CARBAPENEM/MONOPENEM/BETA-LACTAMASE INHIBITORS

Carbapenam MONOPENEM BETA LACTAMASE INHIBITOR

Example :
EXAMPLES 1. IMIPENEM  Disrupt bacterial
cell wall 1. CLAVULANIC ACID
 resist hydrolysis of MOST beta synthesis – same 2. SULBACTAM
lactamases but not mettalo-beta like other beta- 3. TAZOBACTAM (IV WITH
lactamase lactam. piperacillin)
 imipenem undergoes cleavage by  Unique: BETA-  Have beta-lactam ring but do
DEHYDROPTIDASE (found in the LACTAM IS not have significant
brush boarder of the proximal renal NOT FUSED antibacterial activity
tubule). Combine imipenem and WITH OTHER  Bind and inactivate beta-
cilastatin prevent the parent drug from RING. lactamase (protecting
being inactive toxic metabolite. Lead to antibiotics that normally
nephrotoxic. 1. AZTREONAM substrate for these enzyme)
(IV or IM)  Formulated in combination
(do not need co-administered cilastatin) with beta-lactamase sensitive
2. MEROPENEM antibiotics.
3. DORIPENEM
4. ERTAPENEM (IV &IM)

Synthetic beta-lactam antibiotic based

on thienamycin (from Streptomyces
cattleya)

SPECTRUM  Imipenem, meropenem and  Lack / narrow

doripenem (have empirical therapy antimicrobial
because active against beta (thus, empirical
lactamase producing (broad therapy) activity
spectrum): against Gram
+ve and
1. Gram +ve COCCI: anaerobes
o staphyloc. Aureus*  Antimicrobial
o staphy. Epidermidis mainly against
o staph. Faecalis Enterobacteriace
o strepto. Group A,B,C ae including P.
o strep. Pneumonia aeruginosa
 Resistant against
*staphyl. are resistance to most of beta-
METHICILLIN lactamases
EXCEPT
2. Gram +ve BACILLI EXTENDED-
o Listeria monocytogenes SPECTRUM
beta-lactamases
3. Gram -ve COCCI:  Relatively
o Neisseria meningitidis nontoxic
o N. gonorrhoeae  Has low
immunogenic
4. Gram -ve RODS: potential and
o Acinobacter sp. little cross-
o Citrobacter sp. reactivity
o E. coli  Can be used
o Gardnella vaginalis in pt with
 o H. influenza penicillin
o Klebsiella sp. hypersensiti
o P. aeruginosa vity
o Salmonella sp 
o Serratia sp
5. Anaerobes
o Clostridium sp.
o Propionibacterium
o Peptostrepto/ peptococcus
o Bacteroides sp.
o Fusobacterium sp
6. Others
o Actinomyces
o Spirochetes
o Chlamydia

 ERTAPENEM lack coverage for:

 P. aeruginosa
 Enterococcus
 Acinetobacter

RESISTANC Resistance to carbapenem Azobactam is Bacteria resistance to beta lactamase

E 1. Reduced permeability of the outer resistance to most inhibitor:
membrane of Gram-negative beta-lactamase 1. Due to genetic mutation:
bacteria (due to diminished except extended  Clavulanic acid cause
production of porins) causing spectrum beta mutation in
reduced bacterial uptake lactamase chromosomally encoded
2. Reduced affinity of the target class C B-lactamases
penicillin binding proteins (PBP)  Depression of inducible
3. Increased expression of efflux chromosomally encoded
pump components (bacteria has B-lactamase
the ability to pump out  Overproduction of
carbapenem out of the cell wall WILD type class A
4. Production of antibiotic-destroying penicillinase (TEM 1
enzymes (carbapenemases, and TEM 2) that cause
METALLO-Β-LACTAMASES- low sensitivity to b-
class b). lactam inhibitor

PHARMAC  Carbapenems and monobactams are  IRREVERSIBLE binding with

OKINETICS NOT ABSORBED after oral most β-lactamases.
/ administration.  Combine with β-lactams
PHARMAC  Use IV or IM (ertapenem) antibiotics increase the
ODYNAMI  Imipenem/cilastatin and meropenem antibacterial activity
C administered IV and PENETRATES approximately 4- to 32-fold.
WELL into most body fluids and  Increase the inoculum size
tissues including cerebrospinal fluid, decrease the effectiveness of the
achieving concentrations matching combination.
or exceeding those required to  β-lactamases inhibitors can
inhibit most susceptible bacteria. paradoxically induce increased
 Plasma protein binding is production of β-lactamases
approximately 2%. There is one from the bacteria they
metabolite which is encountered.
microbiologically inactive.  The relative ability of the β-
 The elimination half-life is lactamases inhibitor to induce β-
 approximately 1 hour. lactamases production is in the
following order: clavulanic acid
> sulbactam > tazobactam.

ADR/ Side 1. Nausea/ vomiting/ diarrhea (GIT 1. Due to given by Absorption

Effect disturbance) – 1 mark
2. Eosinophilia
3. Neutropenia
High imipenem / cilastatin lead to
seizure
* Carbapenem differs from penicillin
where the sulphur atom in the
thiazolidine ring is replaced with carbon.
Monobactam unique one ring only
injection it cause  Clavulanic acid absorbed with
phlebitis oral bioavailability of 89 –
2. Skin rash 97%.
3. Test for liver  Sulbactam is not well absorbed
abnormality but use of prodrug in
4. Can accumulate combination with ampicillin
in patient that increase it bioavailability.
has renal failure  Tazobactom is not absorbed by
the oral route.
HOWEVER, THIS Distribution
DRUG SAFE FOR  Clavulanic acid is 20% bound
THOSE WHO to serum protein and distributed
ALLERGIC AGAIN into liver, kidneys, lymph node,
PENICILLIN AND bile, peritoneal fluid, CSF,
CEPHALOSPORIN bone and synovial fluid.
(sbb low  Sulbactam is 38% bound to
immunogenic serum protein and penetrates
potential as it has into fluids and tissues
little cross reaction (intraperitoneal fluid, sputum,
with antibodies CSF in inflamed meninges,
induced by other beta intestinal mucosa and
lactam. myometrium)
 Serum binding of tazobactam is
20 – 26% and penetrates
bronchial secretion, fat, muscle,
lung, appendix, skin prostate
and gallbladder.
Metabolism/Excretion
 Clavulanic acid undergoes
some hepatic metabolism to
give two major metabolites that
eliminated by renal and do not
have antibacterial or β-
lactamases inhibitors activity.
Approximately 40 – 75% of
clavulanic acid excreted
unchanged in urine.

 Sulbactam does not undergo
metabolism. Excreted by renal
unchanged and clearance of
sulbactam is greatly decreased
in patients with renal
impairment.
 Tazobactam is primarily
excreted in urine and no-nrenal
clearance via biliary excretion
and hepatic metabolism.