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Article
Five ampicillin resistant strains of Escherichia coli were exposed to cephalosporins in an in vitro model which simulates the hydrokinetic features of the urinary bladder. Although the strains showed substantial zones of inhibition when tested against cephalosporins by the disc diffusion method, the results in the bladder model suggest that, in conditions where the antibiotic concentration is being reduced by dilution and micturition as well as enzymic hydrolysis by the organism, activity of this group of agents may be insufficient to eradicate infection. It is suggested that the results warrant a closer investigation into the efficacy of cephalosporins against ampicillin resistant Gram negative bacilli in vivo.
Article
The in vitro antibacterial activity of cefamandole, a new cephalosporin antibiotic, was compared with that of cephaloridine, cephalothin, and cephalexin against 1,213 strains of gram-positive and gram-negative bacteria recently isolated from clinical sources. The decreasing order of activity of the four agents against gram-positive cocci was cephaloridine, cephalothin, cefamandole, and cephalexin. However, cefamandole was the most active of the four against Haemophilus species and gram-negative bacilli susceptible to cephalosporins. It was also active against many strains resistant to the other cephalosporins, such as Enterobacter species and indole-positive Proteus species, but there was a marked inoculum effect with all of these organisms, and minimal bactericidal concentrations were usually considerably higher than minimal inhibitory concentrations. Cefamandole, like other cephalosporins, had no useful activity against Pseudomonas species.
Article
Full-text available
Methicillin-resistant strains of Staphylococcus aureus, in total 84, representing 16 laboratories in 8 different countries were all resistant to 32 μg of cephalothin per ml with the same typical heteroresistant pattern. With the disc diffusion method, they were easily detected when cephalexin discs were used. With cephalothin discs, on the other hand, 26 to 49% would have been falsely categorized as Group I or II after 24 hr. It is recommended that susceptibility testing of S. aureus to cephalosporins by using the paper disc method be performed with 30-μg cephalexin discs on Mueller-Hinton agar without blood. With an inoculum of 106 bacteria/ml, an incubation temperature of 30 C, and an incubation time of 24 hr, a zone of less than 10 mm indicates presumptive heteroresistance. This corresponds to the international recommendation with a minimal inhibitory concentration of 32 μg/ml as the upper limit of Group II.
Article
Synopsis: Cephalexin2 is an orally active semisynthetic derivative of the cephalosporin nucleus (7-amino cephalosporanic acid) with a spectrum of activity against both Gram-positive and Gram-negative bacteria. The side chain substituents on the cephalosporin nucleus of cephalexin are the same as the substituents on the penicillin nucleus (6-amino penicillanic acid) of ampicillin. Cephalexin is advocated for the treatment of infections of the upper and lower respiratory tract, genitourinary system, skin and soft tissue, bones and joints and certain other infections due to susceptible organisms. In concentrations which are achieved with usual oral doses, cephalexin is bactericidal against most susceptible organisms. Its activity in vitro is generally less than that of cephaloridine or cephalothin against susceptible organisms, and less than that of ampicillin against ampicillin-sensitive bacteria, notably Enterobacteriaceae and Haemophilus influenzae. Cephalexin does however, attain much higher serum concentrations than ampicillin in equivalent oral doses and is much less bound to serum proteins than cephalothin. Whether such pharmacokinetic differences make cephalexin comparable in therapeutic efficacy with ampicillin (particularly against H. influenzae infections) and cephalothin, remains to be established. Successful therapeutic results have however, been obtained with doses of 1 to 4 g daily (usually given at intervals of 6 hours), particularly in acute infections. The published experience on long-term administration in chronic cases is limited, as are direct comparisons with penicillin, ampicillin and the penicillinase-resistant penicillins. Tolerance is good, although diarrhoea, vomiting and vulvo-vaginitis have occasionally been troublesome. Cephalexin does not appear to have any nephrotoxic effects and thus may be used in patients with renal failure.
Article
In the present study, oral cephalexin in a dose of 500 mg given 6 or 8 hourly was used to treat 21 soft tissue infections, 9 urinary tract infections, and 8 respiratory tract infections. Treatment time averaged ten days. Although serum and urine levels observed were lower than in other reported studies, soft tissue infections responded very well. Acute pulmonary lesions also showed quick clearing. Despite high urinary levels of cephalexin, urinary infections in this group of elderly males showed a rather poor response. This is felt to be related to chronic long standing renal pathology and catheter drainage. The study indicates that cephalexin has a wide range of clinical applicability in acute, soft tissue, pulmonary, and urinary tract infections. The bacteriologic spectrum is wide, and side effects are minimal.
