ANTIMICROBIAL THERAPY

Antimicrobial therapy takes advantage of the

biochemical differences that exist between microorganisms
and human beings. Antimicrobial drugs are effective in the
treatment of infections because of their selective toxicity; that
is, they have the ability to injure or kill an invading
microorganism without harming the cells of the host. In most
instances, the selective toxicity is relative rather than
absolute, requiring that the concentration of the drug be
carefully controlled to attack the microorganism, while still
being tolerated by the host.

a)Anti- Bacterial
1.
2.
3.
4.
5.

CELL WALL INHIBITORS

INHIBITORS OF PROTEIN SYNTHESIS
INHIBITORS OF CELL MEMBRANE FUNCTION
Nucleic acid Function............... *
Metabolism.............. *

PENICILLINS

1. CELL WALL INHIBITORS

PENICILLINS
Amoxicillin AMOXIL
Ampicillin OMNIPEN
Dicloxacillin DYNAPEN
Indanyl carbenicillin GEOCILLIN
Nafcillin NALLPE
Oxacillin OXACILLIN
Penicillin G PFIZERPEN
Penicillin V VEETIDS
Piperacillin PIPRACIL
Ticarcillin TICAR
CEPHALOSPORINS
CEPHALOSPORINS
Cefadroxil DURICEF 1st
Cefazolin KEFZOL 1st
Cephalexin KEFLEX 1st
Cefaclor CECLOR 2nd
Cefprozil CEFZIL 2nd
Cefoxitin MEFOXIN 2nd
Cefdinir OMNICEF 3rd
Cefixime SUPRAX 3rd
Ceftazidime FORTAZ 3rd
Ceftriaxone ROCEPHIN 3rd
Ceftizoxime CEFIZOX 3rd
Ceftibuten CEDAX 3rd
CARBAPENEMS
Ertapenem INVANZ
Imipenem/cilastatin PRIMAXIN
Meropenem MERREM IV
MONOBACTAMS
MONOBACTAMS
Aztreonam AZACTAM
OVERVIEW
Some antimicrobial drugs selectively interfere with synthesis of the
Bacterial cell walla structure that mammalian cells do not
possess. The cell wall is composed of a polymer called

peptidoglycan that consists of glycan units joined to each other by

peptide cross-links. To be maximally effective, inhibitors of cell wall
synthesis require actively proliferating microorganisms; they have
little or no effect on bacteria that are not growing and dividing. The
most important members of this group of drugs are the -lactam
antibiotics (named after the -lactam ring that is essential to their
activity) and vancomycin.
PENICILLINS
The penicillins are among the most widely effective and the least
toxic drugs known, but increased resistance has limited their use.
Members of this family differ from one another in the R substituent
attached to the 6-aminopenicillanic acid residue. The nature of this
side chain affects the antimicrobial spectrum, stability to stomach
acid, cross-hypersensitivity, and susceptibility to bacterial
degradative enzymes (-lactamases).
A. Mechanism of action
The penicillins interfere with the last step of bacterial cell wall
synthesis (transpeptidation or cross-linkage), resulting in
exposure of the osmotically less stable membrane. Cell lysis can
then occur, either through osmotic pressure or through the
activation of autolysins. These drugs are thus bactericidal. The
success of a penicillin antibiotic in causing cell death is related to
the antibiotics size, charge, and hydrophobicity. Penicillins are
only effective against rapidly growing organisms that synthesize a
peptidoglycan cell wall. Consequently, they are inactive against
organisms devoid of this structure, such as mycobacteria, protozoa,
fungi, and viruses.
Pharmacokinetics
1. Administration: The route of administration of a -lactam
antibiotic is determined by the stability of the drug to gastric acid
and by the severity of the infection.
a. Routes of administration: Ticarcillin, piperacillin, and the
combinations of ampicillin with sulbactam, ticarcillin with
clavulanic acid, and piperacillin with tazobactam, must be
administered intravenously (IV) or intramuscularly (IM). Penicillin
V, amoxicillin, and amoxicillin combined with clavulanic acid are
available only as oral preparations. Others are eff ective by the
oral, IV, or IM routes.
b. Depot forms: Procaine penicillin G and benzathine penicillin G
are administered IM and serve as depot forms. They are slowly
absorbed into the circulation.

