Journal of The Association of Physicians of India ■ Vol.

70 ■ January 2022 93

drug corner

Biapenem
Agam Vora1, Mangesh Tiwaskar2

Mechanism of action
Abstract Similar to other β-lactam antibiotics,
Biapenem is a novel parenteral broad spectrum carbapenem primarily used for Biapenem penetrates the cell wall of
the treatment of complicated infections like sepsis, lower respiratory infections, most gram-positive/gram-negative
urinary tract infections, intra-abdominal and genitourinary infections etc. in bacteria to bind penicillin-binding-
Japan, Thailand and China since two decades, has been recently approved in protein (PBP) targets and inhibits
India. Biapenem shows good bactericidal activity against Gram-positive bacteria bacterial cell wall synthesis. 3
including streptococcus pneumoniae, pyogenes and methicillin-susceptible A broad spectrum of antibacterial
staphylococcus aureus (MSSA). It also shows antibacterial activities against activity
Gram-negative bacteria including resistant Pseudomonas aeruginosa and Biapenem has a broad spectrum of
Acinetobacter baumannii. Evidence from international studies confirmed that antibacterial activity encompassing
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.

B iapenem is a novel parenteral broad

spectrum carbapenem primarily
used for the treatment of complicated
administered with a DHP-I inhibitor
e.g. cilastatin. Biapenem is a newer
parenteral carbapenem which, unlike Fig. 1: Structural formula of Biapenem3
infections like sepsis, lower respiratory imipenem, has a 1β-methyl group at
infections, urinary tract infections, the C1 position conferring stability Table 2: Biapenem spectrum of activity1,3
intra-abdominal and genitourinary to hydrolysis by human renal DHP-I Gram-positive aerobes Gram-negative aerobes
infections etc. in Japan, Thailand and (Figure 1). 1 Enterococcus Acinetobacter baumannii
China since two decades (Table1). 1 Meropenem, Biapenem and Staphylococcus Citrobacter freundii, koseri
Biapenem has been approved in India aureus (methicillin- Enterobacter aerogenes,
ertapenem are more stable and do susceptible)
for the management of complicated cloacae
not require protection from DHP-I. Staphylococcus species
urinary tract infections (cUTI) in 2021. Escherichia coli
Comparative in vitro study demonstrate (methicillin-susceptible)
Unique chemical structure that Biapenem was more stable to including Staphylococcus Haemophilus influenzae
epidermidis Klebsiella pneumoniae
The early carbapenems like hydrolysis by human renal DHP-I
Streptococcus Morganella morganii
imipenem are not stable to hydrolysis than imipenem, meropenem and agalactiae (Group B) Neisseria meningitidis
by human renal dihydropeptidase-I panipenem. 1
Streptococcus Proteus mirabilis, vulgaris
(DHP-I) and therefore are co- milleri group
Serratia marcescens
Streptococcus pneumoniae
Table 1: Classification of carbapenems in three groups2 Pseudomonas aeruginosa
Streptococcus
  Group 1 Group 2 Group 3 (under development) pyogenes (Group A)
Carbapenems Ertapenem Imipenem Tomopenem Gram-positive Gram-negative
anaerobes anaerobe
Panipenem Meropenem Razupenem
Clostridium perfringens Bacteroides caccae
Tebipenem Doripenem
Peptoniphilus Bacteroides
Biapenem asaccharolyticus fragilis group
Activity against non-fermentants (P.aeruginosa, No Yes Yes
Peptostreptococcus Prevotella bivia
A. baumanii)
species (including P. Prevotella disiens
Activity vs MRSA No No Yes micros, P anaerobius, P.
magnus) Fusobacterium
Table 3: Mean Pharmacokinetics Parameters of Carbapenems in Healthy Volunteers4
Antibiotic Dose (mg) Cmax (mg/L) Half‐life (h) Protein binding (%) Urinary recovery (%)
Imipenem 500 12–20 0.95 13–20 70 1
Chest Physician, Vora Clinic, Mumbai, Maharashtra;
2
Physician and Diabetologist, Shilpa Medical Research
Meropenem 500 23 0.95 10 70
Centre, Mumbai, Maharashtra
Biapenem 3001 17.35 1.0 4 60
Received: 10.10.2021; Accepted: 12.11.2021
Ertapenem 1000 155 (i.v.)   4.0 95 38
94 Journal of The Association of Physicians of India ■ Vol. 70 ■ January 2022

