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Background: Recent analysis of clinical data and a clearer understanding of the role of chemical structure in the development of cross-reactivity indicate that the increased risk of an allergic reaction to a cephalosporin in penicillin-allergic patients is smaller than previously postulated., Method: Medline and EMBASE databases were searched with the keywords: cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 through 2005. Among 219 articles retrieved, 9 served as source material for this evidence-based meta-analysis., Results: A significant increase in allergic reactions to cephalothin (odds ratio [OR] = 2.5; 95% confidence interval [CI] = 1.1 to 5.5), cephaloridine (OR = 8.7; CI = 5.9 to 12.8), and cephalexin (OR = 5.8; CI = 3.6 to 9.2), and all first generation cephalosporins plus cefamandole (OR = 4.8; CI = 3.7 to 6.2) were observed in penicillin allergic patients; no increase was observed with second generation cephalosporins (OR = 1.1; CI, 0.6 to 2.1) or third generation cephalosporins (OR = 0.5; CI = 0.2 to 1.1). Clinical challenges, skin testing, and monoclonal antibody studies point to the paramount importance of similarities in side chain structure to predict cross-allergy between cephalosporins and penicillins., Conclusion: First-generation cephalosporins have cross-allergy with penicillins, but cross-allergy is negligible with second- and third-generation cephalosporins. Particular emphasis should be placed on the role of chemical structure in determining the risk of cross-reactivity between specific agents.

In a randomized prospective study ampicillin/sulbactam and cefamandole were compared in the therapy of patients hospitalized with community acquired pneumonia. Patients receiving ampicillin/sulbactam (n = 37) and cefamandole (n = 38) were similar with respect to age (mean age 70 vs. 76 years respectively), clinical characteristics, severity of illness and underlying disease. Pathogens isolated from patients in the cefamandole and ampicillin/sulbactam group, respectively, were Streptococcus pneumoniae (7 vs. 7 patients), Haemophilus parainfluenzae (7 vs. 6 patients), Haemophilus influenzae (5 vs. 5 patients), Staphylococcus aureus (5 vs. 4 patients), Escherichia coli (4 vs. 4 patients), Klebsiella pneumoniae (3 vs. 3 patients), Enterobacter spp. (2 vs. 3 patients), Moraxella catarrhalis (1 vs. 2 patients), and organisms of the oral flora (4 vs. 3 patients). The rate of resistance to penicillin was 80%, to clindamycin 76%, to erythromycin 45%, to ampicillin 43%, and to cefazolin 18%. Overall successful treatment rates of 81% for cefamandole and 97% for ampicillin/sulbactam (p = 0.05) were observed. Both cefamandole and ampicillin/sulbactam were shown to be effective agents for therapy of community acquired pneumonia; however ampicillin/sulbactam demonstrated superior overall clinical efficacy.

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.

We report 4 cases in which the use of cephamandole was associated with coagulopathy. All 4 patients had renal impairment, but no other known predisposing factors. It is recommended that the coagulation profile be monitored during administration of cephamandole, especially when there is a background of renal impairment.

Hemolytic anemia occurred in a 70-year-old female after a five-day course of intravenous cefamandole. The patient's serum contained an IgG antibody which was reactive with red blood cells which had been coated in vitro with cefamandole but not with uncoated cells. An in vitro assay of allogeneic mononuclear phagocytosis of cefamandole-coated red cells sensitized with the patient's anti-cefamandole indicated that the anti-cefamandole could induce significant phagocytosis. The anti-cefamandole was easily inhibited in vitro by cefamandole as well as by a variety of related cephalosporins indicating broad cross-reactivity, with the antigenic site primarily the 7-amino-cephalosporanic acid nucleus. Penicillins could inhibit the anti-cefamandole but only when using concentrations 3-10 X those of cephalosporins. Eleven examples of anti-penicillin tested failed to react with cefamandole-coated red cells. Screening of 344 random sera from hospitalized patients found only five (1.5%) reactive with cefamandole-coated red cells; three of these sera were also reactive with penicillin-coated red cells. The patient's hemolysis subsided following cessation of the drug. This is the first report of anti-cefamandole-induced hemolytic anemia.