Article
Healthy volunteers were given a single intramuscular (i.m.) injection of a solution of 1 g, 500 or 250 mg sodium cephalexin or an intravenous (i.v.) injection of 1 g. Following i.m. injection, mean peak serum levels were estimated by computer analysis to be 18.3, 17.9 and 8.2 μg ml−1 respectively. The mean serum level 15min after i.v. injection was 52.5 μg ml−1. The rate of recovery of cephalexin in the urine after i.m. injection was slower than after both i.v. injection and oral administration. Concentrations of cephalexin in the urine reached a higher maximum after i.v. than after i.m. injection, but were maintained for a shorter time. Analysis of the data after i.m. injection suggests the occurrence of a depot-like effect.
Article
The in vitro activity of cefazolin was assessed by continuous turbidimetric monitoring of cultures of gram-negative bacilli and the results were compared with those previously obtained with other beta-lactam agents using the same strains and methods. Cefazolin was found to induce rapid lysis of ampicillin-susceptible and -resistant strains of Escherichia coli at a lower concentration than any other beta-lactam agent tested; its stability to beta-lactamase, as judged by regrowth studies, was generally considerably greater than that of other antibiotics of this group. Tested against 103 ampicillin-resistant enterobacteria, cefazolin was found to be more active than cephalothin against E. coli, but no systematic increase in susceptibility to cefazolin was seen with other species. A study of cefazolin in an in vitro model which simulates the hydrokinetic features of the urinary bladder showed it to be as active as ampicillin against ampicillin-susceptible E. coli and as active as cephalothin against ampicillin-resistant E. coli.
Article
This paper reviews the pharmacokinetics and clinical use of 11 cephalosporin antibiotics. Detailed information of absorption, distribution, metabolism and excretion is included. It is the opinion of these authors that the numerous cephalosporins available must not be automatically looked upon as 'unique' antibiotics, even though they are not exact generic equivalents. The important issue is whether they are equivalent from the pharmacokinetic and therapeutic points of view.
This chapter discusses the cephalosporin group of antibiotics. Two sites in the cephalosporin molecule are: (1) the 7-acyl side chain, leading to the production of 7-acylaminocephalosporanic acids—for example, ring-substituted phenylacetylcephalosporanic acids (analogous to benzylpenicillin) and ring-substituted phenoxyacetylcephalosporanic acids members of both types being active mainly against gram-positive bacteria, and (2) the 3-acetoxymethyl side chain leading to the production of deacetylcephalosporins and deacetoxylcephalosporins. The former have about half the activity of the parent compounds against gram-positive bacteria, such as staphylococci, but much reduced activity against gram-negative bacteria. Removal of the acetoxy group gives 3-hydroxyl derivatives,which are less antibacterial than the parent acetoxy compounds. Cephalosporin C, cephalothin, and cephaloglycin all lose antibacterial activity rapidly when incubated with rat liver homogenate, because of removal of the acetoxy group; however, cephaloridine and cephalexin do not possess these labile ester linkages and are thus, not inactivated.
Article
A new cephalosporin is described that overcomes, in a novel way, the general susceptibility of this group of agents to enterobacterial β-lactamases. The new compound carries a substituent that is released on cleavage of the β-lactam ring and then exhibits antibacterial activity in its own right. The possible therapeutic benefits of such an antibiotic are discussed.
Article
Since the development of the sulphonamides in the 1930s and the subsequent development of antibiotics from the 1940s onwards, there have now been many drugs developed which are capable of chemotherapeutic activity in a patient infected by a susceptible micro-organism. This review is concerned with precise descriptions of important groups of antimicrobial drugs, with emphasis being placed on the more recently developed drugs. With each group of drugs the pharmacology, major therapeutic indications, dosages and adverse reactions are discussed. Part II of the review discusses the cephalosporins, polymyxins and aminoglycosides. The place of each in therapy is defined.
