E-BACT

These are antibiotics having a b-lactam ring. The two major group are penicillins and cephalosporins. Monobactams and carbapenems are the newer additions.

Penicillin was the first antibiotic to be used clinically in 1941. It is a miracle that the least toxic drug of its kind was the first to be discovered. It was originally obtained from the fungs penicillium notatum, but the present source is a high yielding mutant of P.chrysogenum.

These are a group of semisynthetic antibiotics derived from ‘cephalosporin-C’ obtained from a fungus Cephalosporium. They are chemically related to penicillins; the nucleus consists of a b–lactam ring fused to a dihydrothiazine ring,(7-aminocephalosporanic acid).By addition of different side chains at position 7 of b–lactam ring (altering spectrum of activity) and position 3 of dihydrothiazine ring(affecting pharmacokinetics), a large number of semisynthetic compounds have been produced. These have been conventionally divided into 4 generations. This division has a chronological sequence of development, but more importantly, takes into consideration the overall antibacterial spectrum as well as potency.

b-lactamases are a family of enzymes produced by many gram positive and gram negative bacteria that inactivate b-lactam antibiotics by opening the b-lactam ring. Different b-lactamases differ in their substrate affinities. Two inhibitors of this enzyme clavulanic acid and sulbactam are available for clinical use.

Tazobactam is another b-lactamase inhibitor similar to sulbactam which has been combined with piperacillin.

The beta-lactam family of antimicrobials, in particular penicillins and cephalosporins, is the mainstay of treatment for many infections. However, the emergence of resistance to these agents has reduced their usage and raised concerns regarding the continued efficacy of these antibiotics. Resistance to beta-lactams is most commonly expressed by the microbial production of beta-lactamases that hydrolyze the beta-lactam ring. Resistance in gram-negative organisms may be caused by chromosomally or plasmid-mediated beta-latamases. Plasmid mediated beta-lactamases were initially confined to Entero-bacteriaceae but have now spread to other genera and species including Pseudomonas aeruginosa, Haemophilus influenzae, and Neisseria gonorrhoeae.

In recent years there has been an increased incidence and prevalence of extended-spectrum beta-lactamases (ESBLs), enzymes that hydrolyze and cause resistance to second- and third generation cephalosporins and aztreonam. ESBLs have been identified in Enterobacteriaceae, particularly klebsiella spp. And Escherichia coli. Prevalence of beta-lactamase and ESBL producing organisms have been reported from all parts of India and it is increasing.

Infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality, and increased cost of treatment. When bacteria develop resistance during antimicrobial therapy,therapeutic failure results in approximately 50% of patients. Clinical studies demonstrate that resistance mediated by beta-lactamases is a critical issue.

Strategies for overcoming it include use of beta-lactam-beta-latamase inhibitor combinations, development of new antimicrobial compounds, and use of regimens that optimize in vivo exposure to drug. However, beta-lactam-beta-lactamase inhibitor combinations are most frequently used approach to overcome resistance due to beat-lactamases. Several such combinations are currently available, containing inhibitors clavulanic acid, sulbactam and tazobactam. Among them, sulbactam-cefoperazone is found to be effective in respiratory tract, pediatric, obstetric and gynecological, surgical urinary tract and orthopedic infections.

A bacterial antibiotic, inhibits baterial cell wall synthesis of actively dividing cells by binding to one or more penicillin binding proteins(PBPs.) The affinity pattern of Cefoperazone for the PBPs for different bacterial species affects the drugs antimicrobial spectrum of activity.

Spectrum of activity of cefoperazone includes gram-positive, gram-negative aerobic and anaerobic bacteria.Among gram-positive aerobic organisms, it is active against penicilinase-producing S.aureus and Streptococcus pneumoniae. It has some in vitro activity against enterococci including E. faecalis, S.faecium, and S.durans. Generally, cefoperazone is active against the following Enterobacteriaceae: Citrobacter diversus, C. freundii, Enterobacteraerogenes, E. cloacae, Escherichia coli, klebsiella oxytoca, k.pneumoniae, Morganella morganii, Proteus mirabillis, P.vulgaris, Providencia, Salmonella, Shigella and Yershinia enterocolitica.

It is more active than cefotaxime, ceftizoxime, ceftriaxone or moxalactam against pseudomonas, including p.aeruginosa. Cefoperazone also has some activity against H.influenzae and Bordetella pertussis.

Cefoperazone is active in vitro against many anaerobic bacteria including Bifidobacterium, Eubacterium, Fusobactarium, Peptococcus,Peptostreptococcus, Propionibacterium, and Veillonella. Cefoperazone is generally active in vitro against Clostridium, including some strains of C.difficile.

is a beta-lactamases inhibitor and acts primarily by irreversible inactivation of beta-lactamases. It increases the spectrum of activity of cefoperazone, and delays emergence of antibiotic resistance. Its binding to penicillin-binding proteins imparts weak intrinsic antibacterial activity. In vitro, the combination of cefoperazone and sulbactam show a marked synergy against bacterial species in which beta lactamase is a major mechanism of resistance.

