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Antimicrobial Agents I

General consideration

Beta lactam antibiotics

Sulfonamides & quinolones


therapeutics. They are one of the most
frequently used as well as misused drugs.

They are designed to inhibit/kill the infecting

organism and to have no/minimal effect on the
recipient. This type of therapy is generally
called chemotherapy.

Antibiotics are substances produced by

microorganisms, which suppress the growth of or
kill other microorganisms at very low

Antimicrobial agent is a chemotherapeutic agent

that works by reducing the number of bacteria

Antiseptics are chemical antimicrobials that are

applied topically on wounds or intact dermal
surfaces to destroy microorganisms & inhibit their
reproduction or metabolism.

Disinfectants are antimicrobial agents that are

generally applied to inanimate surface to destroy

the term chemotherapeutic agent was

restricted to synthetic compounds, but now both
synthetic and microbiologically produced drugs
need to be included together.

However, it would be more meaningful to use the

term antimicrobial agent (AMA) to designate
synthetic as well as naturally obtained drugs that
attenuate microorganisms.

The history of chemotherapy may be divided into 3 phases.

The period of empirical use : of mouldy curd by Chinese on

boils, chaulmoogra oil by Hindus in leprosy, chenopodium by
Aztecs for intestinal worms, mercury by paracelsus (16th
century) for syphilis, cinchona bark (17th century) for fevers.

Ehrlichs phase of dyes and organometallic compounds

(1890-1935). Arsenicalsatoxyl for sleeping sickness,
arsphenamine in 1906 and neoarsphenamine in 1909 for

He coined the term chemotherapy.

The modern era of chemotherapy was ushered by Domagk in

1935 by demonstrating the therapeutic effect of Prontosil, a
sulfonamide dye, in pyogenic infection.

The phenomenon of antibiosis was demonstrated

by Pasteur in 1877:

Fleming (1929) found that a diffusible substance

was elaborated by penicillium mould which could
destroy staphylococcus on the culture plate. He
named this substance penicillin but could not
purify it.

Chain and Florey followed up this observation in

1939 which culminated in the clinical use of
penicillin in 1941.

In the 1940s Waksman and his colleagues

discovered streptomycin in 1944.

All three groups of scientists Domagk, FlemingChain-Florey and Waksman received Nobel Prize



of infection :

pain, swelling, surface erythema, pus formation and

limitation of motion, fever, lymphadenopathy, malaise, a
toxic appearance and an elevated WBC counts.
If only pain (pulpitis/inflamation) without other signs of
infection : Antibiotic therapy inappropriate
Post surgical pain/swelling/fever : Surgical
stress/Atelectasis : Antibiotics not indicated
Thus the diagnosis of infection and the clinicians
judgement should be based on a logical process of


of host defense :

Host defense mechanisms, inflammatory response and production of

antibodies provides protection. If this mechanism or other host
defenses are impaired, infections may result.
Prophylactic therapy of infection : evaluate the general state of the
host defense mechanisms.
Antibiotics : host has been overwhelmed by bacteria/when especially
virulent bacteria are involved when defense mechanism are impaired.
depressed defenses can be due to.
Physiologic, disease related, defective immune system related and drug
suppression related (anticancer drugs).

If Defences are depressed aggressive antibiotic therapy should be

employed. Bactericidal rather than bacteriostatic antibiotics should be
When surgery is required in any compromised host antibiotic
prophylaxis of wound infection must be considered.


drainage and incision:

necessary in both chronic abscess and acute indurated cellulitis.

incision and drainage of the abscess result in reduction of pressure
in the area of cellulitis. It may also obviate the use of an antibiotic
or may increase the effectiveness of an antibiotic as the vascular
flow is restored.
The host defense mechanisms are also restored with the incision
and drainage.

The decision to use antibiotic therapy:

Minor infections in patients with depressed host defenses must be
treated aggressively with antibiotics and surgery as early as possible

In some case like minor infections or moderate infections, where

the host defense is intact surgical drainage will be sufficient
without the use of antibiotics (controversial).

Principles for choosing the appropriate antibiotic:

Identification of the causative organism

Either in laboratory or empirically based on

knowledge of pathogenesis and clinical picture

Initial empirical therapy can be instituted if

the following criteria are met:
The site and feature of the infection have been well
The circumstances leading to the infection are well
Organisms that most commonly cause such


of the antibiotic sensitivity:

Penicillin is excellent for streptococcus and major

Erythromycin is very effective against streptococcus,
peptostreptococcus and fusobacterium,
Clindamycin is very good for streptococcus and for the
five major anaerobic groups(Peptosteptococci,
Actinomyces,Clostridia,Bacterioids Vellionella.)
Cephalexin is only moderately active against
streptococcus and is good against five groups of
Metronidazole has no activity against streptococcus but
has excellent activity against the five anaerobic groups.


of a specific, narrow-spectrum

broad spectrum antibiotic might lead to

resistance of other bacteria which are not
involved in the infection.
The use of narrow spectrum antibiotics
also minimizes the risk of superinfections.


of the least toxic antibiotic


drug history:


of a bactericidal rather than a

bacteriostatic drug:

Antibacterial therapy reduces the

bacterial challenge and allows host
defenses to complete the treatment.
Bactericidal is the most preferred one
because of the following advantages:
There is less reliance on host resistance.
The antibiotic itself kills the bacteria.
The drug works faster than bacteriostatic
There is greater flexibility with dosage


of antibiotic with a proven

history of success:

Newer antibiotics should be used only

when they offer clear advantages over
older ones.


of antibiotics:

The use of a drug should always

consider the patients compliance and
maximum effectiveness.



The goal of any drug therapy should be to prescribe or

administer sufficient amounts to achieve the desired
therapeutic effect, but not enough to cause injury to the
MIC : Dose should be 3-4 times the MIC



time interval

Each antibiotic has an established half life, during which

one half of the absorbed dose is excreted.
The usual dosage interval for the therapeutic use of
antibiotics is four times the T .


route of administration:

In some infections only parenteral administration produces the

necessary serum level of antibiotic.
The oral results in the most variable absorption.
Most antibiotics should be taken in the fasting state to ensure
maximum absorption.
In long term parenteral administration is necessary. Repeated IM is
poorly accepted in patients in such situations


antibiotic therapy:

It is indicated in few situations like in:

Situations of life threatening infections of unknown cause.