Article
Theinvitroantibacterial activity ofcefamandole, a new cephalosporin antibiotic, was compared withthatofcephaloridine, cephalothin, andcephalexin against 1,213strains ofgram-positive andgram-negative bacteria recently isolated fromclinical sources.Thedecreasing order ofactivity ofthefouragents against gram-positive cocci was cephaloridine, cephalothin, cefamandole, and cephalexin. However, cefamandole was themostactive ofthefouragainst Haemophilus species andgram-negative bacilli susceptible tocephalosporins. It was alsoactive against many strains resistant totheother cephalosporins, such as Enterobacter species andindole-positive Proteus species, butthere was a markedinoculum effect withalloftheseorganisms, andminimalbactericidal concentrations wereusually considerably higher thanminimal inhibitory concen- trations. Cefamandole, like othercephalosporins, hadno useful activity against Pseudomonas species. Cefamandole, 7-D-mandelamido-3-(1-meth- yl-1H-tetrazol-5-ylth iomethyl)-3-cephem-4-car-
Article
Synopsis: Cephalexin2 is an orally active semisynthetic derivative of the cephalosporin nucleus (7-amino cephalosporanic acid) with a spectrum of activity against both Gram-positive and Gram-negative bacteria. The side chain substituents on the cephalosporin nucleus of cephalexin are the same as the substituents on the penicillin nucleus (6-amino penicillanic acid) of ampicillin. Cephalexin is advocated for the treatment of infections of the upper and lower respiratory tract, genitourinary system, skin and soft tissue, bones and joints and certain other infections due to susceptible organisms. In concentrations which are achieved with usual oral doses, cephalexin is bactericidal against most susceptible organisms. Its activity in vitro is generally less than that of cephaloridine or cephalothin against susceptible organisms, and less than that of ampicillin against ampicillin-sensitive bacteria, notably Enterobacteriaceae and Haemophilus influenzae. Cephalexin does however, attain much higher serum concentrations than ampicillin in equivalent oral doses and is much less bound to serum proteins than cephalothin. Whether such pharmacokinetic differences make cephalexin comparable in therapeutic efficacy with ampicillin (particularly against H. influenzae infections) and cephalothin, remains to be established. Successful therapeutic results have however, been obtained with doses of 1 to 4 g daily (usually given at intervals of 6 hours), particularly in acute infections. The published experience on long-term administration in chronic cases is limited, as are direct comparisons with penicillin, ampicillin and the penicillinase-resistant penicillins. Tolerance is good, although diarrhoea, vomiting and vulvo-vaginitis have occasionally been troublesome. Cephalexin does not appear to have any nephrotoxic effects and thus may be used in patients with renal failure.
Chapter
It is now over 30 years since Brotzu recovered the mould Cephalosporium acrimoniurn from Sardinian sewage. This produced a number of antibiotics, but from the clinical standpoint, cephalosporin C and its chemical analogues are so far the most important to have been developed. The important cephalosporins at present available for parenteral use are cephaloridine and cephalothin. For oral use, cephalexin, cephaloglycin and cephradine are now available; the latter can also be given by the parenteral route. The cephalosporins are active against a wide range of organisms and are almost entirely excreted by the kidney. They are active against staphylococci with intrinsic resistance to penicillin and against penicillinase producing strains and may be used alone in the treatment of infections caused by these organisms.
Article
Cephradine, a new semisynthetic cephalosporin derivative, is 7[d(−)-2-amino-2-(1,4-cyclohexadien-1-yl) acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrate. The compound has a broad spectrum of antimicrobial activity in vitro. When given subcutaneously to mice, cephradine was appreciably more effective than cephalothin against infections induced by penicillinase-producing Staphylococcus, Escherichia coli, Klebsiella pneumoniae, or Enterobacter cloacae strains. Cephradine and cephaloridine possessed equivalent activity in treating infections caused by these same three gram-negative bacteria. The mean total bioactivity of cephradine in the serum of mice peaked within 30 min (59 μg/ml) after parenteral administration and was approximately threefold that of cephalothin (20 μg/ml), but less than that of cephaloridine (83 μg/ml). Nearly all of the administered cephradine (84%) and cephaloridine (70%) were excreted in the urine as the parent compounds. In contrast, only 47% (total bioactivity) of administered cephalothin was recovered, an amount that represented only 15 to 20% of the parent substance.
Article
Six (8%) of 75 patients treated with cephaloridine developed a positive direct Coombs' test (DCT). Five of the six were receiving the maximum dose used (4 gm/day) and all were older than the age of 47 years. Positivity was most related to duration of therapy and total dose of drug administered. It was unrelated to serum concentrations of cephaloridine or to hypoalbuminemia and occurred in patients with normal renal function. The incidence of Coombs' positivity with cephaloridine was lower than that previously reported with cephalothin sodium but was likewise unassociated with hemolysis.
