BIAPENEM
Biapenem is a novel parenteral broad spectrum carbapenem primarily used for the treatment of complicated infections like sepsis, lower respiratory infections, urinary tract infections, intra-abdominal and genitourinary infections etc. in Japan, Thailand and China since two decades, has been recently approved in India. Biapenem shows good bactericidal activity against Gram-positive bacteria including streptococcus pneumoniae, pyogenes and methicillin-susceptible staphylococcus aureus (MSSA). It also shows antibacterial activities against Gram-negative bacteria including resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Evidence from international studies confirmed that biapenem can be used as effectively and safely as meropenem or imipenem/ cilastatin in the treatment of various infectious diseases. This article summarizes the milestones, unique structure, mechanism of action, pharmacokinetics, special pharmacological properties and spectrum of in vitro activity of biapenem. The results of comparative clinical trials on Biapenem are also described, as is the patient safety and tolerability observed during these studies.
Biapenem is a novel parenteral broad spectrum carbapenem primarily used for the treatment of complicated infections like sepsis, lower respiratory infections, urinary tract infections, intra-abdominal and genitourinary infections etc. in Japan, Thailand and China since two decades (Table1). 1 Biapenem has been approved in India for the management of complicated urinary tract infections (cUTI) in 2021. Unique chemical structure T h e e a r l y c a r b a p e n e m s l i k e imipenem are not stable to hydrolysis by human renal dihydropeptidase-I (DHP-I) and therefore are co-administered with a DHP-I inhibitor e.g. cilastatin. Biapenem is a newer parenteral carbapenem which, unlike imipenem, has a 1?-methyl group at the C1 position conferring stability to hydrolysis by human renal DHP-I (Figure 1).1 M e r o p e n e m , B i a p e n e m a n d ertapenem are more stable and do not require protection from DHP-I. Comparative in vitro study demonstrate that Biapenem was more stable to hydrolysis by human renal DHP-I than imipenem, meropenem and panipenem.
Mechanism of action:
Similar to other ?-lactam antibiotics, Biapenem penetrates the cell wall of most gram-positive/gram-negative bacteria to bind penicillin-bindingprotein (PBP) targets and inhibits bacterial cell wall synthesis.3 A broad spectrum of antibacterial activity Biapenem has a broad spectrum of antibacterial activity encompassing
Gram-positive aerobes:
Enterococcus Staphylococcus aureus (methicillinsusceptible) Staphylococcus species (methicillin-susceptible) including Staphylococcus epidermidis Streptococcus agalactiae (Group B) Streptococcus milleri group Streptococcus pneumoniae Streptococcus pyogenes (Group A)
Gram-positive anaerobe:
Clostridium perfringens Peptoniphilus asaccharolyticus Peptostreptococcus species (including P. micros, P anaerobius, P. magnus
Gram-negative aerobes:
Acinetobacter baumannii Citrobacter freundii, koseri Enterobacter aerogenes, cloacae Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Morganella morganii Neisseria meningitidis Proteus mirabilis, vulgaris Serratia marcescens Pseudomonas aeruginosa
Gram-negative anaerobes:
Bacteroides caccae, Bacteroides fragilis group, Prevotella bivia, Prevotella disiens, Fusobacterium
Pharmacokinetics:
Following Table 3 g i v e s t h e pharmacokinetic parameters of the licensed carbapenems after intravenous infusion. No metabolites were detected in the plasma following a single IV drip infusion of Biapenem 150, 300 and 600 mg or repeated IV drip infusion of 300 and 600 mg in healthy adults. The cumulative urinary excretion rates from 0 to 12 hours are 62.1, 63.4 and 64.0%, respectively.3 In vitro Efficacy Recent study of Biapenem (BIPM) against 14 IMP (imipenem)-1- producing Enterobacteriaceae strains shown that almost all the isolates have less than 0.5 Β΅g/ml MIC levels, indicating susceptibility to BIPM. Initial killing to a 99.9 % reduction was observed in seven out of eight strains in a time-kill assay. This efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing carbapenemase producing Enterobacteriaceae.5 The in vitro activity of Biapenem was compared to that of imipenem, meropenem and other broad-spectrum ?-lactams. A total of 716 isolates from recent cases of clinical septicaemia and an additional 137 stock strains possessing known ?-lactamases were tested. MIC90 of Enterobacteriaceae species were for Biapenem 0.03 to 1 mg/l and for imipenem 0.25 to 2 mg/l. No member of the Enterobacteriaceae was found to be resistant to Biapenem. Biapenem and meropenem were the most active drugs against Pseudomonas aeruginosa, with MIC90 of 1 mg/l.
