The Use of Noncarbapenem ß-Lactams for the Treatment of Extended-Spectrum ß-Lactamase Infections.

The continued rise in infections caused by extended-spectrum ß-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other ß-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem ß-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.

Correlation between cephamycin consumption and the incidence of antimicrobial resistance in Acinetobacter baumannii at a university hospital in China from 2001 to 2009.

OBJECTIVES: To investigate the correlation between cephamycin consumption and the prevalence of antimicrobial resistance in Acinetobacter baumannii. METHODS: Cephamycins consumption was expressed as defined daily dose (DDD) per 1,000 patient days by World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification index from 2001 to 2009. The incidences of antimicrobial resistance in A. baumannii were calculated using WHONET 5.4 software in the Microbiology Department. Correlation coefficient was used for statistical analysis. RESULTS: The results showed that cefmetazole and total cephamycin consumption (i.e., cefmetazole, cefoxitin, cefminox) both positively correlated with the percentages of A. baumannii resistance to piperacillin/tazobactam, ceftazidime, cefepime, imipenem/cilastatin, amikacin, levofloxacin, meropenem, respectively, these antimicrobial agents involved beta-lactams, carbapenems, aminoglycosides and fluroquinolones. In addition, the A. baumannii resistance rates of piperacillin/tazobactam, ceftazidime, cefepime, imipenem/cilastatin, meropenem, amikacin, levofloxacin were associated with the A. baumannii resistance rates of a number of antimicrobial drugs. This finding indicated the possible cross-resistances in four different classes of antimicrobial drugs. It could be due to multidrug resistance in A. baumannii. CONCLUSIONS: The cephamycin consumption was significantly related to the prevalence of the antimicrobial drug resistance and might be correlated with multidrug resistance in A. baumannii. Hence, the prescription of cephamycin should be reduced and optimized in order to avoid the rapid increase of antimicrobial resistance in A. baumannii.

Gram-negative bacillary meningitis. New therapy and changing concepts.

Because the CSF is deficient in opsonic and phagocytic activity, optimal therapy for meningitis mandates the use of antibiotics that are bactericidal at achievable CSF concentrations. This therapeutic principles is satisfied for the common meningeal pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis) but is not readily achieved for the pathogens causing Gram-negative bacillary meningitis (GNBM), such as Klebsiella and Escherichia coli. The antibiotics used to treat GNBM, chloramphenicol and aminoglycosides, are not bactericidal against enteric pathogens at achievable CSF levels. Two new beta-lactam antibiotics, moxalactam disodium and cefotaxime sodium, are suitable agents for the treatment of GNBM. These antibiotics possess potent bactericidal activity against most enteric pathogens and achieve high levels in the CSF (15 to 35 micrograms/mL for moxalactam disodium and 2 to 10 micrograms/mL for cefotaxime sodium). Recent clinical studies document an 85% cure rate when these agents are used to treat GNBM.

Polymicrobial anaerobic septicemia due to lateral sinus thrombophlebitis.

Continuous polymicrobial anaerobic septicemia was the main manifestation of a lateral sinus thrombophlebitis (LST) in a patient who had a history of chronic otitis media. Five different anaerobic microorganisms were isolated in blood cultures. Three of them were also present in ear cultures. The diagnosis was confirmed at surgery and the patient was successfully treated with moxalactam disodium therapy. This case emphasizes that LST should be considered before polymicrobial anaerobic septicemia, especially if there is a history of chronic otitis media.

Moxalactam therapy for bacterial infections.

Moxalactam, a novel beta-lactam antimicrobial agent in which oxygen has replaced sulfur in the six-membered ring of the conventional cephem nucleus, has in vitro activity against almost all commonly isolated bacterial pathogens including Staphylococcus aureus, the Enterobacteriaceae, Pseudomonas aeruginosa, Bacteroides fragilis, and Haemophilus influenzae. The clinical efficacy an toxicity of moxalactam alone was evaluated in the treatment of 100 infections, including 22 septicemias. Thirty-two infections involved P aeruginosa, while organisms resistant to one or more of the currently available cephalosporins or cefoxitin were isolated from cultures in 63 of the cases. The overall clinical response was favorable (infection cured or improved) in 86% of the infections. A child with Klebsiella pneumoniae ventriculitis and meningitis was cured with intravenous moxalactam alone. Six of 14 treatment failures involved P. aeruginosa, and P aeruginosa isolates resistant to moxalactam emerged during therapy of 12 infections. Side effects, usually mild diarrhea, occurred in only 8.8% of the patients. Except for some severe P aeruginosa infections outside the urinary tract, moxalactam is effective and safe single-agent therapy for infections caused by susceptible organisms and represents a major advancement in beta-lactam antimicrobial therapy.

