Chemotherapy

&
Antimicrobial drugs
Learning objectives:
• define – chemotherapy,
• classify – antimicrobial drugs
• how antimicrobials act
• principles of optimal antimicrobial therapy
• Use of antimicrobial drugs: combinations,
chemoprophylaxis, pre-emptive suppressive therapy
• Special problems with antimicrobial drugs:
resistance, superinfection, masking of infection
• Chemotherapy: The term chemotherapy is used for the
drug treatment of infections in which the infecting
agents (viruses, bacteria, protozoa, fungi and
helminthes) are destroyed or removed without injuring
the host. The term is also used to include therapy of
cancer.
Antibiotics: Antibiotics are the substances produced
by various species of microorganism (bacteria,
fungi) that suppress the growth of other
microorganism. Ex – penicillin.

Chemotherapeutics: are chemical substances that

are obtained from synthetic source and are
intended to be toxic for the pathogenic organism
but innocuous to the host. Ex- sulfonamide.
Classification of antimicrobial drugs:
According to type of organism against which they are
active –
1. Antibacterial drugs
2. Antiviral drugs
3. Antifungal drugs
4. Antiprotozoal drugs
5. Anthelminthic drug
Antimicrobial drugs have been broadly classified
into –

1. Bacteriostatic drugs – those that act primarily

by arresting bacterial multiplication
eg- sulfonamide, tetracycline, chloramphenicol.

2. Bactericidal drugs – those which act primarily

by killing bacteria
ex-penicillin, aminoglycosides, rifampicin.
According to mechanism of action/ site of
action:
1.Inhibition of cell wall synthesis –
penicillin, cephalosporins, vancomycin,
bacitracin, cycloserin.

2. Interference of cytoplasmic membrane

function –
polyenes - nystatin, amphotericin
azoles - fluconazole, itraconazole
3. Inhibition of protein synthesis –
act on 30S ribosomal subunit –
tetracycline, aminoglycosides

act on 50S ribosomal subunit –

chloramphenicol, macrolides, linezolid
4. Inhibition of nucleic acid synthesis –
inhibition of nucleotide synthesis –
sulfonamide , trimethoprim
inhibition of DNA synthesis –
quinolones, metronidazole
inhibition of mRNA synthesis
rifampicin
5. Other mechanism of action –
antibacterial activity –
isoniazid, ethambutal, pyrazinamide
antifungal activity –
griseofulvin, pentamidine
According to spectrum of activity –

1. Broad spectrum –
tetracycline, chloramphenicol

2. Narrow spectrum – against

gm +ve : penicillin G, penicillin V
gm –ve : aminoglycosides (gentamicin)

3. Extended spectrum – against

gm+ve, gm-ve, pseudomonas –
ticarcillin, piperacillin,
MIC: It is the lowest concentration of drug that inhibits
the growth of microorganism.

MBC: It is the lowest concentration of drug that kills

bacteria or inhibits at least 99.9% of bacterial colonies.

.
Post-antibiotic effect: Persistent suppression of bacterial
growth after limited exposure to an antimicrobial agent is
known post-antibiotic effect (PAE). Proposed mechanism
of post-antibiotic effect are –
i) slow recovary after reversible nonlethal damage to cell
structure
ii) persistence of the drug at a binding site or within the
periplasmic space
iii) the need to synthesize new enzymes before growth
can resume
• Principles of antimicrobial chemotherapy –
1. Making a diagnosis as precisely as possible and
define the site of infection, the organism responsible
and their susceptibility to a range of antimicrobial
agents.

2. Removal of barriers to cure , e.g. drainage of

abscesses, removal of obstruction in the urinary tract
and infected intravenous catheter, consideration of
removal of prosthetic devices, e.g. prosthetic joint
prosthesis.
3. Decide whether chemotherapy is really necessary.
Chronic abscesses or empyema respond poorly to
antibiotics alone and require surgical drainage

4. Selection of the best drug. This involve consideration

of the following factors –
i) specificity: indiscriminate use of broad-spectrum
antibiotics promote antimicrobial resistance and
encourages opportunistic infections
ii) pharmacokinetic factors – chosen drug is capable of
reaching to the site of infection in adequate amount
iii) patient: allergy to drug, route of excreation
5. Administering the drug in optimum dose, frequency,
appropriate route. Inadequate doses may encourage
the development of microbial resistance.

6. Continue therapy until apparent cure has been

achieved. Most acute infections are treated for 5-7
days. There are many exceptions to this , such as
typhoid fever, tuberculosis and infective endocarditis.
Relapse is possible long after apparent clinical cure
7. Test for cure – in some infection microbiological
proof of cure is desirable because disappearance of s/s
occurs before the organisms are eradicated. This is
generally restricted to especially susceptible hosts, e.g.
urinary tract infection in pregnancy. Confirmatory
culture must be done after withdrawal of
chemotherapy.

8. Prophylactic chemotherapy for surgical and dental

procedures should be of very limited duration. Often
only a single large dose being given.
9. Carrier of pathogenic or resistant organisms should
not routinely be treated to remove the organism. It
may be better to allow natural re-establishment of a
normal flora.
Use of antimicrobial drugs –
1.Best guess therapy or empirical therapy: It is defined
as use of antimicrobial agents before the pathogen
responsible for a particular disease is known.