To increase the bactericidal effect of a specific antibiotic.
Prevention of the rapid emergence of resistant bacteria.
Empiric therapy of certain odontogenic infections like when the infection
progresses to the lateral and retropharyngeal spaces and caused by aerobes
and anaerobes.

Monitoring the patient


to treatment

Usually starts by second day with

subjective symptoms
Objective signs also appear


the initial therapy fails several

factors should be considered:

Route of administration.
Patient compliance.
Correct antibiotic.


of failure in treatment of

Inadequate surgical treatment.

Depressed host defences.
Presence of foreign body.
Antibiotic problems

Drugs not reaching infection.

Dose not adequate
Wrong bacterial diagnosis.
Wrong antibiotic.


of adverse reactions

Almost 15 to 20% of hospitalized patients experience adverse


Hypersensitivity occurs with all antibiotics.

Most common with penicillins and the cephalosporins.

Manifest as accelerated anaphylactic (Type I) reactions or less

severe reactions associated with edema, urticaria, itching, or they
may be delayed reactions presenting only as a low grade fever.
To prevent toxicity it is important to avoid excessive dose
Antibiotic Associated Collitis : All antibiotics (esp clindamycin,
Amoxicillin, cephalosporins) except aminoglycosides.
Caused by toxins of Clostridium difficile.
Treated with vancomycin/metronidazole


and recurrent


The normal flora as a defense

mechanism against infection, but when
the flora is altered or eliminated by an
antibiotic, the pathogenic bacteria
resistant to the antibiotic may cause
secondary infection or superinfection.

Principles of Therapeutic
uses of antibiotics

a general guidelines, antibiotic therapy should be

reserved for those patients with clearly established
manifestations of infection, that is fever, malaise,
swelling and pain. Such patient should be treated
surgically as early as possible.

Abscess Surgical interventions and antibiotics.

Pericoronitis Preoperative antibiotics and surgery and
postoperative antibiotics.
Osteomyelitis Preoperative antibiotics and surgery and
postoperative antibiotics.
Fractures Immediate preoperative antibiotics and surgery
and postoperative antibiotics.
Soft tissue wounds Debridement and toileting later

Principles of Prophylactic antibiotics:

The operative procedure must have a risk of significant bacteria

contamination and a high incidence of infection.

The organism most likely to cause the infection must be known.

The antibiotic susceptibility of the causative organism must be known.

To be effective and to minimize adverse effects the antibiotic must be in

the tissue at the time of contamination (operation) and it must be
continued for not more than 4 hours after cessation of contamination.
The drug must be given in dosages sufficient to reach four times the MIC
of the causative organisms.

Time the antibiotic correctly.

Use the shortest effective antibiotic exposure.


Chemical structure :

Sulfonamides and related drugs: Sulfadiazine

and Dapsone (DDS), Paraaminosalicylic acid

Diaminopyrimidines: Trimethoprim,

Quinolones: Nalidixic acid, Norfloxacin,


-lactam antibiotics: Penicillins, Cephalosporins,

Tetracyclines: Oxytetracycline, Doxycycline etc.

Nitrobenzene derivative: Chloramphenicol.

Aminoglycosides: Streptomycin, Gentamicin,.

Macrolide antibiotics: Erythromycin,

Roxithromycin, Azithromycin etc.

Polypeptide antibiotics: Polymyxin-B, Colistin,

Bacitracin, Tyrothricin.

Glycopeptides : Vancomycin, Teicoplanin

Oxazolidinone : Linezolid.
Nitrofuran derivatives : Nitrofurantoin,
Nitroimidazoles : Metronidazole, Tinidazole.
Nicotinic acid derivatives: Isoniazid,
Pyrazinamide, Ethionamide.
Polyene antibiotics : Nystatin,
Amphotericin-B, Hamycin.
Azole derivatives: Micoazole, Clotrimazole,
Ketoconazole, Fluconazole.
Others : Rifampin, Lincomycin,
Clindamycin, Spectinomycin, Sod. Fusidate,
Cycloserine, Viomycin, Ethambutol,
Thiacetazone, Clofazimine, Griseofulvin.

Mechanism of action :

Inhibit cell wall synthesis: Penicillins, Cephalosporins,

Cycloserine, Vancomycin, Bacitracin.
Cause leakage from cell membranes: Polypeptides
Polymyxins, Colistin, and Bacitracin. Polyenes
Amphotericin B, Nystatin, Hamycin.
Inhibit protein synthesis: Tetracyclines,
Chloramphenicol, Erythromycin, Clindamycin, and
Cause misreading of m-RNA code and affect
permeability: Aminoglycosides Streptomycin,
Gentamicin etc.
Inhibit DNA gyrase : Fluoroquinolones Ciprofloxacin.
Interfere with DNA function : Rifampin, Metronidazole.
Interfere with DNA synthesis: Idoxuridine, Acyclovir,
Interfere with intermediary metabolism :
Sulfonamides, Sulfones,. PAS, Trimethoprim,
Pyrimethamine, Ethambutol.

Type of organisms against which primarily active :

Antibacterial : Penicillins, Aminoglycosides,
Erythromycin etc.
Antifungal : Griseofulvin, Amphotericin B,
Ketoconazole etc.
Antiviral : Idoxuridine, Acyclovir,
Amantadine, Zidovudine etc.
Antiprotozoal : Chloroquine, Pyrimethamine,
Metronidazole, Diloxanide
Antihelmintic : Mebendazole, Pyrantel,
Niclosamide, Diethyl carbamazine
Spectrum of activity :
Narrow spectrum
Broad spectrum

Penicillin G



Type of action :
Primarily bacteriostatic
sulfonamides, Erythromycin, Tetracycline Ethambutol,
Primarily bactericidal:
Penicillins, Cephalosporins, Aminoglycosides,
Vancomycin, Polypeptides, Nalidixic acid, Rifampin,
Ciprofloxacin, Cotrimoxazole
Antibiotics obtained from :

Fungi: Penicillin, Griseofulvin, Cephalosporin

Bacteria:Polymyxin-B,Tyrothricin, Colistin,
Aztreonam, Bacitracin.

Actinomycetes:Aminoglycosides, Macrolides,
Tetracyclines, Polyenes,Chloramphenicol.