Article
Cephalothin and cephaloridine, semisynthetic congeners of cephalosporin C, are highly active against nearly all Gram-positive bacteria (except enterococci and methicillin-resistant staphylococci) and, at concentrations of 1µg to 10 µg/ml, against most strains of Salmonella, Shigella, Klebsiella, Proteus mirabilis, and many Escherichia coli, paracolon bacteria, and Hemophilus influenzae. These drugs are inactivated by a beta lactamase, cephalosporinase, and are susceptible to very high concentrations of penicillinase. They inhibit cell wall synthesis. Neither cephalothin or cephaloridine is absorbed from the gastrointestinal tract. Two related compounds, cephaloglycine and cephalexin, are absorbed by this route. They are largely excreted by the kidneys. In the presence of renal disease the dose of each must be reduced. Cross-sensitization between penicillin and the cephalosporin C congeners is very uncommon and is not an important contraindication to the use of these agents in individuals allergic to penicillin. Cephalothin may produce Coombs-positive reactions. Doses of cephaloridine greater than 4 g/day may lead to a varying degree of renal dysfunction or acute tubular necrosis. Fever, eosinophilia, anaphylaxis, serum sickness, and various skin rashes occur in about 5% of treated patients. The usefulness of cephalothin and and cephaloridine in the management of a variety of infections is well established.
Article
An analysis of cases of possible nephrotoxicity from cephaloridine (96) and cephalothin (63) reported over the last 10 years shows that in the majority of cases the toxicity was associated with either excessive dosage or previous renal functional impairment without appropriate dosage reduction. Other factors found frequently and thought to predispose towards toxicity are: the concurrent use of other potentially nephrotoxic antibiotics, especially gentamicin or the diuretic frusemide; the presence of intercurrent severe drug allergy and factors leading to temporary reductions in renal clearance such as surgical operations, dehydration and shock
Article
Cephaloridine, a semisynthetic derivative of cephalosporin C, was administered in single doses to mice, rats, guinea pigs, rabbits, cats, dogs, and monkeys. Acute LD50 values, obtained by various routes for mice, rats, and guinea pigs, were high. Rabbits, cats, dogs, and monkeys survived doses of 0.2 g/kg.Sublethal doses of the antibiotic damaged the proximal convoluted tubules of the kidneys of the mice, rats, guinea pigs, rabbits, and, probably, the monkeys. Tubular necrosis in mice was shown to be reversible. The relative sensitivities of the kidneys of various species were assessed by measurement of ND50 values (single doses producing histologic signs of kidney damage after 48 hours in 50% of animals).Sex differences in mortality and nephrotoxicity were observed in some species.Administered subcutaneously in large doses at high concentration, cephaloridine ulcerated the skin of mice and rats, but smaller doses were not irritant to the skin of guinea pigs or dogs. Cephaloridine was much less irritant to rabbit muscle than sodium penicillin G, and did not damage the veins of the mouse tail.Doses up to 25 mg/kg, administered intravenously to anesthetized cats, had no demonstrable pharmacodynamic effect.
Article
Potential nephrotoxicity of cephaloridine and cephalothin was studied in rabbits and monkeys. Dose-related nephrotoxicity caused by cephaloridine, but not cephalothin, was demonstrated. Cephaloridine injections of 500 and 200 mg. per kilogram per day, intramuscularly, in rabbits and monkeys resulted in marked alteration in renal function and necrosis of proximal tubules; 100 and 50 mg. per kilogram per day doses did not appear to cause renal injury. Cephalothin injections in rabbits of 500 and 200 mg. per kilogram per day caused minimal swelling or hydropic changes in proximal tubular epithelium but no functional abnormalities. These data showed that dosages of cephaloridine exceeding 100 mg. per kilogram per day were nephrotoxic, whereas, cephalothin appeared to have much less nephrotoxic potential.
Article
Serum and urinary levels of cephalexin, a semisynthetic cephalosporin antibiotic, were compared in 34 adult patients with normal or impaired renal function. A mean serum level of 11 [mu]g/ml was achieved at one hour after a single 250 mg oral dose in all fasting patients excepts those with severe renal impairment (creatinine clearance less than 2.5 ml/min/1.73m2) in whom peak levels were delayed to four hours. The mean serum half-life renged from 1.2 hours in patients with normal renal function to 21.5 hours in patients with severe renal impairment. Serum levels rose to 19 to 48 [mu]g/ml after repeated 250 mg oral doses in azolemie patients. Hemodialysis reduced serum levels at a rale five times greater than without dialysis. The mean exlraction ration was 51. Urinary levels of 100 [mu]g/ml or greater were achieved in all except anurie patients. Rash, pruritus, fever, emesis or diarrhea occurred in three patients, necessitating stopping therapy in two. An oral dosage regimen designed to produce sustained serum levels of 12 to 30 [mu]g/ml is presented. Cephalexin when given orally, should be useful in the treatment of many becterial infections in patints with impaired renal function. (C) Copyright 1970 Southern Society for Clinical Investigation
Article
The authors believe that this drug has nephrotoxic properties when used in the presence of preexisting renal disease.
