Cefoxitin, a Semisynthetic Cephamycin Antibiotic: Susceptibility Studies

Cefoxitin, 3-carbamoyloxymethyl-7-alpha-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4- carboxylic acid, is a new semisynthetic cephamycin with broad antibacterial activity. It is highly active against gram-negative microorganisms including indole-positive Proteus and Serratia strains, which are ordinarily reistant to the cephalosporins. Cefoxitin is also highly active against many strains of Escherichia coli and Proteus mirabilis which are resistant to the cephalosporins. Furthermore, E. coli and Klebsiella strains which are susceptible to the cephalosporins are generally more susceptible to the cephamycin analog. The susceptibility of the gram-positive bacteria falls well within the effective range of the antibiotic for gram-negative organisms, but cefoxitin is less active than cephalothin or cephaloridine. As is the case with the cephalosporins, strains of Pseudomonas and group D streptococci are resistant to cefoxitin. Changes in pH, inoculum density, and growth medium have no significant effect on the activity of the antibiotic.     

Cefoxitin, a Semisynthetic Cephamycin Antibiotic: In Vivo Evaluation

Cefoxitin, 3-carbamoyloxymethyl-7-alpha-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4- carboxylic acid, a semisynthetic cephamycin antibiotic shown to have broad-spectrum activity in vitro, is active also in vivo against a wide variety of bacteria including penicillin-resistant staphylococci. It is, however, particularly effective against gram-negative organisms including strains of indole-positive Proteus against which cephalothin and cephaloridine are ineffective. When cefoxitin is given subcutaneously, concentrations in mouse blood, urine, and other tissues are higher than those seen for cephalothin. Higher concentrations in the blood and greater therapeutic efficacy are achieved with cefoxitin when it is given with probenecid. For this reason it is believed that cefoxitin is excreted mainly by way of the renal tubules. The data indicate that cefoxitin has potential as a therapeutically useful antibiotic.     

Cefoxitin, a Semisynthetic Cephamycin Antibiotic: Resistance to Beta-Lactamase Inactivation

Cefoxitin is a new, cephalosporin-like antibiotic which is highly resistant to hydrolysis by beta-lactamase. Ninety-one cultures were selected either for their general resistance to cephalosporin antibiotics or for their ability to produce beta-lactamase. Some of these cultures were resistant to cefoxitin. The capacity of each of the 91 strains to hydrolyze cefoxitin with beta-lactamase was determined. Only seven of the cultures degraded the antibiotic as determined by a general assay for beta-lactamase. Several others were able to hydrolyze cefoxitin after enzyme was induced by low concentrations of the antibiotic. The role of the constitutive and inducible enzyme in bacterial resistance to the antibiotic was investigated. Enzymatic destruction of cefoxitin was found to be an important factor contributing to bacterial resistance. However, the complete and rapid degradation of cefoxitin is not essential to resistance since one strain, Enterobacter cloacae 1316, hydrolyzed the antibiotic very slowly but was able to grow unaffected in the presence of cefoxitin. The presence of the enzyme is not necessarily sufficient to confer resistance since another culture, Klebsiella D535, readily hydrolyzed the antibiotic but was susceptible to it.     

Use of Cefoxitin, New Cephalosporin-Like Antibiotic, in the Treatment of Aerobic and Anaerobic Infections

Forty-two patients were treated with intravenous cefoxitin, a new cephamycin antibiotic. These patients had postoperative abdominal sepsis (26), intrathoracic infections (6), urinary tract infections (5), gram-negative bacterial meningitis (2), septic arthritis (1), epidural abscess (1) and isolated septicemia (1). The antibacterial spectrum of cefoxitin was found to be one which included all gram-positive organisms except enterococci, most gram-negative organisms except Pseudomonas aeruginosa, and almost all of the important anaerobic organisms. The only five treatment failures included one patient with empyema and one with septic arthritis, both caused by Serratia marcescens, initially only moderately susceptible to cefoxitin, which subsequently developed increased resistance, two patients with contaminated intravenous catheters, and one patient with epidural abscess and cerebritis, who was treated late in the course. There was one serious clinical superinfection with P. aeruginosa. The drug levels noted in the pus and joint fluid were half to two-thirds of the simultaneous serum level. In inflamed meninges, up to 30% of the serum level was noted in the cerebrospinal fluid, and as the process resolved, 10 to 15% was noted. Toxicity of cefoxitin was mild and constituted skin rash in three patients (7%) and phlebitis in eight (19%).     