ADR: Hiper Sensitivity

Diarrhea
Nephritis
Neurotoxicity
Hematologic Toxicities(Decreased B Coagulation)
Cation toxicity(Eg:- Hypokalemia)
CEPHALOSPORINS
Cephalosporins have the same mode of action as penicillins, and
they are affected by the same resistance mechanisms. However,
they tend to be more resistant than the penicillins to certain
-lactamases.
A. Antibacterial spectrum
Cephalosporins have been classified as first, second, third, and
fourth generation, based largely on their bacterial susceptibility
patterns and resistance to -lactamases. [Note: Commercially
available cephalosporins are ineffective against MRSA, L.
monocytogenes, Clostridium difficile, and the enterococci.]
1. First generation: The first-generation cephalosporins act as
penicillin G substitutes. They are resistant to the staphylococcal
penicillinase (that is, they cover MSSA) and also have activity
against Proteus mirabilis, E. coli, and Klebsiella pneumoniae (the
acronym PEcK has been suggested).
2. Second generation: The second-generation cephalosporins
display greater activity against three additional gram-negative
organisms: H. influenzae, Enterobacter aerogenes, and some
Neisseria species, whereas activity against gram-positive organisms
is weaker (the acronym HENPEcK has been suggested with the
second generations increased coverage). Antimicrobial coverage of
cefotetan and cefoxitin also includes the anaerobe, Bacteroides
fragilis. However, neither cefotetan nor cefoxitin is the preferred
treatment because of the increasing prevalence of resistance
amongst B. fragilis to both agents.
3. Third generation: These cephalosporins have assumed an
important role in the treatment of infectious diseases. Although
inferior to first-generation cephalosporins in regard to their activity

against MSSA, the third-generation cephalosporins have enhanced

activity against gram-negative bacilli, including those mentioned
above, as well as most other enteric organisms plus Serratia
marcescens. Ceftriaxone [sef-trye-AKS-own] and cefotaxime [sef-ohTAKS-eem] have become agents of choice in the treatment of
meningitis. Ceftazidime [sef-TA-zi-deem] has activity against P.
aeruginosa, however, resistance is increasing and appropriate use
should be evaluated on a case-by-case basis. Third generation
cephalosporins must be used with caution, as they are associated
with "collateral damage," essentially meaning the induction and
spread of antimicrobial resistance. [Note: fluoroquinolones use is
also associated with collateral damage.]
4. Fourth generation: Cefepime [SEF-eh-peem] is classified as a
fourthgeneration cephalosporin and must be administered
parenterally. Cefepime has a wide antibacterial spectrum, being
active against streptococci and staphylococci (but only those that
are methicillinsusceptible).
Cefepime is also effective against aerobic gram-negative organisms,
such as Enterobacter species, E. coli, K. pneumoniae, P. mirabilis,
and P. aeruginosa. When selecting an antibiotic that is active
against P. aeruginosa, clinicians should refer to their local
antibiograms (laboratory testing for the sensitivity of an isolated
bacterial strain to different antibiotics) for direction.
Pharmacokinetics
1. Administration: Many of the cephalosporins must
administered IV or IM because of their poor oral absorption.

be

Adverse effects
The cephalosporins produce a number of adverse affects, some of
which are unique to particular members of the group.
1. Allergic manifestations: Patients who have had an
anaphylactic response, Stevens-Johnson syndrome, or toxic
epidermal
necrolysis
to
penicillins
should
not
receive
cephalosporins. The cephalosporins should be avoided or used
with caution in individuals who are allergic to penicillins (about 8
to 10 percent is traditionally cited to show cross-sensitivity).
Current data evaluation suggests a cross-reactivity between
penicillin and cephalosporins to be around 3 to 5 percent and
determined by similarity in the side chain, not the b-lactam
structure. The rate of highest allergic cross sensitivity is between
penicillin and first generation cephalosporins.

CARBAPENEMS
Carbapenems are synthetic -lactam antibiotics that differ in
structure from the penicillins in that the sulfur atom of the
thiazolidine ring has been externalized and replaced by a carbon
atom. Imipenem [i-mi-PEN-em], meropenem [mer-oh-PEN-em],
doripenem [dore-i-PEN-em] and ertapenem [er-ta-PEN-em] are the
drugs of this group currently available. Imipenem is compounded
with cilastatin to protect it from metabolism by renal
dehydropeptidase.