Table 4: Antibacterial Activity (MIC90, µg/ml) of Biapenem7,8 Table 5: Biapenem concentrations in body
fluid and tissues determined
Organism Imipenem Meropenem Ertapenem Biapenem
after 300 mg of biapenem by
Gram-Positive Aerobes intravenous drip infusion for 60
Staphylococcus aureus (MS) 0.06 0.25 0.25 0.12 minutes.
Staphylococcus epidermidis (MS) 0.12 0.5 0.5 <0.063
Tissues/Organ Biapenem
Streptococcus pyogenes <0.015 0.008 0.015 <0.063 concentration
Streptococcus pneumoniae (PS) <0.015 <0.015 <0.015 ≤ 0.06 Sputum 0.1-2.5 µg/ml (within
Streptococcus pneumoniae (PR) 0.12 0.25 2 0.03 -1 6 hr)3,9
Enterococcus faecalis 4 4 >16 8 Alveolar epithelial 3.5 µg/ml (at 0.5-hr) and
Enterococcus faecium 128 128 >16 128 lining fluid 1.3 µg/ml (3-hr)10
Gram -Negative Aerobes Bronchial epithelial 2.35 µg/ml (at 0.5-hr)
lining fluid and 4.36 µg/ml (3-hr)10
Escherichia coli 0.25 0.03 0.016 0.03-0.25
Body Fluids (bile, 0.2-1.8 µg/ml9
Citrobacter freundii 2 0.06 0.25 0.25
middle ear, tonsil,
Salmonella spp. 0.12 0.03 0.016  0.06 aqueous humor, bone
Shigella spp. 0.25 0.06 0.016  0.25 tissues)
Klebsiella pneumoniae 0.25 0.06 0.03 0.06 - 0.5 Gallbladder, maxillary/ 2.0 - 5.7 µg/ml9
Klebsiella oxytoca 0.5 0.03 0.03  0.5 ethmoidal sinus
mucous, oral tissues,
Enterobacter cloacae 0.5 0.06 1 0.5 skin, woman genitals,
Enterobacter aerogenes 0.5 0.06 1   synovia, joint tissue and
Serratia marcescens 1 0.25 0.12 0.5 the eschar
Proteus mirabilis 2 0.06 0.06 0.06-0.25 Pelvic dead space fluid 9.6 μg /ml3 
Proteus vulgaris 4 0.06 0.25  2 Retroperitoneal fluid Similar to cubital vein
plasma9
Morganella morganii 2 0.25 0.06 2
Providencia rettgeri 1 0.12 0.25 8 Biapenem was more active than
Acinetobacter baumannii 2 2 16 0.5 Ceftazidime against most gram-
Pseudomonas aeruginosa 16 8 >16 1 negative and gram-positive bacteria
Haemophilus influenzae 1 0.5 0.06 2 tested. This study results coupled
Moraxella catarrhalis 0.03 <0.03 0.016 0.12 with previously documented favorable
Neisseria gonorrhoeae  0.5 0.03     0.06 qualities of Biapenem, endorse this
Neisseria meningitides 0.03 0.016    0.06 broad-spectrum antibacterial agent
Anaerobes for clinical use. 6 Comparative in vitro
Peptococcus magnus 1 0.25 1 1 activity of Biapenem against clinical
Clostridium perfringens 0.03 <0.06 0.06 0.06 isolates of bacteria is presented in
Clostridium difficile 8 2 8  16 Table 4.
Bacteroides fragilis 0.5 1 1 0.5
Plasma concentration during renal
Prevotella bivia 0.5 0.5 0.5 1
dysfunction
Fusobacterium nucleatum 0.06 0.016 0.12 0.12
MS = methicillin-susceptible; PS = penicillin-susceptible; PR = penicillin-resistant
When Biapenem 300 mg was
administered to patients with renal
many Gram-negative (GN) and have less than 0.5 µg/ml MIC levels,
dysfunction, delayed disappearance of
Gram-positive (GP) aerobic and indicating susceptibility to BIPM.
Biapenem from plasma was observed
anaerobic bacteria, including species Initial killing to a 99.9 % reduction was
as renal function declined. Biapenem
producing β-lactamases 1,3 as presented observed in seven out of eight strains in
300 mg twice daily for 7 days, 14
in detail in Table 2. a time-kill assay. This efficacy of BIPM
times in total, repeated intravenous
Pharmacokinetics suggests that the drug could be a new
infusion over 30 minutes to patients
therapeutic option against infection
F o l l o w i n g Ta b l e 3   g i v e s t h e with moderate renal dysfunction
with IMP-producing carbapenemase
pharmacokinetic parameters of the with creatinine clearance of about
producing Enterobacteriaceae. 5
licensed carbapenems after intravenous 50 ml/ min, in plasma and urine, no
infusion.  The in vitro activity of Biapenem accumulation was observed. 3
was compared to that of imipenem, Special Features and Properties of
No metabolites were detected in
meropenem and other broad-spectrum biapenem
the plasma following a single IV drip
β-lactams. A total of 716 isolates from
infusion of Biapenem 150, 300 and 600 1 . A G rea ter b a c teri c i d a l e f f e c t
recent cases of clinical septicaemia
mg or repeated IV drip infusion of than other carbapenems against P.
and an additional 137 stock strains
300 and 600 mg in healthy adults. The aeruginosa
possessing known β-lactamases were
cumulative urinary excretion rates from Biapenem exerted a greater
tested. MIC 90 of Enterobacteriaceae
0 to 12 hours are 62.1, 63.4 and 64.0%, bactericidal effect than some other
species were for Biapenem 0.03 to 1
respectively. 3 carbapenems against P. aeruginosa,
mg/l and for imipenem 0.25 to 2 mg/l.
In vitro Efficacy No member of the Enterobacteriaceae including some typically resistant,
Recent study of Biapenem (BIPM) was found to be resistant to Biapenem. adherent biofilm-forming strains,
against 14 IMP (imipenem)-1- Biapenem and meropenem were the and several efflux system mutants.
producing  Enterobacteriaceae  strains most active drugs against Pseudomonas of 5 tested agents (biapenem,
shown that almost all the isolates aeruginosa, with MIC 90 of 1 mg/l. imipenem, meropenem, panipenem
 Journal of The Association of Physicians of India ■ Vol. 70 ■ January 2022 95