Citrobacter meningitis and cerebral abscess in early infancy: cure by moxalactam.

A 7-week-old boy developed multiple cerebral abscesses as a complication of neonatal Citrobacter diversus meningitis. He was successfully treated medically with the experimental beta-lactam antibiotic, moxalactam. This is the first nonsurgical cure of brain abscess in early infancy. Fifty-eight percent of all previously reported cases of Citrobacter meningitis were complicated by brain abscess, mandating early, and serial computed tomography scanning in patients afflicted with the disorder. Moxalactam may become the chemotherapeutic agent of choice for the treatment of this serious neonatal infection.

Prospective randomized double-blind comparison of moxalactam and tobramycin in treatment of urinary tract infections.

In a prospective, randomized, double-blind trial, a regimen of 250 mg of moxalactam every 12 hours was compared with 1.0 mg/kg of tobramycin every eight hours in the treatment of urinary tract infections. One hundred and eleven patients were entered into the study; results in 63 (18 men and 45 women) were evaluable for both efficacy and toxicity. Thirty evaluable patients received moxalactam, and 33 received tobramycin. The mean duration of therapy in each group was seven days. There were six treatment failures in the moxalactam group and 10 failures in the tobramycin group (p greater than 0.4). Nephrotoxicity, defined as an increase in serum creatinine levels to 0.5 mg/dl or more, did not occur in either group. Thirteen patients in the moxalactam group and one in the tobramycin group had enterococci isolated from a urine culture specimen during or after therapy. It is concluded that use of the moxalactam regimen is as effective and safe as use of the tobramycin regimen in the treatment of urinary tract infections. The clinical significance of the enterococcal isolates associated with moxalactam therapy is yet to be determined.

Diffusion of a new beta-lactam (LY 127935) into cerebrospinal fluid. Implications for therapy of gram-negative bacillary meningitis.

LY 127935, a new oxa beta-lactam with an expanded gram-negative spectrum, was administered intravenously to seven patients, including two patients with documented gram-negative bacillary meningitis. In the patients receiving continuous therapy (2 g intravenously every 8 hours) cerebrospinal fluid trough levels of LY were never less than 6 micrograms/ml. Peak cerebrospinal fluid levels of LY ranged from 25 to 39 micrograms/ml and occurred approximately 2.5 hours after the intravenous administration of the drug. Cerebrospinal fluid levels of LY were 19 per cent to greater than 100 per cent of simultaneous serum levels. Cerebrospinal fluid bactericidal activity was 1:4 to 1:256. Intravenous LY, because of its expanded gram-negative spectrum and excellent cerebrospinal fluid penetration, is a potentially useful antibiotic in the treatment of gram-negative bacillary meningitis.

Past and current roles for cephalosporin antibiotics in treatment of meningitis. Emphasis on use in gram-negative bacillary meningitis.

The therapy of gram-negative bacillary meningitis is less than adequate to date; the agents recommended do not achieve bactericidal levels in purulent cerebrospinal fluid. Because optimal antibiotic therapy of meningitis occurs when the cerebrospinal fluid level of an antibiotic is above the concentration needed to kill the offending pathogen, another group of agents needs to be considered. The newer cephalosporins or cehalosporin-type antibiotics (cefotaxime, moxalactam), by virtue of their marked activity against gram-negative bacilli and their ability to achieve significant CSF levels, merit serious consideration as therapy for gram-negative bacillary meningitis. Investigators in Europe and the United States have developed preliminary data demonstrating the efficacy of these agents in a growing number of cases. In the group presented herein, of the 35 cases in which gram-negative bacillary meningitis was treated with the newer cephalosporins, there were only four failures.

Treatment of serious infections with moxalactam.

In 93 hospitalized patients, 111 bacterial infections were treated with moxalactam. Eighty-three infections responded well to therapy, nine infections failed to respond to therapy or relapsed, and nine infections showed superinfection with resistant bacteria. The great majority of bacteria isolated had mean inhibitory concentrations below levels readily achieved in plasma, cerebrospinal fluid, bile, abscess fluid, and peritoneal fluid. Among the commonly identified bacteria, only Pseudomonas aeruginosa, enterococci, and Staphylococcus epidermidis had variable sensitivity to moxalactam.

Moxalactam treatment of serious infections primarily due to Haemophilus influenzae type b in children.