The efficacy and safety of piperacillin were compared with those of cefamandole in 72 patients (mean age: 63 years) with complicated urinary tract infections. Efficacy was evaluable in 25/34 piperacillin-treated patients (12 Gm/day) and in 23/38 cefamandole-treated patients (6 Gm/day). Clinical cure or improvement was noted in all patients who were given piperacillin and in 96 per cent (22/23) of those who received cefamandole. Seventy-one per cent (41/58) of the organisms cultured pretherapy were gram-negative aerobic bacteria. Escherichia coli was the most frequently isolated organism (15/58, or 26%), followed by Pseudomonas species (8/58, or 14%), and Proteus species (8/58, or 14%). Adverse clinical experiences were few, and none was directly attributed to therapy with either antibiotic. The changes noted in the results of laboratory tests were considered to be unrelated to the antibiotics administered. Thus, both piperacillin and cefamandole were safe and effective in the treatment of patients with complicated urinary tract infections.

Since the introduction of cephalothin and cephaloridine as the first parenteral cephalosporins and cephalexin as the first member of the group which is absorbed from the gastrointestinal tract, several new cephalosporin derivatives have been developed. Most of these have no major advantages over cephalothin, cephaloridine or cephalexin. Increased knowledge about the importance of beta-lactamases for bacterial resistance against beta-lactam antibiotics has focused interest on development of drugs with increased resistance to degradation by these enzymes. Among the caphalosporins, cefamandole and cefuroxime have been found to be markedly more active against beta-lactamase producing Gram-negative bacteria. A new group of beta-lactam antibiotics, the cephamycins, have been introduced with cefoxitin as the first clinically useful member. Cefoxitin has the spectrum of a beta-lactamase-resistant cephalosporin and is also active against Bacteroides fragilis. The review concentrates on the antibacterial spectrum of these three new antibiotics and on their clinical efficacy.

A double-blind, multicenter trial compared cefonicid and cefazolin for prophylaxis against postoperative infection in 117 patients undergoing joint replacement. Cefonicid, which has an extended serum half-life, was administered once daily, while cefazolin was given every eight hours. The drug was administered one half to one hour before surgery and continued for up to 72 hours. Patients were observed throughout their hospitalization period and followed for 30 days after discharge. No evidence of wound or joint infection was observed in any of the patients who met the criteria for evaluation. Adverse reactions consisted mainly of infrequent gastrointestinal symptoms and laboratory abnormalities. Three patients died from causes unrelated to study medication. No differences between the two regimens were found with respect to safety or efficacy in the prevention of postoperative infection after arthroplasty. The effectiveness of once-daily administration should make cefonicid a highly cost-effective alternative to many of the more expensive first- and second-generation cephalosporin antibiotics currently used in hospital practice.

Forty-seven infants and children with a variety of infections including bacteremia, ethmoiditis, and periorbital cellulitis, soft tissue infection, pneumonia, and lymphadenitis were treated with intravenous cefamandole. The infections were due to Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae. The clinical response was prompt, and, with the exception of two cases who developed skin rash, significant side effects were not noted. In vitro cefamandole was very effective in inhibiting the growth of H. influenzae, including ampicillin-resistant isolates.

Ceftazidime and cefamandole were compared in a randomized multicentre trial in hospitalized patients with pneumonia. Of 290 patients enrolled, 92 patients in the ceftazidime group and 71 patients in the cefamandole group were evaluable. Geometric mean MICs of organisms isolated and tested to ceftazidime were within achievable therapeutic serum concentrations of ceftazidime. Satisfactory clinical responses were observed in 91% (84/92) of ceftazidime-treated patients and 83% (59/71) of cefamandole-treated patients (P greater than 0.05). Superinfection occurred in one (1%) ceftazidime-treated patient and in five (7%) cefamandole-treated patients. Side effects were infrequent with either treatment. Ceftazidime is as safe and effective as cefamandole for the treatment of pneumonia due to a variety of Gram-positive and Gram-negative pathogens.

Our data support the premise that antimicrobial therapy for peritonitis must be individualized. In the patient with minimal and moderate contamination who is not suppressed and who will undergo prompt and correct surgical therapy, then a single antimicrobial agent, such as cefamandole or perhaps even a first generation cephalosporin, such as cefazolin, will be adequate therapy even in instances of polymicrobial peritonitis when anticipated resistant organisms are present. In this situation, a single drug will be just as effective and safer when compared with the combination of an aminoglycoside and a specific antianaerobic agent. On the other hand, in the patient with immunosuppression, who is late to come to treatment or who has hospital acquired sepsis with probably a large contamination of resistant organisms, either a third generation cephalosporin with extended coverage or triple drug therapy, including a broad spectrum penicillin, an aminoglycoside and an anaerobic effective agent, should be the treatment of choice. Also, for infections with a culture proved overwhelming anaerobic flora, an antimicrobial specific for these pathogens should be used. The dictum, however, that all instances of peritonitis mandate double or triple drug therapy is a clinical impression based upon experimental models which do not correctly simulate the clinical situation.