1. Toxicity:
Local irritancy: This is experienced at the site of
Systemic toxicity: all AMAs produce dose related and
predictable organ toxicities. Characteristic toxicities
are exhibited by different AMAs.
Aminoglycosides: 8th cranial nerve and kidney
Tetracyclines: Liver and kidney damage, antianabolic
2. Hypersensitivity reactions:
Practically all AMAs are capable of causing
hypersensitivity reactions. These are unpredictable
and unrelated to dose. The more commonly involved
AMAs are penicillins, cephalosporins, sulfonamides.

3. Drug resistance: refers to unresponsiveness of a

microorganism to an AMA.

Natural resistance: Some microbes have always been

resistant to certain AMAs. They lack the metabolic
process or the target site which is affected by the
particular drug. This is generally a group or species
characteristic, e.g. gram negative bacilli are normally
unaffected by penicillin G,

Acquired resistance: It is the development of

resistance by an organism due to the use of an AMA
over a period of time. e.g. staphylococci, coliforms,
tubercle bacilli.

Mutation: It is a stable and heritable genetic change

that occurs spontaneously and randomly among
microorganisms. It is not induced by the AMA. e.g.
when an antitubercular drug is used alone.

Mutation and resistance may be:

Single step: A single gene mutaton may confer high
degree of resistance; emerges rapidly, e.g.
enterococci to streptomycin, E. coli and Staphylococci
to rifampin.

Multistep: A number of gene modifications are

involved; sensitivity decreases gradually in a stepwise
manner. Resistance to erythromycin, tetracyclines and
chloramphenicol is developed by many organisms in
this manner.

Gene transfer: can occur by

Conjugation: occurs by Sexual contact & is common
among gram negative bacilli of the same or another
species. This may involve chromosomal or extrachromosomal (plasmid) DNA. The gene carrying the
resistance or R factor is transferred only if another

Transduction: It is the transfer of gene carrying

resistance through bacteriophage. The R factor is taken
up by the phage and delivered to another bacterium
which it infects.

Transformation: A resistant bacterium may release the

resistance carrying DNA into the medium and this may
be imbibed by another sensitive organism becoming
unresponsive to the drug.

Resistant organisms can be :

Drug tolerant: Loss of affinity of the target biomolecule
of the microorganism for a particular AMA, e.g. certain
penicillin resistant pneumococcal strains have altered

Drug destroying : The resistant microbe elaborates an

enzyme which inactivates the drug, e.g.-lactamases
are produced by Staphylococci, Haemophilus, and
Gonococci etc. which inactivate penicillin G.

Drug impermeable : many hydrophilic antibiotics gain

access into the bacterial cell through specific
channels formed by proteins called porins, or need
specific transport mechanisms.

These may be lost by the resistant strains, e.g.

concentration of some aminoglycosides and
tetracyclines in the resistant gram negative bacterial
strains has been found to be much lower than that in
their sensitive counterparts when both were exposed
to equal concentrations of the drugs.

Adaptive resistance : a kind of rapidly developing and

reversible resistance based on phenotypic alteration
in the bacteria, not involving genetic change has been
described for aminoglycosides, particularly in
Pseudomonas aeruginosa.

Cross resistance:
Acquisition of resistance to one AMA conferring
resistance to another AMA, to which the organism has
not been exposed, is called cross resistance.

Cross resistance may be two way, e.g. between

erythromycin and clindamycin or one way, e.g.
development of neomycin resistance by
enterobacteriaceae makes them insensitive to
streptomycin but many streptomycin resistant
organisms remain susceptible to neomycin.

Prevention of drug resistance:

No indiscriminate and inadequate or
unduly prolonged use of AMAs should
be made.

rapidly acting and narrow

spectrum AMAs whenever possible;
broad spectrum drugs should be
used only when a specific one cannot
be determined or is not suitable.


combination of AMAs whenever

prolonged therapy is undertaken, e.g.

4. Superinfection :appearance of a new infection as a

result of antimicrobial therapy.
it is commonly associated with the use of broad
spectrum antibiotics, such as tetracyclines,
chloramphenicol, ampicillin, newer cephalosporins;
especially when combinations of these are employed.
5. Nutritional deficiencies:
Some B complex group of vitamins and vit K is
synthesized by the intestinal flora is utilized by man.
Prolonged use of antimicrobials which alter this flora
may result in vitamin deficiencies.
Neomycin causes morphological abnormalities in the
intestinal mucosa steatorrhoea and malabsorption


Masking of an infection:

A short course of an AMA may be

sufficient to treat one infection but
only briefly suppress another one
contacted concurrently. The other
infection will be masked initially, only
to manifest later in a severe form.
Examples are :
Syphilis masked by the use of a
single dose of penicillin which is
sufficient to cure gonorrhoea.

Bacteriological sensitivity testing:

This is generally done by disk-agar diffusion method using
standardized concentrations of antibiotics bases on clinically
attained plasma concentrations of these.
Minimum inhibitory concentration (MIC) i.e. the lowest
concentration of an antibiotic which prevents visible growth of a
Minimum bactericidal concentration (MBC) is the concentration of
the antibiotic which kills 99.9% of the bacteria.
A small difference between MIC and MBC indicates that the
antibiotic is primarily bactericidal, while a large difference
indicates bacteriostatic action.

Postantibiotic effect (PAE) After a brief exposure if the organism is

placed in antibiotic free medium, it starts multiplying again but
after a lag period which depends on the antibiotic as well as the
organism. This lag period in growth resumption is known as
postantibiotic effect. A long postantibiotic effect has been noted
with fluoroquinolones, aminoglycosides and -lactam antibiotics.

Combined use of antimicrobials: objectives are :

1.To achieve synergism: Depending on the drug pair as well as the
organism involved, synergism, additive action, indifference or
antagonism may be observed when two AMAs belonging to
different classes are used together.

Synergism may manifest in terms of decrease in the MIC of one

AMA in the presence of another, or the MICs of both may be
lowered. If the MIC of each AMA is reduced TO 25% or less, the
pair is considered synergistic, 25-50% of each is considered
additive and more than 50% of each indicates antagonism.
General guidelines are :

Two bacteriostatic agents are often additive or synergistic, i.e.

combination of tetracyclines, chloramphenicol, erythromycin

Two bactericidal drugs are frequently additive if the organism is

sensitive to both e.g. Rifampin + isonizid in tuberculosis.
Combination of a bactericidal with a bacteriostatic drug may be
synergistic or antagonistic depending on the organism.