Thirty-eight children completed therapy with moxalactam for a variety of non-CNS infections. Haemophilus influenzae type b (seven ampicillin-resistant strains) was the etiologic agent for 32 children. Doses of moxalactam ranged from 113 to 200 mg/kg/d in three or four divided doses administered parenterally. All children with infections due to H influenzae type b had excellent responses to moxalactam therapy. Children treated for infections due to other agents also responded satisfactorily to moxalactam therapy. Moxalactam concentrations in joint and pleural fluids greatly exceeded the minimal bactericidal concentrations of moxalactam for H influenzae type b. Adverse reactions included neutropenia, eosinophilia, thrombocytosis, and transient elevation of transaminase levels. Moxalactam administered parenterally, at a dose of 113 to 150 mg/kg/d in three or four divided doses is effective therapy for serious infections in children due to H influenzae type b and selected other organisms.

Antibacterial Drugs today: II.

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.

Cefotetan. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Cefotetan is a new semisynthetic cephamycin antibiotic administered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-negative aerobic and most clinically important Gram-positive and anaerobic bacteria, and is generally more active against Gram-negative bacteria than the 'first and second generation' agents. Cefotetan is particularly active against Enterobacteriaceae but has little activity against Pseudomonas aeruginosa. An extended plasma elimination half-life of about 3.5 hours, and relatively high achievable serum and tissue levels, enables cefotetan to be administered on a twice daily basis in the treatment of mild to severe infections. Cefotetan has shown good clinical efficacy in intra-abdominal, obstetric and gynaecological infections, postoperative wound infections, and infections in immunocompromised patients - all of which are often complicated due to their polymicrobial nature or by the presence of anaerobic pathogens. A satisfactory clinical response is achieved in over 90% of paediatric patients with acute otorhinolaryngological infections, whereas in the treatment of chronic disease, as with other agents, the efficacy is dramatically reduced. Like other cephalosporins, cefotetan is effective in treating patients with complicated urinary tract infections and lower respiratory tract infections. Its efficacy in urinary tract infections is at least as good as cefoxitin, although in this and some other clinical areas its activity relative to that of other cephamycins and cephalosporins remains to be assessed. Thus, with its convenient twice daily dosage schedule, cefotetan would appear to be a useful addition to a rapidly expanding group of antibacterial agents.

Prophylactic antibiotics for elective laparoscopic cholecystectomy: are they necessary?

HYPOTHESIS: Prophylactic antibiotic treatment in elective laparoscopic cholecystectomy does not lower the already low infection rate associated with this procedure. DESIGN AND SETTING: Prospective double-blind randomized trial at a community-based training hospital. PATIENTS: Four hundred fifty patients undergoing elective laparoscopic cholecystectomy were randomized into 1 of 3 treatment arms: (1) preoperative cefotetan disodium, 1g intravenously; (2) preoperative cefazolin, 1g intravenously; and (3) intravenous placebo. There were no demographic differences between groups in age, smoking history, American Society of Anesthesiologists score, infection risk class, time of antibiotic administration prior to surgery, and type of skin preparation. INTERVENTIONS: Laparoscopic cholecystectomy was attempted in all cases; however, 10 patients required conversion to an open cholecystectomy and they were included in the statistical analysis. Preoperatively, all patients were randomized in a blinded manner and received cefotetan, cefazolin, or placebo intravenously. RESULTS: There were 10 postoperative infections. In the cefotetan group, there were 3 cases of superficial surgical site infections. In the cefazolin group, there were 2 superficial surgical site infections-1 pneumonia and 1 rhinosinusitis. In the placebo group, there were 2 superficial surgical site infections and 1 urinary tract infection. The overall infection rate in this series was 2.4%. Follow-up was performed at routine postoperative visits and by telephone contact. Data were evaluated using the chi2 test and analysis of variance with Duncan post hoc test (P<.05). CONCLUSION: Based on our data, use of prophylactic antibiotics does not decrease the rate of wound infections in elective laparoscopic cholecystectomy.

Management of intra-abdominal infections. The case for intraoperative cultures and comprehensive broad-spectrum antibiotic coverage. The Canadian Intra-abdominal Infection Study Group.