Article
Cephaloridine serum half-life was determined in 11 patients undergoing maintenance haemodialysis. Three of them were anephric. The mean cephaloridine half-life was 10.4 hours. There was an inverse correlation between cephaloridine half-life and the duration of maintenance haemodialysis treatment. Reasons for this are discussed.The effect of haemodialysis with the Kiil dialyser on cephaloridine half-life was studied in three patients.Dosage recommendations for patients on maintenance haemodialysis are suggested.
Article
Ten patients with bacterial endocarditis were treated with cephalothin. Nine (Streptococcus viridans, four, microaerophilic streptococcus, two, anaerobic streptococcus, one, and Staphylococcus aureus, two) appeared cured when studied six months to four years after therapy ended. The tenth (Staph. albus) had negative blood cultures at the time of death. In seven, bacterial strains were available for testing, and growth was inhibited by a 30-μg cephalothin disk. In two other patients with enterococcal endocarditis, no serum bactericidal activity was demonstrated in vitro after administration of cephalothin in combination with streptomycin. Side effects of cephalothin included mild rashes, fever and superficial thrombophlebitis. An excessive blood level (51 μg per milliliter) developed in a patient who had a serum creatinine of 2.2 mg per 100 ml. In another, serum creatinine rose from 1.7 to 6.6 mg per 100 ml after 8 gm daily for 23 days. Cephalothin appears to be an excellent substitute for penicil...
Article
Cephaloridine, an antibiotic derived from cephalosporin C, was administered parenterally for 5 days to rats (1100 mg/kg/day), for 8 weeks to rats and cats, for 12 weeks to dogs (15, 50, or 150 mg/kg/day) and for 8 weeks to rabbits (15, 30, or 45 mg/kg/day). Large daily doses damaged the kidneys of rats, but less than might have been expected from previous studies of single-dose effects. The nephrotoxic effect of cephaloridine also appeared to be noncumulative in rabbits. The kidneys of rabbits and cats were enlarged, but histologic examination did not present evidence of changes attributable to the antibiotic.Liver weights were increased in rats and cats, but without histologic abnormality. Leukocytopenia occurred in rats and, temporarily, in dogs.Cephaloridine was not toxic to the rabbit fetus, and toxic doses did not impair the fertility or mating ability of buck rabbits.
Article
A TWENTY-SEVEN-year-old woman with rheumatic heart disease had open-heart surgery on April 5, 1966. The direct Coombs tests before operation were negative. She was studied nine days later because of anemia and had a strongly positive direct Coombs test. Isoimmunization to donor cells transfused during surgery was ruled out by an appropriate elution technic. The indirect Coombs test was negative. The patient had been receiving cephalothin (4 gm. daily) in addition to other drugs since April 7. A diagnosis of hemolytic anemia due to cephalothin was considered, blood transfusions were given, and attempts were made to elucidate the mechanism of . . .
Article
Cephaloridine has been shown to possess certain favorable pharmacologic features while retaining the desirable antimicrobial properties of the parent compound, cephalothin. The major advantage of cephaloridine is its relatively greater resistance to metabolic degradation, presumably by the liver. This results in more prolonged blood levels in healthy subjects and a longer half-life in patients with severe renal disease. These features, together with reported enhanced antimicrobial activity and lack of inhibition by serum, suggest that it may replace or substitute for the parent compound, cephalothin, provided further clinical trials indicate that it proves to be an effective agent. Suggestions are given for a modified dosage schedule in uremic patients and during hemodialysis.
Cephaloridine and the kidney
  • R D Foord
Foord, R. D. (1969). Cephaloridine and the kidney. In Progress in Antimicrobial and Anticancer Chemotherapy. Proceedings of the 6th International Congress ofChemotherapy, Tokyo 1969, vol. 1, pp. 597-604.
Personal communication
  • Brumfitt, W.