New Cephamycin Antibiotic, CS-1170: Binding Affinity to Penicillin-Binding Proteins and Inhibition of Peptidoglycan Cross-Linking Reactions in Escherichia coli

The binding activity of CS-1170, a new cephamycin antibiotic, to penicillin-binding proteins (PBPs) in Escherichia coli and Proteus species and the potency of this antibiotic in vitro to inhibit enzymes involved in peptidoglycan cross-linking in E. coli were tested. Similar experiments were carried out with the 7alpha-H analog of CS-1170, R-45656, and the results were compared with those obtained with CS-1170. CS-1170 showed high affinities (compared with that of penicillin G) for E. coli PBP-1A, -1Bs, and -3, the PBPs of higher molecular weight, but not PBP-2. It also inhibited the in vitro peptidoglycan cross linking reaction and concomitant release of d-alanine at very low concentrations (approximately its minimal inhibitory concentration). This antibiotic also showed very high affinity for PBP-4, -5, and -6, the PBPs of lower molecular weight, and at extremely low concentrations it inhibited d-alanine carboxypeptidases IA and IB, corresponding to PBP-5/6 and PBP-4, respectively. CS-1170 seemed to be resistant to the beta-lactamase activity of PBP-5 and -6 in E. coli and Proteus species. R-45656 showed as high an affinity for PBP-1A, -1Bs, and -3 as CS-1170, but unlike CS-1170, it had low affinities for PBP-4, -5, and -6. The concentrations of R-45656 required for inhibition of d-alanine carboxypeptidases IA and IB were also much higher than those of CS-1170. R-45656 showed rather low activities in inhibiting the in vitro cross-linking reaction of peptidoglycan and concomitant release of d-alanine. Synergism was observed in 9 of 22 strains examined between CS-1170 and mecillinam, which bound specifically to PBP-2.     

Clinical and In Vitro Evaluation of Cephapirin, a New Cephalosporin Antibiotic

Cephapirin sodium, a cephalosporin for parenteral use, was evaluated in vitro and in 27 patients. Cephapirin had activity equivalent to cephalothin against 25 strains each of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus aureus; 10 strains each of Diplococcus pneumoniae, Pseudomonas species, and Enterobacter species; and 8 strains of Proteus species other than P. mirabilis. All strains of S. aureus and D. pneumoniae and most strains of E. coli, K. pneumoniae, and Proteus species were inhibited by concentrations of cephapirin achieved in the serum. Of 27 patients (20 with pneumonia, 2 with S. aureus empyema, and 5 with miscellaneous infections), 25 responded to cephapirin therapy. The only major toxicity thought to be drug-related occurred in a patient who developed reversible bone marrow depression with leukopenia, neutropenia, and anemia. Although cephapirin was painful on intramuscular injection, phlebitis and pain were absent in patients treated intravenously. In a controlled comparison of intravenously administered cephalothin and cephapirin in four additional patients, the latter caused much less pain than the former and caused no phlebitis.     

Clinical and In Vitro Evaluation of Cefazolin, a New Cephalosporin Antibiotic

Cefazolin sodium, a cephalosporin for parenteral use, was evaluated in vitro and in 26 patients. Cefazolin had activity equivalent to cephalothin against Streptococcus pneumoniae, Staphylococcus aureus, group A streptococci, and Proteus mirabilis. Cefazolin was four- to eightfold more active against Escherichia coli and slightly more active against Klebsiella pneumoniae, whereas cephalothin was slightly more active against indole-positive Proteus species. After a 500-mg dose of cefazolin intramuscularly, peak concentrations in the serum were high enough to inhibit all strains of S. pneumoniae, S. aureus, group A streptococci, E. coli, K. pneumoniae, and P. mirabilis, as well as 60% of strains of Proteus species other than P. mirabilis. All of 26 patients (18 with pneumonia, 6 with urinary tract infection, and 2 with skin infections) responded clinically and bacteriologically to cefazolin therapy. There were no major side effects of therapy, and no patient complained of pain at the site of intramuscular injection. Cefazolin is an effective cephalosporin which can be used intramuscularly for therapy of serious bacterial infections. Its major advantages over other cephalosporins are higher, more sustained concentrations in the blood and apparent lack of pain on intramuscular injection.     