OBJECTIVE: To test the hypothesis that comprehensive broad-spectrum empirical antimicrobial therapy is superior to limited-spectrum empirical antimicrobial therapy in intra-abdominal infections. DESIGN: Prospective, randomized, double-blinded study. SETTING: University-affiliated hospitals in Canada. PATIENTS: Two hundred thirteen patients with intra-abdominal infections and planned operative or percutaneous drainage. INTERVENTION: Limited-spectrum empirical antimicrobial therapy consisted of cefoxitin sodium, 2 g, intravenously, every 6 hours (n = 109). Comprehensive broad-spectrum empirical antimicrobial therapy consisted of a combination of imipenem and cilastatin sodium, 500 mg, intravenously, every 6 hours (n = 104). MAIN OUTCOME MEASURES: Failure to cure the intra-abdominal infection (persistence of infection or death). RESULTS: Of initial isolates, 98% were sensitive to imipenem plus cilastin sodium compared with 72% for cefoxitin. No difference was found in the failure rate between treatment groups. Among various reasons for failure (including technical), 12 of 80 patients in the limited-spectrum empirical antimicrobial therapy group had resistant organisms at a second intervention compared with 1 of 74 in the comprehensive broad-spectrum empirical antimicrobial therapy group (P < .003, chi 2). One death in the limited-spectrum empirical antimicrobial therapy group was due to autopsy-proved disseminated Pseudomonas aeruginosa (blood, peritoneum, lung, and pleural fluid) that was resistant to cefoxitin, and the other was associated with peritonitis due to cefoxitin-resistant Enterobacter cloacae. One death in the comprehensive broad-spectrum empirical antimicrobial therapy group was associated with peritonitis from Clostridium perfringens that was sensitive to imipenem plus cilastin sodium, and the other was associated with peritonitis from Pseudomonas aeruginosa that was resistant to imipenem plus cilastin sodium. CONCLUSION: Treatment failure of intra-abdominal infection may be due, in part, to the presence of resistant pathogens at the site of infection. Therefore, routine culture of these sites seems worthwhile and empirical therapy should be as comprehensive as possible and should cover all potential pathogens.

Third-generation cephalosporins for polymicrobial surgical sepsis.

During 31 months of study, 808 patients with polymicrobial surgical infection were randomized for antibiotic therapy between a third-generation cephalosporin (moxalactam disodium [149], cefotaxime sodium [125], and cefoperazone sodium [141]) and the combination of gentamicin sulfate plus clindamycin (393). Results based on antibiotic therapy included the following: cure in 83% given cephalosporin, 73% with antibiotic combination; control but recurrent sepsis in 7% and 15%; and failure in 4% and 8%, respectively. Such data support the tenet that third-generation cephalosporins are at least equal, if not superior, to the combination of gentamicin plus clindamycin for treatment of polymicrobial surgical sepsis.

Single dose intra-operative antimicrobial prophylaxis during prostatectomy: gentamicin compared with cefotetan.

Two hundred consecutive patients undergoing prostatectomy were given a single dose of gentamicin or cefotetan intra-operatively. Both antibiotics afforded good protection against postoperative bacteriuria and septicaemic symptoms were fewer in those patients given cefotetan, although this difference was not statistically significant.

A comparison of cefotetan and cephazolin for prophylaxis against wound infection after elective cholecystectomy.

In a prospective randomized study 168 patients received a single dose of either cephazolin or cefotetan (1 g) as a prophylactic against wound infection after cholecystectomy. In the cephazolin group 10.3% and the cefotetan group 14.4% developed wound infections (Chi-squared = 0.34 P = less than 0.6 greater than 0.5).

Experimental studies on the pharmacokinetics and therapeutic effect of cefbuperazone in biliary infection.

A study was carried out using an experimental biliary infection model to investigate the pharmacokinetic characteristics and therapeutic effect of cefbuperazone in the rabbit. Thirty rabbits were divided into three equal groups; a control group of normal animals, a group of infected animals receiving no cefbuperazone, and a group of infected animals receiving 50 mg cefbuperazone/kg intramuscularly. The experimental infection was made by direct inoculation of a suspension of E. coli into the common bile duct after ligation. The results showed that extremely high levels of cefbuperazone were achieved in bile and tissues of the biliary tract and were higher than those in the blood. Moreover, the levels were maintained at effective concentrations even after 6 hours. Viable bacterial cells from bile and the gall-bladder were barely detectable 24 and 48 hours after infection in the cefbuperazone-treated group, whilst counts remained high in the other infected group. White blood cell counts were increased at 24 hours after infection but were significantly lower in the cefbuperazone-treated group. Histological examination revealed marked inflammatory changes in the gall-bladder and bile duct of infected, untreated animals but few, mild changes only were seen in cefbuperazone-treated animals. Similarly, total bilirubin and liver enzymes were markedly increased in infected animals, but transaminases and alkaline phosphatase were significantly lower in the treated compared to the untreated group. The findings indicate, therefore, that cefbuperazone can be a useful antibiotic in biliary infection.