coli may be due in part to an effect on the immunogenicity of the bacteria.

Ampicillin

Cyclacillin: microbiological and pharmacological properties and use in chemotherapy of infection - a critical appraisal.

The pharmacological and microbiological properties of cyclacillin were discussed and its usefulness in the management of a variety of infections was reviewed. The antibacterial spectrum and clinical utility of this agent generally parallels that of ampicillin, but there are minor differences in specificity with regard to individual microorganisms. The in vitro activity of cyclacillin against gram-negative pathogens varies greatly, the results fluctuating in accordance with the composition of the assay medium of method. The drug has demonstrated excellent therapeutic effectiveness against experimental infections produced by both gram-positive and gram-negative pathogens, thus making questionable a prediction of therapeutic effectiveness from in vitro susceptibility tests alone. Cyclacillin is more resistant to beta-lactamase hydrolysis than ampicillin, is much better absorbed when given by mouth and, as a result, the levels reached in the blood and in the urine are considerably higher than those obtained with the same dose of ampicillin. Cyclacillin produces fewer and milder side-effects than ampicillin.

Ampicillin

Cyclacillin: in vitro activity against aerobic and anaerobic bacteria.

Cyclacillin at 50 microgram/ml inhibited streptococci (100%), shigella (72%), and Bacteroides (B) fragilis ss fragilis (84%). At 100 microgram/ml it inhibited proteus (75%), B. fragilis (86%), and E. coli (50%). Cyclacillin was more effective than ampicillin against beta-lactamase-producing H. influenzae. The activity of cyclacillin was found to be more enhanced when tested in nutrient agar and Mueller-Hinton agar than in brain heart infusion agar.

Ampicillin

[Comparative experimental study of cyclacillin and ampicillin].

Cyclacillin was compared with ampicillin by its bacteriostatic efficiency in vitro, chemotherapeutic efficiency in experimental infections of mice and rats and pharmacokinetic characteristics. It was found that cyclacillin was not superior to ampicillin by its antibacterial action. By a number of characteristics it was even significantly inferior. The pharmacokinetic advantages of cyclacillin were not considered significant.

Ampicillin

Double-blind clinical trials of oral cyclacillin and ampicillin.

A double-blind study was performed to compare the clinical response and the incidence of side effects in 2,581 patients administered ampicillin or cyclacillin for infections of the genitourinary or respiratory tract, infections of the skin and soft tissues, or for otitis media. There was no significant difference in clinical response and bacterial eradication. All side effects, including diarrhea and skin rash, were approximately twice as frequent in patients treated with ampicillin.

Administration, Oral

[Studies on absorption and excretion of cyclacillin granules (vastcillin granules 'Takeda') (author's transl)].

Vastcillin granules 'Takeda', a cyclacillin (AC-PC) preparation for children were orally administered to nine children at a single dose of 10 mg/kg and its blood concentrations and urinary excretion were studied. From the results obtained, the following conclusions were obtained as to clinical dose and indications. (1) Absorption of AC-PC of Vastcillin granules is excellent . At 15 minutes after administration, 9.3 mcg/ml of AC-PC blood level was attained and its peak appeared 30 minutes after administration. The mean peak level was 17.6 mcg/ml.

Adolescent

Absorption of amino penicillins from everted rat intestine.

1. Using an in vitro everted gut sac method based on that of Wilson & Wiseman (1954), a number of amino penicillins were tested in order to identify the involvement of any specialized transport mechanisms in their absorption across rat intestine. 2. Only one of the amino penicillins, cyclacillin (1-amino-cyclohexyl penicillin) was shown to be actively transported. The other penicillins appeared to diffuse passively across the intestine. 3. Cyclacillin was found to concentrate against a gradient at 37 degrees C but not at 19 degrees C. 4. Transport of cyclacillin across the mucosal membrane was saturated at mucosal concentrations greater than 1000 microgram/ml. 5. The rate of the forward flux of cyclacillin was many times that of its back flux. 6. No relationship between the active transport of cyclacillin and that of amino acids could be demonstrated.

Amoxicillin

Comparative assessment of cylacillin and ampicillin by experimental therapy and by serum level determinations in rats and mice.

Therapy of chronic E. coli pyelonephritis in rats was equally effective with cyclacillin and oral ampicillin, whereas intramuscular ampicillin had a significantly higher therapeutic activity than oral cyclacillin. Serum concentrations in rats and mice were consistently higher with cyclacillin than with ampicillin and showed great variations depending on the animal species. It was concluded that there is a good correlation between in vivo and in vitro activity of both antibiotics, provided that the serum levels are taken into consideration. On this basis it may be predicted that a man cyclacillin will exhibit lower therapeutic activity in gram-negative infections than ampicillin.

Administration, Oral

Physicochemical properties of amphoteric beta-lactam antibiotics I: Stability, solubility, and dissolution behavior of amino penicillins as a function of pH.