Recently marketed drugs have limited experience in clinical use. Follow-up evaluation is therefore needed, particularly when these drugs are "restricted use" medicines, such as the second-generation cephalosporins. We present a follow-up of the first use of cefonicid, which was carried out after its substitution for cefuroxime in our hospital. The indication for use, dosing, therapeutic effects, and possible adverse reactions were recorded in 210 of the first 319 medical-surgical inpatients who received cefonicid. Cefonicid was administered to patients who could have been treated with free-use antibiotics on at least 128 occasions; these were cases of community-acquired pneumonia without any risk factor, urinary tract infections, acute exacerbations in patients with chronic lung disease, surgical prophylaxis, and intraabdominal infections. One fatal case of Stevens-Johnson syndrome was seen. Other recorded adverse events were two skin reactions, one tachyarrhythmia with evidence of low cardiac output, six episodes of phlebitis, and nine superinfections during treatment with cefonicid. The use of cefonicid instead of cefuroxime was associated with 20 percent cost savings; however, this study shows that optimal antibiotic prescribing may produce much greater savings.

Within a span of four months at a 550 bed community hospital, four elderly patients who had been taking cefamandole for various infections developed a severe coagulopathy within 10 days after initiation of cefamandole. All patients had a prolonged prothrombin time and activated partial thromboplastin time with a marked decrease of the vitamin K dependent clotting factors II, VII, IX, X, and also were found to have mild to moderate renal function impairment. The coagulopathy was promptly corrected to normal with or without treatment of vitamin K and/or fresh frozen plasma when the drug was discontinued. Treatment with vitamin K while on cefamandole also corrected the coagulation abnormalities and in vitro cefamandole had no direct effect on prothrombin time and activated partial thromboplastin time in therapeutic concentrations. These clinical and laboratory observations and the nature of high excretion rate of cefamandole in bile suggest cefamandole induced coagulopathy is caused by decreased vitamin K synthesis, probably secondary to rapid depletion of vitamin K producing intestinal organisms.

Cefamandole 3 g daily gave poor results in the treatment of severe purulent respiratory infections in 50 patients. A further 71 patients were treated with 4 g daily and the results were excellent with 86% clinical success. Apart from muscle pain with the injection, side-effects were minimal.

Thirty-five patients with cellulitis were treated with ceforanide, 1 g every 12 h, intramuscularly. A good clinical response was observed in 33 cases. Drug failure in the remaining two patients was thought to be due to the lack of surgical debridement. Drug concentrations well in excess of inhibitory levels for Streptococcus pyogenes were generally present throughout the treatment period; although this was not true of ceforanide concentrations relative to inhibitory levels for Staphylococcus aureus, the clinical response in patients with staphylococcal infection still appeared to be entirely satisfactory. Killing of S. pyogenes by 5, 50, and 500X the minimum inhibitory concentration of ceforanide proceeded at the same rate in vitro as did killing by 5, 50, and 500X the minimum inhibitory concentration of penicillin.

Disulfiram-type reactions after ingestion of alcohol have been reported in patients treated with a number of cephalosporin antibiotics; predominantly with agents containing the methylthiotetrazole side chain, although other similar configurations have also been implicated. Since cefonicid has a sulphonic acid thiotetrazole substitution, we investigated the possibility of a cefonicid-ethanol interaction in 15 healthy volunteers. During the first two crossover phases of the study, single 1 g doses of cefonicid followed by ethanol challenges were compared to placebo followed by ethanol challenges. In the third phase, all volunteers received three consecutive 1 g doses of cefonicid given at 24 h intervals followed by an ethanol challenge. At no time did any of the subjects experience a disulfiram-type reaction, and their blood aldehyde concentrations did not increase throughout the study.