If the organisms is highly sensitive to the cidal drug response

to the combination is equal to the static drug given alone
(apparent antagonism), because cidal drugs act primarily on
rapidly multiplying bacteria, while the static drug retards
multiplication. This has been seen with penicillin + tetracycline.
If the organism has low sensitivity to the cidal drug synergism
may be seen, e.g. :Penicillin + sulfonamide for actinomycosis
Thus, wherever possible, synergistic combinations may be
used to treat infections that are normally difficult cure.

2.To reduce severity or incidence of adverse effects : This is possible

only if the combination is synergistic so that the doses can be
reduced. Streptomycin + penicillin G for SABE due to Strep.
3.To prevent emergence of resistance : Mutation conferring resistance
to one AMA is independent of that conferring resistance to
4.To broaden the spectrum of antimicrobial action : This is needed in :
Treatment mixed infection:
Initial treatment of severe infections

Disadvantages of Antimicrobial Combinations :

They foster a casual rather than rational outlook in the
diagnosis of infections and choice of AMA.
Increased incidence and variety of adverse effects.
Increased chances of superinfections.
If inadequate doses of nonsynergistic drugs are usedemergence of resistance may be promoted.
Increased cost of therapy.

Failure of chemotherapy :

Improper selection of drug, dose, route or duration of


Treatment begun too late.

Failure to take necessary adjuvant measures.

Poor host defence as leukemias, neutropenia and other

Infecting organism present behind barriers, such as vegetation
on heart valves (SABE), inside the eye ball, blood brain barrier.
Trying to treat untreatable (viral) infections or other causes of
fever (malignancy, collagen diseases).


-lactam antibiotics: These are the antibiotics having -lactam ring

Its chemical structure was determined by Dorothy In the early

1940s enabling synthetic production.

Florey and chain with Fleming got Nobel Prize in 1945 in medicine

Penicillin was isolated from the penicillum notatum mold.

five groups of antibiotics, with the -lactam nucleus are





Chemistry: Basic nucleus of penicillin consists of (6-aminopenicillamic

Thiazoldine ring

-lactam ring

Attachment of different chemical moieties (R) through the amino

group of 6-aminopenicilliamic acid produces different derivatives of

Cephalosporin - -lactam ring fused with a six member ring

structure that contains an additional substitution site (R2)

Monobactams contains substituted -lactam ring and an ionizing

acid moiety indicating that this is the minimal structure required
for antibiotic activity.

Carbapenems resembles penicillins with two important

the stereochemistry at the carbon in the lactam ring is
there is no hetero atom in the equivalent position of A ring

lactam ring is absolutely required for antibiotic efficacy,


All -lactam antibiotics interfere with the synthesis of Bacterial
cell wall. The bacteria synthesize N- acetylmuramic acid & Nacetyl glucoseamine. The peptidoglycan residue are linked
together forming long strands. The final step is cleavage of the
terminal D alanine of the pepide chains by transpeptidases; this
cross linking provides stability & rigidity to the cell wall.
The -lactam antibiotics inhibit the transpeptidases so that
crosslinking does not take place. When bacteria divide in the
presence of a -lactam antibiotics cell wall deficient (CWD) forms
are produced. Because interior of cell wall is hyperosmotic the
CWD forms swell & burst causing bacteriolysis.
-lactam resistance:
Production of a -lactamase:
By Hydrolysing the lactam bond of -lactam antibiotics and
rendering the drug inactive
Resistance to -lactam antibiotics due to the production of a lactamase can be
Chromosomally mediated OR
Plasmid mediated - Can be transferred to other organism
by R-factors

Mutations that affect outer membrane permeability:

In gram negative bacteria:

Proteins called porins form hydrophilic channels or pores in the
outer membrane through which antibiotics and other
substances can enter

Mutations in these proteins decrease permeability

Increased resistance.

Inability to activate all the lytic enzymes: Normally antibiotic

inhibits peptidoglycan synthesis and activate autolysis which
degrade existing peptidoglycan. in some species staph and
strepto the enzymes will be inhibited but not killed and can
grow back following the cessation of -lactam antibiotics.

Mutations in Penicillin binding proteins lower their affinity for lactam antibiotics:

These new Penicillin binding proteins can arise from



1.Natural penicillins

Penicillin G (benzyl penicillin)

Procaine penicillin-G

Benzathine penicillin-G
2.Acid resistant penicillins

Phenoxymethyl penicillins (penicillin V)

Phenoxyethyl penicillins (Phenethicillin)

3.Penicillinase resistant penicillins
1. Methicillin.
2. Oxacillin
4. Dicloxacillin
5. Flucloxacillin

3. Cloxacillin
6. Nafcilin

4.Penicillins effective against gram positive and some gram negative


1. Ampicillins
2. Amoxycillins

3. Talampicillin
4. Pivampicillin
5.Extended spectrum penicillins
Carboxy penicillins a) Cerbenicillin b) Ticarcillin
a) Piperacillin
b) Mezlocillin
Amidinopenicillins a) Mecillinam
b) Pivmecillinam
6.Penicillins with betalactamase inhibitors

Amoxicillin clavulinic acid (augmentin)

Ticarcillin- clavulinic acid

Classification based on their spectra of antimicrobial activity

1.Active against gram negative and readily hydrolyzed by penicillinase

Penicillin G

Penicillin V

2.Penicillinase resistant penicillins Methicillin, Cloxacillin, Oxacillin

3.Active against gram negative organisms- 1.Ampicillin

2. Amoxicillin
4.Carbenicillin and ticarcillin
Active against pseudomonas enterobacter and proteus
5.Mezlocillin, azlocillin and piperacillin pseudomas klebsiella

Adverse effects:
Minor reactions
Nausea, Vomiting, inflammatory reaction at the site of
injection (pain, aching), Diarrhea
Local reaction-Erythema, Induration
Prolonged injury-Thrombophlebitis
Accidental IV procaine PnG-Anxiety, Mental disturbances,
Major reactions:
Allergy and anaphylaxis, Jarish herxheimer reaction, Super
Hyperkalemia, Acute non-allergic reactions,
Twitchings, Auditory and visual
If insoluble procaine particles deposited in the lungs
produce small pulmonary infarcts
Large doses of PnG may cause irritation of CNS
PnG large doses if injected in uremic patients

Available in the form of its water soluble Na+ and K+ salts
Dry state Stable for years
Aqueous solution

Require refrigeration and deteriorates considerable within 72

Absorption, fate and excretion:

Inactivated to a significant amount by gastric acid

Drug absorbed from the duodenum

Only small proportion found in feces

oral dosage should be 4-5 times larger than IM dose

Food interferes with its absorption, so it should be given orally at

least 30 minutes before or 2 to 3 hours after a meal.