Table 6: Summary of comparative clinical evidence of biapenem against other carbapenems the 1β position, a triazolium radical on
Study Interventions Study Results / Main outcome
the side chain at position 2 and lower
Population potential for biapenem to inhibit GABA
Wang X Biapenem (300 272 patients of Efficacy receptor binding than imipenem. 1
201311 mg 12 hrly) bacterial lower - Overall clinical efficacies of biapenem and meropenem
Vs.Meropenem respiratory
4. Post-antibiotic Effects
were not significantly different, 94.70 % (125/132) vs. 93.94 %
(500 mg 8 hrly) tract infections (124/132). In contrast to many other β-lactam
for 7 to 14 or UTIs
days - overall bacterial eradication rates of biapenem and agents, but in common with imipenem,
meropenem showed no significant difference, 96.39 % (80/83) Biapenem has shown a marked post-
Multi-center vs. 93.75 % (75/80) respectively.
RCT antibiotic effect against gram-negative
Safety
and gram-positive bacteria. The post-
- adverse reactions were comparable in biapenem and antibiotic effect of Biapenem against
meropenem groups with incidence of 11.76 % (16/136) and
15.44 % (21/136), respectively. P. Aeruginosa was augmented in the
- Most common biapenem-related adverse reactions were rash presence of fresh human plasma.
(2.2%) and gastrointestinal distress (1.5%). D e l a ye d b a c t e r i a l r e g r o w t h a f t e r
Jia B 201012 Biapenem 216 patients Efficacy Biapenem exposure was reported with
300 mg vs with Cure and effective rates were 67.92 and 88.68% in the biapenem E. faecalis and P. aeruginosa. 1
Imipenem/ respiratory or group and 76.02 and 93.40% in imipenem/cilastatin group, the
cilastatin 500 urinary tract bacterial eradication rates were 93.83 and 98.82% (p > 0.05). Indications
mg/500 mg infections
two or three multi-center, Safety DCGI approved the Biapenem in
times daily, open-label, - adverse-event rates were 6.54 and 7.41%, respectively. (p > India for the treatment of complicated
i.v. - 7-14 days. RCT 0.05). Urinary Tract Infections (cUTI).
-No significant differences between the two groups
Biapenem usage are approved
Biapenem is as effective and well-tolerated as imipenem/
internationally in Japan: Sepsis, Lower
cilastatin for the treatment of intermediate and severe bacterial
infections. respiratory infections- Pneumonia,
Kawada Biapenem 300 Biapenem Efficacy pulmonary abscess, secondary
200013 mg b.i.d. vs (N=75) -After 5 days’ treatment with Biapenem, excellent or moderate infection of chronic respiratory
imipenem/ Patients Vs. clinical responses were achieved in 94.7% (71/ 75) of patients. lesions, Complicated urinary tract
cilastatin Imipenem/
500/500 mg Cilastatin - Response rates did not differ significantly from those infections- cystitis, pyelonephritis,
twice daily for (N=76) obtained with imipenem/ cilastatin 93.4% (71/76). Intra-abdominal infections- peritonitis,
5 days. -Similarly, bacterial eradication rates in Biapenem-treated uterine inflammation/infection etc. 3
Complicated patients 95% (115/121) did not differ significantly from those
urinary tract obtained with imipenem/cilastatin 94.4% (117/124). Contraindications
infections Safety Patients with a history of
-Clinical adverse reactions were experienced in 2.2% of the 92 hypersensitivity to the ingredients of
patients in the BIPM group and in 4.4% of the 90 patients in the
IPM/CS group.
this drug (to carbapenem, penicillin
-No statistically significant differences in the incidences of
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