Cefamandole, a new parenteral cephalosporin antibiotic, was administered to 23 newborn infants with pustular skin infection due to Staphylococcus aureus for an average duration of 7.5 days. All the patients improved clinically. Elevation of serum glutamic oxaloacetic transaminase and eosinophilia were observed in nine infants each transiently during treatment. There were no abnormalities of renal functions and Coombs' test results remained negative. The levels of cefamandole in serum after either intravenous or intramuscular administration were higher and the mean life was longer than those previously reported in older infants, children, and adults.

A combination of tobramycin sulfate and cefamandole nafate was used as initial empiric therapy for the treatment of 71 evaluable febrile (temperature greater than 38.5 degrees C) episodes in 64 (neutrophils, less than 1,000/microL) adult patients with cancer and granulocytopenia. Carbenicillin sodium or ticarcillin disodium was substituted for cefamandole in patients with Pseudomonas infections and in patients in whom the initial regimen was unsuccessful. Twenty-nine episodes were randomized to receive tobramycin by continuous infusion, while 42 were randomized to receive tobramycin by interrupted infusion. Twenty-seven (79%) of the 34 documented infections responded to the initial empiric antibiotic combination, ten (83%) of 12 being given continuous infusion and 17 (77%) of 22 being given interrupted infusion of tobramycin. Nephrotoxic reaction occurred in 7% of patients treated with continuous infusion and 15% treated with interrupted infusion, mostly patients older than 60 years. Tobramycin, by either continuous or interrupted infusion, plus cefamandole is safe and efficacious empiric therapy for infections in patients with cancer and granulocytopenia.

Ceforanide, a new cephalosporin antibiotic with a long half-life (three hours), was evaluated for its antimicrobial activity, pharmacology, and clinical efficacy. Fifty-two patients with 56 infections due to susceptible organisms received ceforanide, 0.5 g, 1 g, or 2 g, intramuscularly or intravenously every 12 hours for four to 60 days (average: 14.1 days). The in vitro studies of our clinical isolates showed that 12.0 micrograms/ml or less of ceforanide inhibited all Streptococcus pneumoniae, beta hemolytic streptococci group A, B, F, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Hemophilus influenzae. After a 1 gram intramuscular dose, the mean peak serum concentration at one hour was 44.0 micrograms/ml, and at 12 hours was 3.8 micrograms/ml. After a 1 gram intravenous dose, the mean peak serum concentration was 65.0 micrograms/ml, and the mean trough serum concentration at 12 hours was 9.6 micrograms/ml. The infections treated included ten pneumonias, ten urinary tract infections, seven bacteremias, two osteomyelitis, and 35 skin-soft tissue infections. Of the 56 evaluable infections treated, 52 had a clinical cure with only four failures. Ceforanide was well tolerated, with no patients developing thrombophlebitis, or liver or renal abnormalities. Three patients developed abnormal Coombs' reactions and one had diarrhea.

In a single blind study we compared the efficacy of aztreonam (Az), a novel monocyclic beta-lactam antibiotic, to that of cefamandole (Cef) in the treatment of serious urinary tract infections (UTIs). Twenty-one patients were studied (6 men and 15 women, 18-75 years old), 12 suffering from an upper and 9 from a lower UTI; 14 of them received Az and 7 Cef (2:1 ratio), according to a prospective randomization schedule. Az or Cef were administered intramuscularly (1 g every 8 hours) for 5 to 10 days. Patients were followed up for 28 to 42 days after end of treatment. The following bacteria were isolated in the urine cultures: E. coli (in 14 cases), Proteus sp. (4), Klebsiella sp. (2) and Pseudomonas sp. (in 1 case). All 21 bacterial isolates were susceptible to Az while 19 of them were susceptible to Cef (the Pseudomonas strain was sensitive to Az but resistant to Cef). During the entire period of observation, we had 13 cures and 1 relapse in Az-group and 5 cures and 2 relapses in the Cef-group. Aztreonam was as equally well tolerated as cefamandole and no major side effects were observed in either group. In 4 Az- and 3 Cef-patients a rise of SGOT and SGPT (up to 2 1/2 times the upper normal limits) was observed, but it subsided a few days after the end of treatment. Our study shows that aztreonam is at least as effective, safe and well tolerated an antimicrobial agent for the treatment of serious urinary tract infections as cefamandole; In the future aztreonam deserves a large scale, systematic trial in all infections caused by gram-negative bacteria.