The degradation rate, solubility, and dissolution rate of amino penicillins, amoxicillin, ampicillin, epicillin, and cyclacillin, were determined quantitatively as a function of pH. In the pH range studied, 0.30-10.50, the degradation of amoxicillin and epicillin followed pseudo-first-order kinetics to give the same type of pH-rate profiles as those of ampicillin and cyclacillin. Cyclacillin anhydrate was the most soluble, followed in order by ampicillin anhydrate, ampicillin trihydrate, amoxicillin trihydrate, and epicillin anhydrate. These pH-solubility profiles showed showed U-shaped curves. The dissolution rate constants from the rotating disk were analyzed by the simultaneous chemical reaction and diffusion models. Their relative bioavailability after a single oral administration was assessed from their physicochemical properties determined in vitro.

Chemical Phenomena

Intestinal absorption kinetics of a series of aminopenicillins and azidocillin. A comparative study in the rat.

Intestinal absorption rate constants of amoxicillin, ampicillin, epicillin, cyclacillin and azidocillin, by means of a static in situ intestinal perfusion method has been estimated. Luminal remaining antibiotic concentrations were determined using a standard microbiological technique. In order to establish statistically better absorption kinetics, five dose levels were used, ranging from 10 to 1000 micrograms/ml, and first order, Michaelis-Menten and combined first-order and Michaelis-Menten differential model equations were fitted to experimental data found for each antibiotic. According to the AIC test, the best equation for absorption kinetics was selected. Amoxicillin and ampicillin absorption mechanisms were better described by combined kinetics, while for cyclacillin and epicillin the most probable kinetics was that of Michaelis-Menten. For azidocillin, the only non-aminopenicillin component of this series, first order kinetics should be statistically selected.

Amoxicillin

Saturable uptake of cefixime, a new oral cephalosporin without an alpha-amino group, by the rat intestine.

The mechanism of intestinal uptake of cefixime, a new oral cephalosporin antibiotic, has been examined using the everted jejunum of rats. The initial uptake rates were apparently pH-dependent with the maximum rate at pH 5.0 and a 3-fold reduction at pH 7.0. The uptake at pH 5.0 followed mixed-type kinetics involving saturable and non-saturable processes in a manner similar to that for several amino-beta-lactam antibiotics. Cefixime uptake was inhibited significantly by 20 mM permeants such as cyclacillin, cephradine, benzylpenicillin, propicillin, glycyl-L-proline and glycyl-glycine. Replacement of Na+ in the medium with choline produced a slight but significant inhibition of cefixime uptake. In spite of the absence of significant inhibition by the amino acids glycine and proline, the dipeptide, glycyl-L-proline in Na+-free medium showed a marked inhibitory effect. The inhibition kinetics of cefixime uptake by glycyl-L-proline and cyclacillin were consistent with competitive-type inhibition. This study provides the first evidence of saturable intestinal uptake of a cephem antibiotic without an alpha-amino group in the side chain, suggesting transport through the dipeptide carrier system(s).

Animals

Aminopenicillins - clinical pharmacology and use in disease states.

Ampicillin introduced in 1961 has been administered in the treatment of diverse infections by both oral and parenteral means. Oral infections of the upper airways such as otitis media, bronchitis, and pneumonia have responded with high success rates since the microorganisms involved have remained sensitive to ampicillin. Similarly, out-patient urinary tract infections caused by Escherichia coli, Proteus mirabilis, and enterococci are cured. Typhoid fever may yet be treated with ampicillin, but shigellosis has become refractory with the development of resistant strains. Ampicillin has assumed a prominent role in the treatment of gonorrhoea. Parenteral ampicillin is still a mainstay of the treatment of Hemophilus meningitis, but the recent appearance of ampicillin resistant strains may become a serious problem. A number of derivatives and analogues of ampicillin have been developed. Among the compounds, hetacillin, metampicillin and pivampicillin which hydrolyze in the body to yield ampicillin, only pivampicillin appears to offer advantage over the parent compound. Blood levels are twice those of a comparable dose of ampicillin. However, more comparisons with ampicillin in clinical situations are needed. The other analogues of ampicillin are epicillin, cyclacillin and amoxicillin. Epicillin has no superiority to ampicillin, and the cyclacillin data do not show clear superiority over ampicillin in spite of initially high blood levels, since the compound is less active and so rapidly cleared from the body. Amoxicillin, on the other hand, has been shown to have it vitro activity equal to ampicillin and to produce higher blood levels for a longer period of time. Clinical studies have substantiated efficacy in treatment of otitis media, pharyngitis, bronchitis, pneumonitis, and urinary tract infections at doses half those of ampicillin. It has been effective in gonorrhoea and typhoid, but not in shigellosis. It would seem that to date only pivampicillin and amoxicillin, particularly the later, should be considered as replacements of ampicillin in oral therapy.

Acetamides

[Distribution and changes of antibiotic susceptibility of genus Haemophilus (author's transl)].