Amoxicillin, a New Penicillin Antibiotic

Amoxicillin (alpha-amino-p-hydroxybenzyl penicillin, BRL 2333) is a new semisynthetic penicillin which is structurally similar to ampicillin, but which is better absorbed and yields higher concentrations in serum and urine. The in vitro susceptibility of 145 strains of Enterobacteriaceae and 30 isolates of Pseudomonas aeruginosa was determined against various concentrations of amoxicillin and ampicillin in agar. In addition, inhibitory zones around discs containing 10 mug of amoxicillin were measured and compared with results of agar dilution studies. The drug also was evaluated in the treatment of 38 patients with bacteriuria, who received doses of either 750 mg or 1 g/day for 10 days. In vitro, amoxicillin was comparable in activity to ampicillin; most isolates of Escherichia coli and Proteus mirabilis were inhibited by 10 mug or less/ml, whereas the majority of strains of Enterobacter, Klebsiella, indole-positive Proteus species, and Pseudomonas grew in concentrations greater than 50 mug/ml. Clinically, amoxicillin was effective in eradicating bacteriuria due to susceptible organisms and was very well tolerated. For practical purposes, however, amoxicillin performed no better than a host of other drugs presently available for the treatment of acute, uncomplicated bacteriuria.     

Cairomycin B, a New Antibiotic

Cairomycin B is a new cyclic peptide antibiotic that was isolated from Streptomyces As-C-19 obtained from the soil of Cairo. The antibiotic had the following empirical formula: C₁₀H₁₅N₃O₃; on acid hydrolysis, it yielded aspartic acid and lysine. Spectral analysis and its chemical characteristics indicated that it was a cyclic peptide. The antibiotic melted at 120 to 121°C and was freely soluble in chloroform, ethyl acetate, and acetone, slightly soluble in alcohols, and rather insoluble in water and petroleum ether. Cairomycin B was mainly active against gram-positive bacteria, with high toxicity to experimental animals and weak serum-binding properties.     

Evaluation of Cefazolin, a New Cephalosporin Antibiotic

Cefazolin sodium was tested in vitro against 308 isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus aureus, and enterococcus. Broth and agar dilution and disk diffusion techniques were used with at least two sizes of inocula of organisms. Cefazolin was also studied in the treatment of 85 hospitalized patients with a variety of serious infections. In concentations of 5 μg or less/ml, cefazolin inhibited and killed more than 90% of isolates of Enterobacteriaceae with the exception of indole-positive Proteus and Enterobacter species. No isolate of P. aeruginosa and only a few of Enterobacter and enterococci were killed by 25 μg of cefazolin/ml, a concentration readily attainable in serum with a 500-mg dose given intramuscularly. Penicillin-susceptible as well as penicillin-resistant isolates of S. aureus were killed by 1 μg or less of cefazolin per ml; however, 25 μg/ml was required to kill 100% of the strains when the inoculum size was increased 100-fold. Cefazolin treatment appeared effective in 82 of 85 patients, including four with endocarditis. Pain was minimal after intramuscular injection, and thrombophlebitis was not observed in those treated intravenously. No patient developed a positive Coombs test, and no evidence of renal toxicity was apparent in clinical studies.     

Evaluation of a New Cephalosporin Antibiotic, Cephapirin

Cephapirin sodium, a parenterally administered derivative of cephalosporanic acid, was tested in vitro against 150 stock cultures of Enterobacteriaceae and 30 stock cultures each of Pseudomonas aeruginosa and Staphylococcus aureus. Both broth- and agar-dilution techniques were employed with two sizes of inocula of organisms. At a concentration of 7.5 mug or less/ml, cephapirin inhibited and killed 100% of strains of Escherichia coli and Proteus mirabilis and more than 80% of Klebsiella species when tested against an inoculum of 10(5) bacterial cells/ml. However, even at 100 mug/ml, only a few isolates of other Enterobacteriaceae and Pseudomonas were inhibited. A 100-fold increase in the inoculum resulted in decreased susceptibility of organisms. All penicillin-susceptible as well as penicillin-resistant S. aureus isolates were inhibited and killed by 5 mug or less of cephapirin/ml when tested with an inoculum of either 10(4) or 10(6) organisms/ml. The drug also was studied in various doses in the treatment of 77 patients with diverse infections. Cephapirin was effective in the treatment of 27 of 32 patients with pulmonary infection, as well as in 6 of 7 patients with staphylococcal or streptococcal soft tissue infection. Of 25 patients with urinary-tract infections, 19 developed a negative culture during therapy. A single 4-g intramuscular dose of cephapirin was effective in only 2 of 11 patients with gonococcal urethritis or endocervicitis. Two patients with gonococcal urethritis treated with multiple injections were cured. The drug was well tolerated except for pain at the site of injection in 14 patients and phlebitis in 4 patients. No abnormalities in renal or hepatic function could be attributed to cephapirin. In addition, no abnormalities were found in the renal tubules of rabbits challenged with 500 mg of cephapirin/kg. If further studies document that cephapirin is well tolerated by the parenteral route, it may have advantages over cephalothin or cephaloridine.     