Three different intramuscular formulations of cefonicid (a new long acting cephalosporin) have been tested for bioavailability in 12 healthy volunteers, using a triple crossover design. No significant differences were detectable between the bioequivalence of the three formulations in terms of area-under-curve and 24-h urinary excretion. However, one of the formulations (A) was absorbed significantly more rapidly from the site of injection, causing higher serum levels for up to 1.5 h after administration. A significantly greater urinary excretion was also found up to 8 h after administration of formulation A. All three formulations were well tolerated, and no side-effects or significant changes in laboratory tests were observed.

Eighty-two adult hospitalized patients suffering from respiratory tract infections were treated with cefotiam or cefamandole in an open comparative study. The patients were allocated randomly to one of the two treatments. The recommended dosage regimens (i.m. or i.v.) were used for both groups (cefotiam 1 g b.i.d., cefamandole 1 g t.i.d.). The duration of treatment was 7 to 14 days according to the response of the disease condition. 80 patients were analyzed. The tolerability of both drugs was good and comparable. The clinical and bacteriological efficacy of both drugs was equivalent. The radiological examinations showed a better improvement of the patients treated with cefotiam.

The pharmacokinetics of cefoperazone, a new beta-lactam antibiotic, were studied in normal volunteers and compared with the pharmacokinetics of cefamandole. After a 30-min infusion of 2 g of cefoperazone, the mean serum level was 256 micrograms/ml; at 4 h, the serum level was 20 micrograms/ml, and at 24 h, the level was 1.25 micrograms/ml, compared with levels of cefamandole of 188 micrograms/ml at the end of infusion, 1.8 micrograms/ml at 4 h, and none detected thereafter. The mean half-life of cefoperazone was 1.6 h, compared with 0.7 h for cefamandole. The area under the curve was 356 micrograms/ml per h for cefoperazone, which was three times that for cefamandole. The apparent volume of distribution for cefoperazone was 9.9 liters/1.73 m2 compared with 12.5 liters/1.73 m2 for cefamandole. Serum clearance of cefoperazone was 85 ml/min, and renal clearance was 25 ml/min, compared with a serum clearance of 224 ml/min and a renal clearance of 213 ml/min for cefamandole. Urine levels exceeded 25 micrograms/ml in the first 8 h after injection. Renal recovery of cefoperazone was only 29%.

Ceforanide is a 'second generation' cephalosporin administered intravenously or intramuscularly. It is similar to cefamandole and cefonicid in its in vitro superiority to 'first generation' cephalosporins against several species of Enterobacteriaceae as well as its activity against Haemophilus influenzae, including beta-lactamase-producing strains. Its activity against Staphylococcus aureus is less than that of cefamandole, cefuroxime and first generation cephalosporins. The in vitro activity against Neisseria gonorrhoeae is excellent. Pseudomonas, Acinetobacter and Serratia species, and Bacteroides fragilis are resistant, as are many strains of Proteus and Providencia species. The elimination half-life is relatively long, although shorter than that of cefonicid, and in most clinical trials ceforanide has been administered twice daily. It appeared to be comparable in therapeutic efficacy to procaine penicillin and cephazolin in the treatment of patients with community-acquired pneumonia, to cephazolin in the treatment of skin and soft tissue infections due to S. aureus or beta-haemolytic streptococci and to cefapirin in S. aureus endocarditis in parenteral drug abusers. Also, it was comparable in efficacy to cephalothin in the prophylaxis of infection in patients undergoing open heart surgery or vaginal hysterectomy, and to cephazolin in patients undergoing cholecystectomy. Thus, ceforanide is an alternative to first and certain other second generation cephalosporins in several important therapeutic and prophylactic situations. It has no advantage over other cephalosporins with regard to spectrum of antibacterial activity, but has a longer half-life than other second generation cephalosporins, except cefonicid, and can be administered according to a twice daily dosage schedule.