We studied on the distribution and changes of antibiotic susceptibility of H. influenzae, H. parainfluenzae and H. parahaemolyticus isolated from clinical materials, mainly from sputum and pharyngeal swabs. In this study we used 132 strains of H. influenzae, 89 strains of H. parainfluenzae and 43 strains of H. parahaemolyticus isolated during January and June of 1975, and estimated the susceptibility for the following eighteen antibiotics by the agar plate dilution method: ampicillin, amoxicillin, ciclacillin, sulbenicillin, carbenicillin, cephalothin, cefazolin, ceftezole, cephalexin, streptomycin, kanamycin, gentamicin, dibekacin, tetracycline, doxycycline, chloramphenicol, thiamphenicol and colistin. We compared these with previously reported results and observed the changes of antibiotic susceptibility. Ampicillin has the strongest antibiotic activity on three species of Haemophilus and the activity of four cephalosporins was weakest. Among three species H. parahaemolyticus was most susceptible and H. influenzae least susceptible to cephalosporins. Antibiotic activity of cyclacillin was rather weak. Other twelve antibiotics have good activity on Haemophilus. We could not find any ampicillin-resistant strain, but found five (3.8%) streptomycin-resistant, one (0.8%) kanamycin-resistant, eleven (8.3%) tetracycline-resistant, and seven (5.3%) chloramphenicol-resistant strains of H. influenzae. Six years ago we found five (9.6%) streptomycin-resistant and one (1.9%) tetracycline-resistant strains, but no resistant strain to other antibiotics. Tetracycline- and chloramphenicol-resistant strains are supposed to have a tendency to increase. There were very few strains which were resistant to more than two antibiotics among H. influenzae. We found a few strains resistant to tetracycline or chloramphenicol among H. parainfluenzae and H. parahaemolyticus, and one strain of H. parainfluenzae was less susceptible to ampicillin.

Amoxicillin

Susceptibility to beta-lactam antibiotics and production of beta-lactamase in Bacteroides fragilis.

Using the agar dilution technique, 231 strains of Bacteroides fragilis, isolated during a 2-year period from human infections, were identified at subspecies level and were tested for susceptibility to 13 beta-lactam antibiotics. The penicillins were benzylpenicillin, ampicillin, carbenicillin, cloxacillin, and the recently described penicillin derivatives cyclacillin, ticarcillin, and PC-904. The following cephalosporin derivatives were tested: cephaloridine, cephalothin, cephalexin, cefamandole and cefuroxime. The cephamycin C derivative cefoxitin was also included in the study. Cefoxitin was the most effective drug tested since more than 80% of the strains were inhibited by 8 microgram/ml or less, and no strain had a minimal inhibitory concentration (MIC) of more than 64 microgram/ml. There was no marked difference in sensitivity among the subspecies with exception of subspecies vulgatus, which was slightly more sensitive to all antibiotics tested. The size of the inoculum was an important factor for obtaining reproducible results in the sensitivity tests. Increased inocula resulted in markedly higher MICs for cephaloridine and cefuroxime. Production of beta-lactamase was performed on all isolates by a chromogenic cephalosporin substrate and about 90% of the strains were found to be beta-lactamase producers.

Amidohydrolases

The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies.

Pretreatment sinus puncture was performed on 339 patients with acute community-acquired sinusitis (ACAS) between 1975 and 1990. Bacterial species recovered in titers of greater than or equal to 10(4) colony-forming units per milliliter (CFU/ml) from 383 sinus aspirates included Streptococcus pneumoniae, 92 (41%); Haemophilus influenzae, 79 (35%); anaerobes, 17 (7%); streptococcal species, 16 (7%); Moraxella catarrhalis, 8 (4%); Staphylococcus aureus, 7 (33%); and other, 8 (4%). Viruses (rhinovirus, parainfluenza virus, and influenza virus) and fungi (Aspergillus, zygomycoses, Phaeohyphomycis, Pseudallescheria, and Hyalohyphomycis) have also been reported to cause ACAS. Posttreatment sinus puncture was performed on 220 of the 339 patients in six studies to evaluate efficacy of selected antimicrobial agents in producing bacteriologic cure. Ampicillin, 500 mg four times daily; amoxicillin, 500 mg three times daily; trimethoprim-sulfamethoxazole, twice a day; cefaclor, 500 mg four times daily; bacampicillin, 800 mg twice a day; cyclacillin, 500 mg three times a day; cefuroxime axetil, 250 mg twice daily; amoxicillin-clavulanate, 500/125 three times daily; and loracarbef 400 mg twice daily, given in 10-day courses, produced bacteriologic cure in more than 90% of patients. Early studies were done before beta-lactamase-producing strains of H. influenzae were a frequent cause of ACAS in Charlottesville. Management of therapeutic failures is a difficult problem for which diagnostic and therapeutic sinus puncture and lavage, prolonged antimicrobial therapy, steroid therapy, and evaluation of allergy, immunodeficiency, and surgically correctable lesions of the osteomeatal complex are recommended.

Acute Disease