In infants, gastric acidity is lower than in adults and hence, higher

blood levels are achieved relatively early on oral administration.

IM or I/V
Rapidly absorbed
Peak plasma level is reached within 15 to 30 minutes and drug disappears
from plasma by 3 to 6 hours

Use in Lozenges and Troches contraindicated because of high risk of


Penicillin widely distributed in the body after absorption.

Very high concentrations are detected in kidney

Significant amounts are seen in bile, liver, intestine, skin

While brain, bone marrow, skeletal and cardiac muscles contain

smaller amounts

Drug penetrates poorly into the serous cavities, ocular pericardial,

pleural, peritoneal fluids

But in the presence of inflammation, the concentrations in these fluids is


BBB blood brain barrier is not readily crossed by the drug but
therapeutically enough drugs are passed in meningeal infections,
trasverses the placental barrier.

In plasma
60% bound to albumin bacteriologically inactive & 40% Free form
30% parental dose metabolized in the body and small amounts
appear in bile, milk and saliva major portion is eliminated by the
50% of drugs elimination occurs within 1st hour
Plasma half life 30 minutes.
20% of oral penicillin detected in urine
Prolonged plasma levels seen in neonates and infants.
Probenecid an uricosruric agent, competes with penicillin for
tubular transport and can promote higher blood levels by
delaying its excretion.
Preparation & dosage:
Benzylpenicillin (penicllin G) injection contains 5,00,000 units of
drug per ml 0.5mu im/iv 6-12 hourly Benzyl penicillin 0.5
IM units

Benzyl penicillin tablet contains 50,000 to 5,00,000 units

Dose 2,00000 to 4,00000 units 4 hourly

Repository preparation:
Procaine benzylpenicillin injection available in powder form to be
suspended in distilled water prior to injection.
Dose 6,00,000 units daily by IM injection.
Aqueous solution are stable for many months at temperature
below 25C
Forfitied benzylpenicillin forfied PP inj. 3 + 1 lakh unit Inj. contain
a mixture of 3,00000 units of procaine benzyl penicillin and
1,00000 units of benzyl penicillin per ml.
Benzithine penicillin (penidure, benapen)

A dose of 1.2 million units produce detectable blood levels of upto 3 weeks.

When administered orally in the dose of 29mg/day in divided along
with penicillin raises its plasma level to two fold to 4 fold.
Therapeutic plasma levels of penicillin are maintained for
approximately twice as long with Probencid. Probencid is capable
of producing allergic reactions, so not recommended in children
under 2 years of age.

Therapeutic use:
Pneumococcal pneumonia
Pneumococcal empyema and pericarditis
Penumococal meninigitis
Streptococcal infections
Acute otitis media
Streptococcal osteomyelitis and arthritis
Streptococcal SABE
Staphylococcal infections
Meningococcal meningitis
Penicillin prophylaxis
Rheumatic fever and streptococcal infections

Potassium phenoxymethyl penicillin (penicillin V)

Similar antibacterial spectrum like penicillin G

More active against resistant staphylococci

Less inactivated by gastric acid

Plasma levels achieved is 4 to 5 times higher than benzylpenicillins

50-70% of the drug is bound to the plasma proteins

Nearly 25% of the drug is eliminated by a similar fasthion as benzylpenicillin

Freely soluble in water

250 to 500mg 4 to 8th hourly at least 30 minutes before food.

Infants 60mg, Children 125-250mg

Given in less serious condition due to penumococci and streptococci and in infections which
require a prolonged treatment.

Less active than penicillin G against gonococci H-influenzae species and hence not used in


These have side chains that protect the -lactam ring from

Non penicillinase producing organisms are less sensitive to these

than penicillin G.

Drug of choice in penicillinase producing organisms


Not resistant to gram negative -lactamases


IM or IV slow infusion 1gm 4-6 hours

Highly penicillinase resistant but not acid resistant

Must be injected

Its also an inducer of penicillinase production

Methicillin resistant staphylococcus aureus (MRSA) have

It has a side chain, has weak antibacterial activity & acid resistant
than benzyl penicillin-G. Food interferes with absorption.
peak plasma level occurs within an hour and persists for 4-6
Drug distributed throughout the body but highest concentration
in the kidney and 90-95% bound to plasma proteins 30% of single
dose excreted in the urine.
Over 95% of the 24 hour urinary excretion occurs within first 6
Significant amounts are excreted in the bile
Less active against penicillin G sensitive organism
More active against penicillinase producing organisms but not
against MRSA

Dose: 0.5 to 1gm orally 6 hours, 0.25-1gm inj IM/IV to get

higher blood levels
Children 50-100mg/kg daily divided into 4-6 portions.
Drug administration 1 hour before or 2 hour after food
250-5mg IM or IV bolus 4-6 hourly


This drug is the prototypical agent of the group
Antibacterial action similar to PnG. more effective against gram
negative bacteria than PnG.
Gram positive less sensitive than PnG
Effective against: H. influenzae, Strep viridians,, Nesseria
Inactivated by penicillinase
Absorption, Fate, Excretion:
Water soluble and acid resistant
Readily but incompletely absorbed by oral route
Food does not interfere with its absorption.
Peak plasma levels reached within 2 hours and 1 hours
respectively after administration of a single and IV or IM dose
Drug persists in the plasma for 6 to 8 hours and only 20% bound to
plasma protein.
Excreted unchanged in urine and high concentrations are present
in bile
In premature and very young infants excretion delayed.
Drug crosses placental barrier and achieves therapeutic
concentration in the amniotic fluid

Adverse effect:
Similar to penicillin
Skin rashes, Diarrhea common with oral administration
Therapeutic uses:
1. UTI:
2. Respiratory tract infection
3. Meningitis and SABE
4. Biliary tract and intestinal infections
5. Miscellaneous:

Better than tetracyclines in pregnant women and infants

Intestinal malabsorption and whooping cough it is better than


Effective on oral administration

Blood levels are twice as higher those after similar dose of


Absorption not influenced by food

Less highly protein bound

Urinary excretion higher than that of ampicillin

The antimicrobial spectrum of amoxicillin is essentially identical to

that of ampicillin; with the important exception that amoxicillin
appears to be less effective than ampicillin for shigellosis.

the incidence of diarrhea with amoxicillin is less than that following

administration of ampicillin.