A review is made of the pharmacological, biochemical and chemical aspects of the unpleasant 'Antabuse-like' reaction that may be induced in drinkers of alcohol by pre-treatment with certain beta-lactam antibiotics with a 1-methyltetrazole-5-thiol sidechain (such as moxalactam, cefamandole and cefoperazone). The symptoms are due to abnormally elevated blood acetaldehyde levels consequent upon the inactivation of hepatic aldehyde dehydrogenase. There is very little direct effect of the antibiotics on this enzyme and therefore it is concluded that a reactive metabolite of the antibiotics' essential sidechain is responsible for the reaction. A likely candidate for this active species is either the symmetrical disulphide 5,5'-dithiobis(1-methyltetrazole) formed by oxidation of 1-methyltetrazole-5-thiol, or the related mixed disulphide, methyl 5-(1-methyltetrazolyl) disulphide. The first of these is a potent inactivator of cytoplasmic aldehyde dehydrogenase only, the second affects both cytoplasmic and mitochondrial isoenzymes. 1-Methyltetrazole-5-thiol or derivatives have the potential to be used therapeutically as 'anti-alcohol' compounds in the same way as disulfiram (Antabuse) or calcium cyanamide.

Twenty patients with skin and soft-tissue infections were treated with parenteral cefonicid. Cultures obtained in cellulitis cases from an aspirate of a leading edge of inflammation were positive in 42% of these patients. Pathogens isolated were Staphylococcus aureus (six strains), Proteus mirabilis (one strain), and Streptococcus agalactiae. Adverse effects were pain on intramuscular injection (two patients), rash (one patient), and positive Coombs test (one patient). All side effects were mild and none required discontinuing antibiotic therapy. A single treatment failure occurred in a patient with an undrained perirectal abscess. Cefonicid may be a useful drug in the treatment of skin and soft-tissue infections. The long half-life of cefonicid (4.8 h) is a valuable advantage and may facilitate patient compliance and convenience.

The in vitro activity, pharmacokinetics, adverse effects, and clinical efficacy of cefonicid are reviewed. Also discussed are formulary considerations and bacterial resistance. Cefonicid, an investigational agent near approval, is less active than other currently available first- and second-generation cephalosporins against gram-positive cocci, particularly Staphylococcus. Cefonicid and cefamandole have similar activity that is superior to the first-generation cephalosporins against Escherichia coli, Klebsiella, Citrobacter spp., Enterobacter spp., indole-negative Proteus spp., and Providencia spp. Organisms such as Serratia marcescens, Acinetobacter, Pseudomonas, and Bacteroides fragilis are resistant to cefonicid. Despite a small volume of distribution and high protein binding, cefonicid achieves high tissue concentrations. Approximately 90% of an administered dose is excreted unchanged in the urine, and the elimination half-life is approximately four hours. Cefonicid is usually well tolerated. In treating skin infections, cefonicid was usually less effective than cefazolin against Staphylococcus aureus. In genitourinary infections, cefonicid 1 g daily (as the sodium salt) in a single dose has shown comparable efficacy to cefamandole or amoxicillin given in multiple daily doses. Based on available data, single daily dosing of cefonicid in the therapy of Staph. aureus endocarditis is not effective. In studies of patients undergoing hysterectomy, cesarean section, cholecystectomy, and colorectal surgery, cefonicid 1 g given as a single preoperative dose has produced results comparable with those of cefoxitin 1-2 g (as the sodium salt) given preoperatively and for several doses postoperatively. The major clinical uses of cefonicid will probably be as a possible cost-reducing alternative (based on a single daily dose) to currently available first- and second-generation cephalosporins for the treatment of community-acquired pneumonia and infections caused by enteric organisms. It may also be useful as a possible cost-reducing alternative to cefoxitin for prophylaxis in hysterectomy and biliary tract surgery.

One hundred and five patients with penetrating abdominal injuries were treated with single-antibiotic regimens. Forty-seven patients were treated with intravenous (IV) cefamandole and for comparison 58 patients were treated with IV carbenicillin previously shown to be effective against postoperative infections associated with abdominal trauma. The overall incidence of deep infection on a single antibiotic therapy was 8.6 per cent, including two patients on cefamandole alone (4.3%) and seven (12.1%) on carbenicillin alone. One in each antibiotic group died of sepsis with a total mortality of 1.9 per cent. The authors concluded that cefamandole when used alone was found to be safe and more effective than carbenicillin alone in preventing sepsis in patients with abdominal trauma.

Cefamandole nafate was effective in the treatment of a variety of infections caused by Staphylococcus aureus, Streptococcus pyogenes group A, Streptococcus pneumoniae, and Haemophilus influenzae in infants and children. The infections included periorbital cellulitis and ethmoiditis, bacteremia, cellulitis, pneumonia, and lymphadenitis. In vitro, cefamandole was effective in inhibiting the growth of H. influenzae isolated from blood or cerebrospinal fluid of patients with meningitis or sepsis. In two patients rash developed and cefamandole was discontinued. Other significant adverse effects were not noted.