adverse reactions. receiving sodium valproate (Blood
Matsumoto BIPM 300 mg 88 patients in Efficacy levels of valproic acid may decrease and
200014 twice daily vs BIPM group - Clinical efficacy rates were 93.2% (82/88) in the BIPM group epileptic seizures may recur ) 3
IPM/CS 500 and 93 patients and 91.4% (85/93) in the IPM/CS group.
mg/500 mg in IPM/CS Dosage Administration
twice daily group of lower - Bacteriological eradication rates were 89.1% (41/46) in the
BIPM group and 97.5% (39/40) in the IPM/CS group, with no • Biapenem 300 mg twice daily,
upto 14 days respiratory
tract infections significant difference between the two groups. administered as an infusion over 30 to
Safety 60 minutes (600 mg/day). 1,3
Side effects were observed at a rate of 1.9% (2/103) in the • Biapenem is available as single
BIPM group and 6.3% (7/111) in the IPM/CS group, with no
significant difference between the two groups. 300mg vials and must be reconstituted
in 100ml of 0.9% sodium chloride before
and ceftazidime), only biapenem 3. No risk of convulsions/seizures
administration. Dosage can be adjusted
showed bactericidal activity against β-lactams antibiotics, including according to the age and symptom
P. aeruginosa KG5007 (a mutant strain penicillin and imipenem, occasionally of individual patient, but should not
overexpressing mexcd-oprj). Strains of cause convulsions/seizures in humans. exceed 1.2 g/day. 1,3
P. aeruginosa resistant to ceftazidime However, Biapenem appeared to
or ofloxacin were also susceptible to • Use for the minimum period
have weaker convulsant activity than
Biapenem, as were strains producing necessary to prevent the development
imipenem, panipenem and cefazolin
β-lactamases. 1 of resistant bacteria. 3
in in vitro and in vivo investigations.
2. Improved Tissue Penetration Biapenem did not induce severe • Patients with severe renal
convulsions or show neurotoxic impairment- Monitor and administer
After intravenous administration,
potential in animal studies and showed Biapenem carefully, reducing the
Biapenem is widely distributed,
a substantially lower potential than dose or increasing the dosing interval.
penetrates well and achieves
imipenem for evoking convulsions in Hemodialysis patients should be
clinically relevant concentration into
experimental studies. These beneficial administered once daily. 3
respiratory tract, genitourinary tract,
gastrointestinal system, skin (Table features of Biapenem were attributed Tolerability
5). 1,3,9,10 to the presence of a methyl group at Similar to other carbapenems, the
96 Journal of The Association of Physicians of India ■ Vol. 70 ■ January 2022
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
carbapenem antibacterial agent
recently approved for use in India. 1
Biapenem exerted a greater bactericidal
effect than other carbapenems
(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/
c i l a s t a t i n o r m e r o p e n e m a n d wa s
generally well tolerated, in the treatment
of adults with complicated intra-
abdominal infections, lower respiratory
tract infections, complicated urinary
tract infections and gynaecological
infections. 1,3,15
The tolerability profile of Biapenem
is generally similar to that of
meropenem, importantly, the seizures
potential in patients with meningitis is
not increased following administration
of Biapenem in studies. 1,11
T h u s , B i a p e n e m i s a n e f f e c t i ve
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.
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