By restoring or expanding the activity of well-established beta-lactam antibiotics, sulbactam offers a new approach to the management of bacterial infections; the minimal toxicity of sulbactam-cefoperazone makes the combination appealing for the treatment of gram-negative nonpseudomonal and anaerobic infections.

Plus sulbactam showed 100% clinical efficacy in the treatment of puerperal, intrauteuterine, intrapelvic and external genital organ infections. The eradication ratio was more than 80% against beta-lactamase producing organisms.

A study evaluated the clinical efficacy of sulbactam/cefoperazone in 217 patients with lower respiratory tract infections. Clinical efficacy rates of sulbactam/cefoperazone were 93.1% for pneumonia, 93.3% for lung abscess, 78.9% for acute exacerbation of chronic bronchitis, 57.1% for diffuse panbronchiolitis, 72.4%, 74.4% and 100% for infections concurrent to bronchiectasis, chronic respiratory disease and pulmonary emphysema, respectively.

Cefoperazone plus sulbactam showed excellent to moderate efficacy in patients with urinary tract infections. In this study, isolates resistant to cefoperazone were susceptible to combination.

In postoperative infections and intraabdominal infections, cefoperazone sulbactam showed better clinical efficacy than ceftizoxime and gentamicin/clindamycin. It also showed excellent to good efficacy in patients with cholesystitis,cholangitis and liver abscess.

Mean peak sulbactam and cefoperazone concentrations after the administration of 2 grams of E-BACT (1gm sulbactam, 1gm of cefoperazone) intravenously over 5 minutes were 130.2 and 236.8 mcg/ml respectively. This reflects the larger volume of distribution for sulbactam (Vd=18.0-27.6L) compared to cefoperazone (Vd=10.2-11.3L).

The pharmacokinetics of E-BACT has been studied in elderly individuals with renal insufficiency and compromised hepatic function. Both sulbactam and cefoperazone exhibited longer half-life, lower clearance, and large volumes of distribution when compared to data from normal volunteers.

Both sulbactam and cefoperazone distribute well into a variety of tissues and fluids including bile., gall bladder,skin,appendix,fallopian tubes,ovary,uterus, and others.

Sulbactam plus cefoperazone is used in the treatment of respiratory tract infections, intra-abdominal infections (including peritonitis), urinary tract infections, septicemia, orthopedic and gynecologic infections (including pelvic inflammatory disease and endometritis) caused by susceptible organisms. It has been used for perioperative prophylaxis in a limited number of patients undergoing abdominal hysterectomy of coronary artery bypass surgery.

E-BACT is available in 1.0g and 2.0 g strength vials.

The usual adult dose of E-BACT is 2 to 4 g per day (i.e 1 to 2 g per day cefoperazone activity, given intravenously or intramuscularly in equally divided doses every 12 hours.)

In severe refractory infections the daily dosage of E-BACT may be increased upto 8g of the 1:1 ratio(i.e. 4 g cefoperazone activity). Patients receiving the 1:1 ratio may require additional cefoperazone administered separately. Doses should be administered every 12 hours in equally divided doses. The recommended maximum daily dosage of sulbactam is 4g (8g of E-BACT). Dosage regimens of E-BACT should be adjusted in patients with marked decrease in renal function (creatinine clearance of less than 30ml/min ) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearances between 15 and 30 ml/min should receive a maximum of 1 g of sulbactam administered every 12 hours(maximum daily dosage of 2 sulbactam), while patients with creatinine clearances of less than 15ml/min should receive a maximum of 500 mg of sulbactam every 12 hours (maximum daily dosage of 1 g Sulbactam). In severe infections it may be necessary to administer additional cefoperazone separately.

The usual dosage of E-BACT in children is 40 to 80 mg/kg/day (i.e. 20-40 mg. Kg.day cefoperazone activity). In serious refractory infections, these dosages may be increased upto 160 mg/kg/day. Doses should be administered in 2 to 4 equally divided doses. For neonates in the first week of life, the drug should be given every 12 hours. The maximum daily dosage of sulbactam in paediatrics should not exceed 80 mg/kg/day (160mg/kg/day E-BACT. In cases where doses above 80 mg/kg/day of cefoperazone activity are necessary, additional cefoperazone should be administered separately.

For intermittent infusion, each vial of E-BACT should be reconstituted with the appropriate amount (see section 6.6. Instructions for Use/Handling Reconstitution) of 5% Dextrose in water, 0.9 Sodium Chloride injection or Sterile Water for injection and then diluted to 20 ml with the same solution followed by administration over 15 to 60 minutes.

Lactated Ringer’s Solution is a suitable vehicle for intravenous infusion, however, not for initial reconstitution (see section 6.2 Incompatibilities Lactated Ringer’s solution and section 6.6 Instructions for Use/Handling Lacteted Ringer’s solution).

For intravenous injection, each vial should be reconstituted as above and administered over a minimum of three minutes.