In review of our data, 12 of 38 patients (31.5 percent) had adverse drug reactions, a somewhat bothersome factor. Disturbing side effects of leukopenia and pancytopenia were seen in two patients, respectively, who were receiving cefamandole 12 g/d. Other cephalosporins, including cephalothin and cefazolin, have been reported to cause leukopenia. Eosinophilia and elevations of alkaline phosphatase and SGOT levels were noted with other cephalosporins. We observed no adverse clinical reactions associated with these findings. Although our study was able to demonstrate the therapeutic effectiveness of cefamandole in the treatment of soft tissue and skeletal infections, it should be reemphasized that cefamandole should be used only as an alternative treatment for the penicillin-allergic patient. In reality, a first-generation cephalosporin should be used for gram-positive organisms if one is required in soft tissue infections.

Clinical and bacteriologic results are reported for 80 patients treated with 1.5--12 g of cefamandole daily for a variety of infections caused by Enterobacter and indole-positive Proteus, organisms that have been resistant to most available cephalosporins. Of 45 patients with infections due to Enterobacter, 41 (91%) had satisfactory clinical responses; 36 were bacteriologic successes, and six cases of complicated urinary tract infections relapsed. Of 37 patients with infections due to indole-positive Proteus, 28 (88%) were clinical successes and 30 (81%) were bacteriologic successes. Fourteen cases of complicated urinary tract infection relapsed. Of 104 patients in whom the drug was evaluated for safety, use of cefamandole was discontinued in five; nine adverse reactions were considered drug-related. A summary of published in vitro data shows that the majority of strains of these organisms were susceptible to cefamandole at concentrations achievable in the serum. Minimal inhibitory concentrations are variable, and there is a significant inoculum effect, the clinical significance of which has not been determined.

Ceforanide is a new cephalosporin with a longer elimination half-life than any currently available cephalosporin. Its activity is very similar to that of cefamandole, a second-generation cephalosporin, except that ceforanide is less active against most gram-positive organisms. Many coliforms, including Escherichia coli, Klebsiella, Enterobacter, and Proteus, are susceptible to ceforanide, as are most strains of Salmonella, Shigella, Hemophilus, Citrobacter and Arizona species. However, most strains of Serratia marcescens and all Pseudomonas aeruginosa are resistant to this compound. Peak serum concentrations in excess of 100 micrograms/ml are achieved after a 1 g intravenous dose. The elimination half-life of ceforanide is about 3 hrs in patients with normal renal function; this allows twice daily dosing for the majority of patients. As renal excretion amounts for 85-90% of drug elimination, the serum half-life increases to approximately 20 hours in anuric patients. Tissue penetration studies demonstrate inhibitory concentrations in cardiac tissue, bone, and joint fluid. Minor adverse effects have been reported after large doses of ceforanide. Clinical trials indicate that ceforanide is effective in the treatment of skin and soft tissue, pulmonary and urinary tract infections, bone and joint infections, and endocarditis. Ceforanide also has been shown to be as effective as cephalothin or cephaloridine when given prophylactically for vaginal hysterectomy.

35 males and 23 females with skin and soft tissue infection, lower respiratory tract infection, urinary tract infection or septicemia with known etiology were treated with cefamandole nafate. The patients were to a large extent (30%) alcoholics and/or drug abusers. Cefamandole was given intravenously as 4 daily doses of 1 g in 52 cases and of 2 g in 6 cases for 8 to 16 (mean 10) days. The effect was considered to be good in 40 patients (70%). Adverse reactions, mostly slight and transient, were seen in 22 patients (38%). Peak serum levels varied from 26 to 82 (mean 50) micrograms/ml after 1 g doses and from 68 to 100 micrograms/ml after 2 g. Previous statements of a better in vitro activity of cefamandole than of older cephalosporins against some gram-negative bacilli were corroborated.

Cefamandole, a new cephalosporin derivative, has been used in treatment of six patients who had diminished renal function and respiratory infections, and of 14 patients with urinary tract infections (UTI). Infection was eliminated in all patients with respiratory infections, and in seven of the patients with UTI. No serious side effects were encountered and, even in patients with pre-existing renal dysfunction, no reduction in renal function occurred.