1. Antibacterial spectrum: Imipenem resists hydrolysis by most

-lactamases, but not the metallo- -lactamases. This drug plays a
role in empiric therapy because it is active against b-lactamaseproducing gram-positive and gram-negative organisms, anaerobes,
and P. aeruginosa (although other pseudomonal strains are
resistant, and
resistant strains of P. aeruginosa have been reported to arise
during therapy). Meropenem and doripenem have antibacterial
activity similar to that of imipenem . However, ertapenem is not an
alternative for P. aeruginosa coverage because most strains exhibit
resistance. Ertapenem also lacks coverage versus Enterococcus
species and Acinetobacter species.
2. Pharmacokinetics: Imipenem/cilastatin and meropenem are
administered IV and penetrate well into body tissues and fluids,
including the CSF when the meninges are inflamed. They are
excreted by glomerular filtration. Imipenem undergoes cleavage by a
dehydropeptidase found in the brush border of the proximal renal
tubule. This enzyme forms an inactive metabolite that is potentially
nephrotoxic. Compounding the imipenem with cilastatin protects
the parent drug and, thus, prevents the formation of the toxic
metabolite. Meropenem, ertapenem, and doripenem do not require
co-administration of cilistatin. Ertapenem can be administered via
IV or IM injection once daily. [Note: Doses of these agents must be
adjusted in patients with renal insufficiency.]
3. Adverse effects: Imipenem/cilastatin can cause nausea,
vomiting, and diarrhea. Eosinophilia and neutropenia are less
common than with other -lactams. High levels of imipenem may
provoke seizures, but meropenem is possibly less likely to do so.
Doripenem has not demonstrated any potential to cause seizures in
animal studies.
MONOBACTAMS
The monobactams, which also disrupt bacterial cell wall synthesis,
are unique because the -lactam ring is not fused to another ring.
[az-TREE-oh-nam], which is the only commercially available
monobactam, has antimicrobial activity directed primarily against
the Enterobacteriaceae, including P. aeruginosa. It lacks activity
against gram-positive organisms and anaerobes. This narrow
antimicrobial spectrum precludes its use alone in empiric therapy.

Aztreonam is resistant to the action of most -lactamases, with the

exception of the extended-spectrum -lactamases (ESBLs). It is
administered either IV or IM and can accumulate in patients with
renal failure. Aztreonam is relatively nontoxic, but it may cause
phlebitis, skin rash, and occasionally, abnormal liver function
tests. This drug has a low immunogenic potential, and it shows
little cross-reactivity with antibodies induced by other -lactams.
Thus, this drug may offer a safe alternative for treating patients
who are allergic and unable to tolerate penicillins and/or
cephalosporins.
-LACTAMASE INHIBITORS
Hydrolysis of the -lactam ring, either by enzymatic cleavage with a
-lactamase or by acid, destroys the antimicrobial activity of a lactam antibiotic. -Lactamase inhibitors, such as clavulanic [clavue-LAN-ick] acid, sulbactam [sul-BACK-tam], and tazobactam [tazoh-BACK-tam], contain a -lactam ring, but by themselves, do not
have significant antibacterial activity. Instead, they bind to and
inactivate -lactamases, thereby protecting the antibiotics that are
normally substrates for these enzymes. The -lactamase inhibitors
are therefore formulated in combination with -lactamase sensitive
antibiotics. For example, shows the effect of clavulanic acid and
amoxicillin on the growth of -lactamase producing E. coli.
VANCOMYCIN
Vancomycin [van-koe-MYE-sin] is a tricyclic glycopeptide that has
become increasingly important because of its effectiveness against
multiple drugresistant organisms, such as MRSA and enterococci.
The medical community is presently concerned with emergence of
vancomycin resistance in these organisms. Two examples are
vancomycin resistant enterococci (VRE) and increased MICs of
MRSA. [Note: Bacitracin [bass-i-TRAY-sin] is a mixture of
polypeptides that also inhibits bacterial cell wall synthesis. It is
active against a wide variety of gram-positive organisms. Its use is
restricted to topical application because of its potential for
nephrotoxicity with systemic use.]
Mechanism of action
Vancomycin inhibits synthesis of bacterial cell wall phospholipids
as well as peptidoglycan polymerization in a time-dependant
fashion by binding to the D-Ala-D-Ala side chain of the precursor
pentapeptide. This prevents the transglycosy lation step in

peptidoglycan polymerization, thus weakening the cell wall and

damaging the underlying cell membrane.
Antibacterial spectrum
Vancomycin is eff ective against gram-positive organisms. It has
been lifesaving in the treatment of MRSA and methicillin-resistant
Staphylo coccus epidermidis (MRSE) infections as well as
enterococcal infections. With the emergence of resistant strains, it
is important to curtail the increase in vancomycin-resistant
bacteria (for example, Enterococcus faecium and Enterococcus
faecalis) by restricting the use of vancomycin to the treatment of
serious infections caused by -lactam resistant, gram-positive
microorganisms or for patients with gram-positive infections who
have a serious allergy to the -lactams. Oral vancomycin is limited
to treatment for potentially life-threatening, antibiotic-associated
colitis due to C. diffi cile. Intravenous vancomycin is used in
individuals with prosthetic heart valves and in patients undergoing
implantation with prosthetic devices, especially in those hospitals
where there is a problem with MRSA or MRSE. Vancomycin acts
synergistically with the aminoglycosides, and this combination can
be used in the treatment of enterococcal endocarditis. Daptomycin,
a cyclic lipopeptide antibiotic, and two protein synthesis inhibitors
quinopristin/ dalfopristin and linezolidare currently available for
the treatment of vancomycin-resistant organisms.]
Adverse effects: Fever, Chill, Flushing, Phlebitis