2.Specific or definitive therapy - Administration of an

antimicrobial drug after confirming the sensitivity of
the pathogen to that drug by C/S test is called specific
therapy.
Combinations –
Treatment with a single antimicrobial is sufficient for
most infections. The indication for use of two or more
antimicrobials are:
• To avoid the development of drug resistance,
especially in chronic infections where many bacteria
are present (hence the chance of a resistant mutant
emerging is high), e.g. tuberculosis.
• To broaden the spectrum of antibacterial activity :
i) in a known mixed infection, peritonitis following gut
perforation,
ii) where the infecting organism cannot be predicted
but treatment is essential before a diagnosis reached,
septicemia complicating neutropenia or
severe community-acquired pneumonia.
• To obtain potentiation (or synergy) i.e. an effect
unobtainable with either drug alone, e.g. penicillin
plus gentamicin for enterococcal endocarditis.

• To enable reduction of the dose of one component

and hence reduce the risks of adverse drug reactions,
e.g. flucytosine plus amphotericin B for Cryptococcus
neoformans meningitis.
Chemoprophylaxis –
use of drug in a healthy person to prevent infection
by one organism of reliable and predictable
susceptibility, e.g. benzylpenicillin against a beta-
haemolytic Group A streptococcus. However, the term
chemoprophylaxis is commonly extended to include
suppression of existing infection.
The main categories of chemoprophylaxis may be
summarised as follows:
• The prevention of primary infection: rheumatic fever,
recurrent urinary tract infection
• Prevention of opportunistic infection, e.g.
pneumocystis carinii pneumonia with co-trimoxazole.
• Suppression of existing infection before it causes
overt disease, e.g. tuberculosis, malaria.
• Prevention of acute exacerbation of a chronic
infection, e.g. bronchitis, cystic fibrosis
• Prevention of spread among contacts (in epidemics
or sporadic)
Problem with antimicrobial drugs –
• Resistance
• Superinfection
• Masking of infection
Resistance:
• Microbial resistance to antimicrobials is a matter of
great importance , if sensitive strains are supplanted
(remove) by resistant ones , then a valuable drug
may become useless
• `Some are born great, some achieve greatness, and
some have greatness thrust upon them’
• Microorganism may be naturally (`born’) resistant,
`achieve’ resistance by mutation or have resistance
`thrust upon them’ by transfer of plasmids and other
mobile genetic elements
Mechanism of resistance:
• Naturally resistant strains - some bacteria are
innately resistant to certain classes of antimicrobial
agents, e.g.
i) coliforms and many other gm-ve bacteria posses
outer cell membranes which protect their cell walls
from the action of certain penicillin and cephalosporin.
ii) facultative anaerobic bacteria (E.coli) lack the ability
to reduce the nitro group of metronidazole which
therefore remains in an inactive form
• Spontaneous mutation brings about organisms with
novel antibiotic resistance mechanism.
• Transmission of genes from other organisms is the
commonest and most important mechanism –

 Genetic material may be transferred, e.g. in the form

of plasmids which are circular strands of DNA that lie
outwit the chromosomes and contain genes capable
of controlling various metabolic processes.

 Genetic transfer may occur through bacteriophages

(viruses which infect bacteria)
• Resistance is mediated most commonly by the
production of enzymes that modify the drug,
ex- b-lactamases hydrolyse penicillin,
aminoglycosides are phosphorylated by enzymes.
• Decreasing passage into the drug .
• Increasing efflux of drug from bacteria,
ex – meropenem resistance in Pseudomonas aeruginosa
• Modification of the target site so that the antimicrobial
binds less effectively .
ex- methicillin resistance in staphylococci.
• By passing of inhibited metabolic pathways,
ex- resistance to trimethoprim in many bacteria.
Limitation of resistance:
 Avoidance of indiscriminate use of antimicrobials
 Restricting use of antimicrobial combinations to
appropriate circumstances, ex- tuberculosis.
 The requirement of prescription for antimicrobials.
 Constant monitoring of resistant pattern in the hospital
or community.
 Restricting use of new drug as long as the currently
used drugs are effective.
 Avoiding transmission of resistant bacteria among
patients and stuff in hospital by proper hand hygiene
maintenance.
Superinfection :
• Clinical and bacteriological appearance of sign
symptom of new infection while treating the primary
infection.
• When any antimicrobial drug is used, there is usually
suppression of part of the normal bacterial flora of
the patient which is susceptible to the drug.
• Often, it causes no ill effects, but sometimes a drug-
resistant organism, freed from competition,
proliferates to an extent which allows an infection to
be established.
• The principal organisms responsible are Candida
albicans and pseudomonas
• Ex- antibiotic-associated (or Clostridium difficile-
associated) colitis (cephalosporins and quinolones)
• s/s – diarrhoeal stools containing blood or mucus,
abdominal pain, leucocytosis, dehydration
• Conformed by detection of C. difficile toxin in the
stools
• Treatment-
- discontinuation of the offending antimicrobial
- allowing re-establishment of the patient’s
normal flora
- metronidazole or oral vancomycin
- combined therapy with oral vancomycin and
parenteral metronidazole in the most serious cases
Opportunistic infection: arises in patients whose
immune systems are compromised or whose
phagocytic cellular defences have been reduced by
disease(e.g. AIDS, hypogammaglobulinaemia,
leukaemia) or drugs (e.g. cytotoxics).
Such infections may involve organisms that rarely or
never cause clinical disease in normal hosts. Ex-
i) pneumocystis carinii pneumonia
ii) septicemia in neutropenic patients with gut
organisms such as E coli & Klebsiella
iii) Staphylococcus epidermis infection of intravenous
catheter
Masking of infection: masking of infections by
chemotherapy is an important possibility. Ex – a course
of penicillin adequate to cure gonorrhoea may prevent
simultaneously contracted syphilis from showing
primary and secondary stages without effecting a cure,
and a serological test for syphilis should therefore be
done 3 months after treatment for gonorrhoea.
THANK YOU