Probencid delays excretion of the drug.

Therapeutic Indications for the Aminopenicillins.

1Upper Respiratory Infection.

2. Urinary Tract Infection.

3. Meningitis

4. Salmonella infections


Carboxypenicillins,Urido penicillins,Amidino penicillins

Highly active against anaerobes

Useful in pseudomonas aeruginosa infection and other gram

negative infections

Act synergistically with aminoglycoside particularly against

pseudomonas aeruginosa, enterobacterioceae

CNS penetration 10% of their serum levels and hence not

recommended in treatment of meningeal infections

They may inactivate aminoglycoside in patients with renal


P.aeruginosa may develop resistance but prevented by giving



Similar spectrum but less antibacterial activity than ampicillin, but

advantages over ampicillin is effective against all strains of proteus
and pseudomonas aeruginosa.

It is inactivated by penicillinase

Acid labile so has to be administered by parenteral route

IM Peak plasma levels within 2 hours and eliminated in urine within

6 hours

47% bound to plasma proteins

Dose 2gm 6 hourly IM

Slow IV injection or rapid infusion in severe systemic infections in

dose of 5gm 4-6 hourly or combined with aminoglycosides

Drug can cause CCF because of large Na+ content of the drug and
bleeding because of abnormal platelet aggregation.


Beta lactamase sensitive

Broad spectrum of activity against gram negative bacilli Ps.

Aeruginosa (3 times more active than ticarcillin)

Regarded as one of the most broadly active of the currently

available penicillins with regard to other bacterial species
especially proteus, klebsiella, bacterioids fragilis, H. influenza,

Acid labile given parenterally

70-90% excreted in urine by GFR and tubular secretion hence in

renal damage adjustments should be made

crosses BBB used in neonatal meninigits



Obtained from streptomyces clavuligerus

it has a -lactam ring but no antibacterial activity of its own.
It inhibits a wide variety of -lactamases produced by both
gram-positive and gram negative bacteria.
Progressive Suicide Inhibitor
Reestablishes the activity of amoxicillin against -lactamase
producing resistant staph. aureus, peptococcus, H. influenzae,
N. gonorrhoae, E.coli, proteus, klebsiella, salmonella, shigella
and bact. Fragilis.
Amoxicillin sensitive strains are not affected by the addition of
clavulnaic acid.


It is a semisynthetic -lactamase
Absorption of sulbactam is inconsistent.
Therefore, it is preferably given
Indications are:
PPNG; sulbactam per se inhibits N.
Mixed aerobic-anaerobic infections, tooth
abscess, intra-abdominal, gynaecological,


First used clinically in the early 1960s.

They have an important role in the modern treatment

of bacterial infections.

A wide variety of cephalosporins have become


Semisynthetic antimicrobial agents closely related to

the penicillins.

Commercially available cephalosporins contain the 7amino cephalosporanic acid nucleus.


Generation Cephalosporins.




Generation Cephalosporins.


Generation Cephalosporins.



active vs gram positive cocci.


activity against gram negative bacteria.

not penetrate the CNS.


is via the kidney and dose adjustments must

be made for impaired renal function.


agents are used primarily for prophylaxis in

various surgical procedures.


drugs used for minor staph infections or some

polymicrobial infections.


for gram negative infections.



gram negative coverage (less

active vs gram positive organisms).


orally and parenterally available



penetration into the CNS.


adjustments must be made in renal


of gram negative infections.

Ceftriaxone and ceftazidime


gram-negative coverage.


and ceftazidime have excellent activity vs



the blood brain barrier well.


and the necessary dosing intervals vary greatly

(ceftriaxone once every 24h).


are excreted by the kidney and require dosage adjustment

(cefoperazone and ceftriaxone are exceptions).

wide variety of serious infections caused by organisms resistant

to other drugs. Gonorrhea, Meningitis.


neutropenic febrile immunocompromised patients (with an



to the 3rdgen. cpds, but more

resistant to hydrolysis by some betalactamases.


penetration into the CSF.


mainly by the kidneys.


use similar to the third

generation cephalosporins.


Sulfonamides: Sulfonamides were the first AMAs effective against

pyogenic bacterial infections.

Sulfonamido-chrysoidine (Prontosil Red) was one of the dyes

included by Domagk to treat experimental streptococcal infection in
mice and found it to be highly effective.

He subsequently cured his daughter of streptococcal septicaemia

By prontosil.

By 1937 A large number of sulfonamides were produced and used

extensively, but because of rapid emergence of bacterial resistance
and the availability of many safer and more effective antibiotics,
their current utility is limited, except in combination with
trimethoprim or pyrimethamine.

Chemistry : All sulfonamides may be considered to be derivatives of

sulfanilamide (p-aminobenzene sulfonamide). Individual members
differ in the nature of N1 (Sulfonamido N) substitution, which
governs solubility, potency and pharmacokinetic property. A free
amino group in the para position (N4) is required for antibacterial

Sulfonamides are classified as

Short acting (4-8 hr) : Sulfadiazine

Intermediate acting (8-12 hr) : Sulfamethoxazole, Sulfamoxole

Long acting (7 days) : Sulfadoxine, Sulfamethopyrazine

Antibacterial spectrum :Sulfonamides are primarily bacteriostatic
against many gram positive and gram negative bacteria.
However, bactericidal concentrations may be attained in
Sensitive are :Many Strepto pyogenes, Haemophilus influenze,
few Staph. aureaus, gonococci, meningococci, pneumococci,
Escherichia coli, and Shigella, but majority are resistant .
Mechanism of action : Sulfonamides, being structural analogues
of PABA, inhibit bacterial folate synthetase FA is not formed
and a number of essential metabolic reactions suffer.
Being chemically similar to PABA, the sulfonamide may itself get

Resistance to sulfonamides : Most bacteria are capable of

developing resistance to sulfonamides. Prominent among these are
gonococci, pneumococci, Staph, aureus, meningococci, E. coli,
Shigella and some Strep. pyogenes.