Cefoxitin Resistance to Beta-Lactamase: a Major Factor for Susceptibility of Bacteroides fragilis to the Antibiotic

Toluene-treated cell suspensions of Bacteroides fragilis were used to screen clinical isolates for the production of β-lactamase. Approximately one-third of the isolates possessed considerable cephalosporinase activity. A significant correlation was found between β-lactamase production and resistance to cephalosporin antibiotics. Several isolates were resistant to cefuroxime and cefamandole and produced enzymes capable of hydrolyzing these antibiotics. However, none of the 79 strains tested could hydrolyze the cephamycin derivative, cefoxitin. A large percentage (>90%) of the strains were susceptible to cefoxitin. Therefore, resistance to lactamase hydrolysis is a major factor for the effectiveness of cefoxitin against B. fragilis. Detailed studies of four isolates suggest that two different enzymes may be produced. Both are cephalosporinases but differ with regard to cellular distribution and substrate specificity. Cefoxitin is not a substrate for either enzyme, but it is an excellent competitive inhibitor (K_i ≈ 0.1 μM).     

Verdamicin, a New Broad Spectrum Aminoglycoside Antibiotic

Verdamicin is a new aminoglycoside antibiotic isolated from fermentation broths of a species of the genus Micromonospora, M. grisea. It has been differentiated from other known related antibiotics by a variety of chemical and biological methods. Its in vitro and in vivo spectrum of activity appears to be similar to those of gentamicin and sisomicin.     

Gardimycin, a New Antibiotic Inhibiting Peptidoglycan Synthesis

Gardimycin, a new antibiotic, at 100 mug/ml, specifically inhibited cell wall synthesis and induced accumulation of uridine 5'-diphosphate-N-acetylmur-amylpentapeptide in whole cells of Bacillus subtilis. The antibiotic was active in a particulate enzyme preparation from Bacillus stearothermophilus: 60 mug/ml caused 50%, and 200mug/ml caused 100%, inhibition of peptidoglycan synthesis. Suppression of peptidoglycan synthesis was accompanied by parallel accumulation of the lipid intermediate. This mechanism of action is discussed in comparison with those of other antibiotics that are known to inhibit bacterial cell wall biosynthesis.     

Chemical Modification of Maridomycin, a New Macrolide Antibiotic

Maridomycin, a new macrolide antibiotic, and tetrahydromaridomycin were acylated into their mono, di, and tri acyl derivatives.These derivatives were compared with the parent antibiotic, maridomycin, for their (i) in vitro antimicrobial activities, (ii) protective effect in mice infected with Staphylococcus aureus (oral administration), (iii) blood levels attained in rats, and (iv) acute toxicity in mice (intraperitoneal administration). All the derivatives showed either the same or less activity in vitro, but 9-acyl, 9, 2'-diacylmaridomycin and 9, 13, 2'-triacetyltetrahydromaridomycin demonstrated improved therapeutic effects together with higher blood levels and low toxicity. 9-Propionylmaridomycin showed the most favorable biological properties.     

Comparison of Cefazolin, a New Cephalosporin Antibiotic, with Cephalothin

Resistance to cephalothin was associated in general with a lack of susceptibility to cefazolin, a new 7-amino cephalosporanic acid derivative.     

Hypnotic Relaxation Therapy and Sexual Function in PostmenopausalWomen: Results of a Randomized Clinical Trial

Sexual dysfunction is a common problem for postmenopausal women. This study, as part of a larger randomized controlled trial, examined the effect of hypnotic relaxation therapy on sexual dysfunction, a secondary study outcome, in postmenopausal women. Sexual function was assessed using the Sexual Activity Questionnaire (SAQ). Significant improvement in sexual pleasure and discomfort were reported following 5 weekly sessions of hypnotic relaxation therapy, compared with those receiving an attention control. Total SAQ scores showed significant improvement in the hypnotic relaxation therapy treatment group while holding baseline SAQ scores constant. Improvements showed a slight increase at the Week 12 follow-up. The results of this analysis provide initial support for the use of hypnotic relaxation therapy to improve sexual function in postmenopausal women.