Review of Pharmacology - 9E (2015)

Review of Pharmacology
Carbapenems are the only
β-lactams which are reliably
efficacious against ESBL (extended
spectrum β-lactamase)
producing organisms.
it is combined with cilastatin, an inhibitor of this enzyme. Cilastatin increases the half life
of imipenem and also inhibits the formation of nephrotoxic metabolite. Main adverse effects of
imipenem-cilastatin combination include seizures and gastrointestinal distress. Meropenem,
doripenem and ertapenem are not metabolized by renal dehydropeptidase and are less likely to cause
seizures. Ertapenem is very long acting and is inactive against Pseudomonas.
Loracarbef: It is chemically similar to cefaclor. It can be administered orally and its uses and
spectrum resembles second generation cephalosporins. Its overdose can cause seizures.
Chemotherapy A: General Considerations and Non-specific...
522
CA is Clavulanic acid, TZB is
Tazobactam, EDTA is chelating
agent
• Cephamycins include cefoxitin,
cefmetazole and cefotetan
*Early cephalosporins include
cephaloridine, cefazolin and
cephalothin
**Oxyimino beta-lactams
include cefotaxime, ceftazidime,
ceftriazone, cefepime
and aztreonam.
Beta lactamase inhibitors
• These include clavulanic acid, sulbactam, tazobactam and avibactam. These are more
active against plasmid encoded beta-lactamases (produced by gonococci and E. coli)
than against inducible chromosomal beta-lactamases (produced by pseudomonas
and enterobacter)
- Amoxicillin is combined with clavulanic acid (Co-amoxy-clav).
- Ampicillin is combined with sulbactam (Sultamicin).
- Piperacillin is combined with tazobactam.
– Ceftazidime-avibactam combination is recently approved for complicated UTI
(including pyelonephritis) and complicated intra-abdominal infections.
Beta-Lactamases
These are the enzymes that hydrolyze beta-lactam antimicrobials. These enzymes may be
located on chromosome (e.g. SHV-1 enzyme mediating resistance to Ampicillin and ticarcillin
in Klebsiella) or on the plasmid (e.g. enzyme mediating penicillin resistance in Staphylococci).
Further, these can inducible (the production is initiated when bacteria is exposed to betalactams
e.g. in penicillin resistance in Staphylococci) or constitutive (bacteria continue to
produce them whether exposed to beta-lactams or not e.g. SHV-1).
Two major schemes are adopted to classify beta lactamases:
• Molecular classification (Amber classification): It is based on structure (amino acid
sequence). Beta lactamases are classified into four categories; A, B, C and D. Class A,
C and D enzymes require serine residue to hydrolyze beta lactams whereas Class B
require zinc ions (therefore also known as metallo-beta lactamases).
• Functional classification (Bush Classification): This classification is based on the
type of substrate of beta lactamase (i.e. which beta-lactam is hydrolyzed). It also takes
into consideration whether the enzyme is inhibited by clavulanic acid or other drugs.
According to this scheme, beta lactamases are classified into three (previously there
were four) categories: 1, 2 and 3.
Beta-lactamase
Cephalosporinase
Serine
b-lactamases
Functional
Group
Molecular
Group
Inhibited
by Substrates Example
1 C None Cephalosporins,
cephamycins, Aztreonam
2 A or D CA and TZB
Amp C
Penicillinase 2a A CA and TZB Penicillin G PCI
Extended
Spectrum Betalactamases
(ESBL)
2b A CA and TZB Penicilin and early
cephalosporins*
2be A CA and TZB Penicillins,
Cephalosporins, Oxyimmino
beta lactams**
NOT cephamycins and
carbapenems
TEM-1, TEM-
2, SHV-1
TEM-3,
SHV-2
Carbenicillinase 2c A CA and TZB Carbenicillin CARB-1
Oxacillinase 2d D CA and TZB Cloxacillin, Oxacillin OXA-1
Contd...
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