The resistant mutants either :

Produce increased mounts of PABA, or

Their folate synthetase enzyme has low affinity for sulfonamides,


Adopt an alternative pathway in folate metabolism.

Development of resistance has markedly limited the clinical

usefulness of this class of compounds

Pharmacokinetics :

Sulfonamides are rapidly and nearly completely

absorbed from g.i.t. Extent of plasma protein binding
differs considerably. The highly protein bound members
are longer acting.

Sulfonamides are widely distributed in the body enter

serous cavities easily. attains the same concentration in
CSF as in plasma. They cross placenta freely.

The primary pathway of metabolism of sulfonamides is

acetylation at N4 by nonmicrosomal enzyme, primarily
in liver.

Sulfonamides are excreted mainly by the kidney

through glomerular filtration. Both renal tubular

Sulfadiazine : It is the prototype of the general purpose

sulfonamides which are rapidly absorbed orally and rapidly
excreted in urine. It is 50% plasma protein bound and 20-40%
acetylated. The acetylated derivative is less soluble in urine,
crystalluria is likely. It has good penetrability in brain and CSF-was
is the preferred compound for meningitis.
Dose : 0.5 g QID to 2g TDS;

Sulfamethoxazole : It has slower oral absorption and urinary

excretion intermediate duration of action, t in adults averages
10 hours. It is preferred compound for combining with
trimethoprim because the t of both is similar. However, a high
fraction is acetylated, which is relatively insoluble-crystalluria can
Dose : 1 g BD for 2 days, then 0.5 g BD.

Sulfamoxole : It has properities similar to sulfamethoxazole and is

employed when a sulfonamide alone has to be used for respiratory
or urinary tract infection.
Dose : 1 g BD on first day, then 0.5 g BD.
SULFUNO 0.5 g tab.

Sulfadoxine, Sulfamethopyrazine : These are ultralong acting

compounds, action lasting > 1 week because of high plasma
protein binding and slow renal excretion (t 5-9 days). They
attain low plasma concentration and are not suitable for
treatment of acute pyogenic infections.

Adverse effects :
Nausea, vomiting and epigastirc pain.
Crystalluria is dose related.
Hypersensitivity reactions occur in 2-5% patients.
Steven-johnson syndrome and exfoliative dermatitis are more
common with long acting agents.
Contact sensitization.
Sulfonamides cause haemolysis & Kernicterus.
Interactions :Sulfonamides inhibit the metabolism of phenytoin,
tolbutamide and warfarin enhance their action.

Uses :
Systemic use of sulfonamides alone is rare now.

Though they can be employed for suppressive therapy

of chronic urinary tract infection, for streptococcal
pharyngitis, gum infection and as second, choice drug
in lymphogranuloma venereum.

Combined with trimethoprim (as cotrimoxazole)

sulfamethoxazole is used for many bacterial infections,
P. carinii and nocardiasis.

Ocular sulfacetamide sod. (10-30%) is a cheap

alternative in trachoma/inclusion conjunctivitis, Topical
silver sulfadiazine or mafenide are used for preventing
infection on burn surfaces.

The fixed dose combination of trimethoprim and sulfamethoxazole
is called cotrimoxazole. selectively inhibits bacterial dihydrofolate
reductase (DHFRase).

Cotrimoxazole introduced in 1969 causes sequential block of

folate metabolism.

human folate metabolism is not interfered at antibacterial

concentrations of trimethoprim.

Individually both sulfonamide and trimethoprim are bacterisotatic,

but the combination becomes cidal against many organisms.

Sequential block in bacterial folate metabolism

Sulfamethoxazole was selected for combining with trimethoprim

because both have nearly the same t (~10hr).

Optimal synergy is exhibited at a concentration ratio of

sulfamethoxazole 20 : trimethoprim 1.

the MIC of each component may be reduced by 3-6 times. This

ratio is obtained in the plasma when the two are given in a dose
ratio of 5:1, because trimethoprim enters many tissues, has a
larger volume of distribution than sulfamethoxazole and attains
lower plasma concentration.

Trimethoprim adequately crosses blood brain barrier and placenta,

while sulfamethoxazole has a poorer entery.

trimethoprim is more rapidly absorbed than sulfamethoxazole.

Trimethoprim is 40% plasma protein bound, while
sulfamethoxazole is 65% bound.

Trimethoprim is partly metabolized in liver and excreted in urine

Spectrum of action ;
Antibacterial spectra of trimethoprim and sulfonamides
overlap considerably.
Additional organisms covered by the combination are-S.
typhi, Serratia, Klebsiella, Enterobacter, Pneumocystic
carnii and many sulfonamide resistant strains of Staph
aureus, Strep, pyogenes, Shigella, enteropathogenic E.
coli, H. influenzae, gonococci and meningococci.
Resistance : Bacteria are capable of acquiring
resistance to trimethoprim mostly through mutational
or plasmid mediated acquisition. Slow to develop
compared to either drug along. Widespread use of the
combination has resulted in reduced responsiveness of
over 20% originally sensitive strains.

Adverse effects :
Nausea, vomiting, stomatitis, headache and rashes
Blood dyscrasias occur rarely.
It should not be given during pregnancy :
Patients with renal disease may develop uremia.
A high incidence of fever, rash and bone marrow
hypoplasia due to cotrimoxazole has been reported
among AIDS patients with Pneumocystis carinii
The elderly are also at greater risk of bone marrow
toxicity from cotrimoxazole.
Diuretics given with cotrimoxazole have produced a
higher incidence of thrombocytopeina.



Trimethoprim80 mg +Sulfamethoxazole 400 mg tab : 2 BD for 2

days then 1 BD.
Uses :
Cotrimoxazole Common indications are :

1.Urinary tract infections.

2.Respiratory tract infections
4.Bacterial diarrhoeas and dysentery
6.Granuloma inguinale
7.Pueumocystis carinii.


These are entirely synthetic antimicrobials having a

quinolone structure that are active primarily against
gram negative bacteria.