Biapenem was more active than Ceftazidime against most gramnegative and gram-positive bacteria tested. This study results coupled with previously documented favorable qualities of Biapenem, endorse this broad-spectrum antibacterial agent for clinical use.6 Comparative in vitro activity of Biapenem against clinical isolates of bacteria is presented in Table 4. Plasma concentration during renal dysfunction W h e n B i a p e n e m 3 0 0 m g wa s administered to patients with renal dysfunction, delayed disappearance of Biapenem from plasma was observed as renal function declined. Biapenem 300 mg twice daily for 7 days, 14 times in total, repeated intravenous infusion over 30 minutes to patients with moderate renal dysfunction with creatinine clearance of about 50 ml/ min, in plasma and urine, no accumulation was observed.3 Special Features and Properties of biapenem 1. A Greater bactericidal effect than other carbapenems against P. aeruginosa B i a p e n e m e x e r t e d a g r e a t e r bactericidal effect than some other carbapenems against P. aeruginosa, including some typically resistant, adherent biofilm-forming strains, and several efflux system mutants. o f 5 t e s t e d a g e n t s ( b i a p e n e m , imipenem, meropenem, panipenem and ceftazidime), only biapenem showed bactericidal activity against P. aeruginosa KG5007 (a mutant strain overexpressing mexcd-oprj). Strains of P. aeruginosa resistant to ceftazidime or ofloxacin were also susceptible to Biapenem, as were strains producing ?-lactamases.1 2. Improved Tissue Penetration After intravenous administration, B i a p e n e m i s w i d e l y d i s t r i b u t e d , p e n e t r a t e s w e l l a n d a c h i e v e s clinically relevant concentration into respiratory tract, genitourinary tract, gastrointestinal system, skin (Table 5).
3. No risk of convulsions/seizures ?-lactams antibiotics, including penicillin and imipenem, occasionally cause convulsions/seizures in humans. However, Biapenem appeared to have weaker convulsant activity than imipenem, panipenem and cefazolin in in vitro and in vivo investigations. Biapenem did not induce severe c o n v u l s i o n s o r s h o w n e u r o t o x i c potential in animal studies and showed a substantially lower potential than imipenem for evoking convulsions in experimental studies. These beneficial features of Biapenem were attributed to the presence of a methyl group at the 1? position, a triazolium radical on the side chain at position 2 and lower potential for biapenem to inhibit GABA receptor binding than imipenem.1 4. Post-antibiotic Effects In contrast to many other ?-lactam agents, but in common with imipenem, Biapenem has shown a marked postantibiotic effect against gram-negative and gram-positive bacteria. The postantibiotic effect of Biapenem against P. Aeruginosa was augmented in the presence of fresh human plasma. Delayed bacterial regrowth after Biapenem exposure was reported with E. faecalis and P. aeruginosa.1 Indications DCGI approved the Biapenem in India for the treatment of complicated Urinary Tract Infections (cUTI). Biapenem usage are approved internationally in Japan: Sepsis, Lower respiratory infections- Pneumonia, p u l m o n a r y a b s c e s s , s e c o n d a r y i n f e c t i o n o f c h r o n i c r e s p i r a t o r y lesions, Complicated urinary tract infections- cystitis, pyelonephritis, Intra-abdominal infections- peritonitis, uterine inflammation/infection etc.3 Contraindications P a t i e n t s w i t h a h i s t o r y o f hypersensitivity to the ingredients of this drug (to carbapenem, penicillin o r c e p h e m a n t i b i o t i c s ) . Pa t i e n t s receiving sodium valproate (Blood levels of valproic acid may decrease and epileptic seizures may recur)3 Dosage Administration β’ Biapenem 300 mg twice daily, administered as an infusion over 30 to 60 minutes (600 mg/day).1,3 β’ Biapenem is available as single 300mg vials and must be reconstituted in 100ml of 0.9% sodium chloride before administration. Dosage can be adjusted according to the age and symptom of individual patient, but should not exceed 1.2 g/day.1,3 β’ Use for the minimum period necessary to prevent the development of resistant bacteria.3 β’ Pa t i e n t s w i t h s e v e r e r e n a l impairment- Monitor and administer Biapenem carefully, reducing the dose or increasing the dosing interval. Hemodialysis patients should be administered once daily.3 Tolerability Similar to other carbapenems, the most common adverse effects were rash, pruritus, gastrointestinal distress (diarrhea, nausea), increased ALT, AST or alkaline phosphatase, eosinophilia.1 Warning & Precautions Use with caution in patients who are allergic to carbapenems, penicillins and cephalosporins and in patients with history of epilepsy and CNS illness.3 Comparative clinical evidence of Biapenem versus Meropenem or Imipenem/Cilastatin is presented in Table 6 Place in Therapy Biapenem is a novel parenteral c a r b a p e n e m a n t i b a c t e r i a l a g e n t recently approved for use in India.1 Biapenem exerted a greater bactericidal e f f e c t t h a n o t h e r c a r b a p e n e m s (imipenem, meropenem, panipenem and ceftazidime) against P. aeruginosa, including some typically resistant strains. In vitro efficacy of Biapenem suggests that the drug could be a new therapeutic option against infection with imipenem producing carbapenemase producing Enterobacteriaceae.1 Biapenem has shown clinical and bacteriological efficacy in the treatment of a wide range of serious infections in adults and children which is at least comparable with that of currently available treatment options.11,15 Evidence from international studies shows that Biapenem can be used as effectively and safely as imipenem/ cilastatin or meropenem and was generally well tolerated, in the treatment of adults with complicated intraabdominal infections, lower respiratory tract infections, complicated urinary tract infections and gynaecological infections.1,3,15 The tolerability profile of Biapenem i s g e n e r a l l y s i m i l a r t o t h a t o f meropenem, importantly, the seizures potential in patients with meningitis is not increased following administration of Biapenem in studies.1,11 Thus, Biapenem is an effective broad spectrum antibacterial drug for the treatment of a wide range of infections including polymicrobial infections in both adults and children, with comparable efficacy to imipenem/ cilastatin, meropenem and various other treatment regimens. Biapenem is likely to be of greatest value as empiric therapy in the treatment of serious infections caused by multiple-resistant polymicrobial pathogens.