The first member Nalidixic acid introduced in mid

1960s had usefulness limited to urinary and G.I. tract
infections because of low potency, modest blood and
tissue levels, limited spectrum and high frequency of
bacterial resistance.

A breakthrough was achieved in the early 1980s by

fluorination of the quinolone structure at position 6
and introduction of a piperazine substitution at
position 7 resulting in derivatives called
fluoroquinolnes with high potency, expanded
spectrum, slow development of resistance, better
tissue penetration and good tolerability.

Nalidixic acid:

It is active against gram negative bacteria, specially coliforms : E.

coli, Proteus, Klebsiella, Enterobacter, Shigella but not

It acts by inhibiting bacterial DNA gyrase and is bactericidal.

Resistance to nalidixic acid develops rather rapidly.

Nalidixic acid is absorbed orally, highly plasma protein bound and

partly metabolized in liver; It is excreted in urine with a plasma t
8hrs .

Fist generation fluoroquinolones:

Norfloxacin, Ofloxacin, Ciprofloxacin, Pefloxacin
Second generation fluoroquinolones:
Lomefloxacin, Levofloxacin, Sparfloxacin, Moxifloxacin

Mechanism of action:
The FQs inhibit the enzyme bacterial DNA gyrase. The DNA gyrase
consists of two A and two B subunits; FQs bind to A subunit with
high affinity and interfere with its strand cutting and resealing
Greater affinity for topoisomerase IV may confer higher potency
against gram positive bacteria.
The bactericidal action probably results from digestion of DNA by
exonucleases whose production is signaled by the damaged DNA.
Mechanism of resistance : Resistance noted so far is due to
chromosomal mutation producing a DNA gyrase or topoisomerase
IV with reduced affinity for FQs, or due to reduced permeability /
increased efflux of these drugs across bacterial membranes.

ciprofloxacin :
It is the most potent first generation FQ active against a broad
range of bacteria; the most susceptible ones are the aerobic gram
negative bacilli, especially the enterobacteriaceae and Neisseria.
gram positive bacteria are inhibited at relatively higher

Highly susceptible: E. coli, N. gonorrhoea K. pneumoniae N.

meningitides Enterobacter H. Influenzae
Moderately susceptible :
Pseudomonas aeruginosa, Legionella, Staph. Aureus, Brucella
The remarkable microbiological features of ciprofloxacin are :
Rapid bactericidal activity and high potency
Relatively long post-antbiotic effect on enterobacteriaceae,
Pseudomonas and Staph.
Low frequency of mutational resistnace.
Low propensity to select plasmid type resistant mutants.
Protective intestinal streptococci and anaerobes are spared
Active against many lactam and aminoglycoside resistant
Less active at acidic pH.

Pharmacokinetics :
Ciprofloxacin is rapidly absorbed orally, but food delays absorption,
and first pass metabolism occurs.
The most prominent feature of ciprofloxacin is high tissue
penetrability: concentration in lung, sputum, muscle, bone,
prostate and phagocytes exceeds that in plasma, but CSF and
aqueous levels are lower.
It is excreted primarily in urine.
Adverse effects: Ciprofloxacin has good safety record
nausea, vomiting, bad taste, anorexia.
dizziness, headache, restlessness, anxiety, insomnia, impairment
of concentration
rash, pruritus, photosensitivity, urticaria.
Interactions :
Plasma concentration of theophylline, caffeine and warfarin are
increased by ciprofloxacin due to inhibition of metabolism : toxicity
of these drugs can occur.
NSAIDs may enhance the CNS toxicity of FQs.
Antacids, sucralfate and iron salts given concurrently reduce
absorption of FQs.


tab, 200 mg/100 ml i.v. infusion,
Uses: 1.Urinary tract infections.
4. Bacterial gastroenteritis

It can also be used to treat.

1. Bone, soft tissue, gynaecological and wound infections
2. Respiratory infections
3. Tuberculosis
4. Gram negative septicaemias
5. Meningitis
6. Prophylaxis
7. Conjunctivitis

Norfloxacin :less potent than ciprofloxacin, Many Pseudomonas

and gram positive organisms are not inhibited at clinically attained
concentrations. Moreover, it attains lower concentration in tissue.
It is metabolized as well as excreted unchanged in urine.

Norfloxacin is primarily used for urinary and genital tract infection.

It is also good for bacterial diarrheas, because high concentrations
are present in the gut and anaerobic flora is not disturbed.


200, 400 mg tab.

Ofloxacin :Another FQ; intermediate between ciprofloxacin and

norfloxacin in activity against gram negative bacteria. is
comparable to or more potent than ciprofloxacin for gram positive

Good activity against Chlamydia and Mycoplasma has been noted :

it is an alternative drug for nonspecific urethritis, cervicitis and
atypical pneumonia. It is highly active against M. leprae : is being
used in alternative multidrug therapy regimens.

Ofloxacin is relatively lipid soluble; and bioavailability is high :

attains higher plasma concentrations. Food does not interfere with
its absorption. It is excreted largely unchanged in urine; dose

Sparfloxacin :It is a second generation difluorinated quinolone with enhanced

activity against gram positive bacteria Bacteroides fragilis, other
anaerobes and mycobacteria.

Its major indications include pneumonias, exacerbations of chronic

bronchitis, sinusitis and other ENT infections.

It has caused a higher incidence of phototoxic reaction : Should be

avoided in patients taking cisapride, tricyclic antidepressants, etc.

Because of longer t it is suitable for single daily dosing.

TOROSPAR 200, 400 mg tab; SPARTA, SPARQUIN, SPARDAC 100, 200 mg


Gatifloxacin : Another 2nd generation FQ that has excellent activity

against Strep. Pneumoniae, Chlamydia pneumoniae and certain
anaerobes. A greater affinity for topoisomerase IV may be responsible for
improved activity against gram positive cocci.

The major indication of gatifloxacin is community acquired pneumonia,

exacerbation of chronic bronchitis, and other upper/lower respiratory tract
infections. It has also been used in urinary tract infections and
gonorrhoea. Its t is 8 hr.

Dose : 400 mg on 1st day, followed by 200-400 mg OD, oral or i.v.

Basic & Clinical Pharmacology 12th ed :
Oral & Maxillofacial Infections 4th ed :
Essential of medical pharmacology 5th ed :
The pharmacological basis of therapeutics
10th ed : Goodman & gilman

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