Chemotherapeutic agents:

Antimicrobial agents of synthetic origin useful in the treatment of microbial or viral disease. Examples
are sulfonilamide, isoniazid, ethambutol, AZT, nalidixic acid and chloramphenicol. Note that the
microbiologist's definition of a chemotherapeutic agent requires that the agent be used for antimicrobial
purpose and excludes synthetic agents used for therapy against diseases that are not of microbial origin.
Hence, pharmacology distinguishes the microbiologist's chemotherapeutic agent as a "synthetic
antibiotic".

(1)SELECTIVE TOXICITY :- The drug should demonstrate selective toxicity. This means that, at
the optimum concentration, the drug should be toxic for the microorganism, but not for the host.
(2)ANTIMICROBIAL SPECTRUM :- The drug should be able to destroy or inhibit many kinds of
pathocenic microorganisms. The larger the number of different microbial pathogenic soedes
affected,
thebetter.
(3)NO SIDE EFFECTS :- The drug should no produce undesirable side effects, such as allergic
reactions, nerve damage, irt of the kidney or damaging blood cells etc.
(4)NO KILLING EFFECT ON NORMAL FLORA :- The drug should not eliminate the normal
icrobiat flora that inhabits the intestinal tract or other areas of the body. The normal flora also play
an
important
role
in
preventing
pathogens
form
growing.
(5)NO INACTiVATION :- If the drug is given orally, it should not be inactivated by stomach acids,
and it should be absorbed into The body from the intestinal tract. If it is administrated by injection
it
shoudbe
inactivated
by
binding
to
blood
proteins.
(6)No Development of Drug Resistance: The drug should inhibit microorganism in such a way as to
prevent the development of drug resistance forms of pathogens.
A. Narrow-spectrum antibiotics
Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a
narrow spectrum. For example, isoniazid is active only against Mycobacterium tuberculosis.
B. Extended-spectrum antibiotics
Extended spectrum is the term applied to antibiotics that are modified to be effective against grampositive organisms and also against a significant number of gram-negative bacteria. For example,
ampicillin is considered to have an extended spectrum because it acts against gram-positive and some
gram-negative bacteria.
C. Broad-spectrum antibiotics
Drugs such as tetracycline, fluoroquinolone and carbapenems affect a wide variety of microbial species
and are referred to as broad- spectrum antibiotics. Administration of broad spectrum antibiotics can

drastically alter the nature of the normal bacterial flora and precipitate a superinfection due to organisms
such as Clostridium difficile, the growth of which is normally kept in check by the presence of other
colonizing microorganisms

Drug Resistance
Bacteria are considered resistant to an antibiotic if the maximal level of that antibiotic that can be
tolerated by the host does not halt their growth. Some organisms are inherently resistant to an antibiotic.
For example, most gram-negative organisms are inherently resistant to vancomycin. However, microbial
species that are normally responsive to a particular drug may develop more virulent or resistant strains
through spontaneous mutation or acquired resistance and selection. Some of these strains may even
become resistant to more than one antibiotic.
A. Genetic alterations leading to drug resistance
Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic
information. Resistance develops due to the ability of DNA to undergo spontaneous mutation or to move
from one organism to another.
B. Altered expression of proteins in drug-resistant organisms
Drug resistance is mediated by a variety of mechanisms, such as an alteration in an antibiotic target site,
lowered penetrability of the drug due to decreased permeability, increased efflux of the drug, or presence
of antibiotic-inactivating enzymes.
1. Modification of target sites:
Alteration of an antibiotics target site through mutation can confer resistance to one or more related
antibiotics. For example, S. pneumonia resistance to -lactam antibiotics involves alterations in one or
more of the major bacterial penicillin-binding proteins, resulting in decreased binding of the antibiotic to
its target.
2. Decreased accumulation:
Decreased uptake or increased efflux of an antibiotic can confer resistance because the drug is unable to
attain access to the site of its action in sufficient concentrations to injure or kill the organism. For
example, gram-negative organisms can limit the penetration of certain agents, including -lactam
antibiotics, as a result of an alteration in the number and structure of poor in in the outer membrane. Also,
the presence of an efflux pump can limit levels of a drug in an organism, as seen with tetracycline.

3. Enzymatic inactivation:
The ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms.
Examples of antibiotic-inactivating enzymes include
1) -lactamases that hydrolytically inactivate the -lactam ring of penicillin, cephalosporin, and related
drugs;
2) Acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or
aminoglycosides; and
3) Esterase that hydrolyze the lactone ring of macrolides.

A. Isoniazid
Isoniazid, along with rifampin, is one of the two most important TB drugs.
1. Mechanism of action:
Isoniazid is a prodrug activated by a mycobacterial catalaseperoxidase (KatG). Isoniazid targets the
enzymes acyl carrier protein reductase (InhA) and -ketoacyl-ACP synthase (KasA), which are essential
for the synthesis of mycolic acid. Inhibiting mycolic acid leads to a disruption in the bacterial cell wall.
2. Antibacterial spectrum:
Isoniazid is specific for treatment of M. tuberculosis, although M. kansasii may be susceptible at higher
drug concentrations. Most NTM are resistant to INH. The drug is particularly effective against rapidly
growing bacilli and is also active against intracellular organisms.
3. Resistance:
Resistance follows chromosomal mutations, including 1) mutation or deletion of KatG (producing
mutants in capable of prodrug activation), 2) varying mutations of the acyl carrier proteins, or 3)
overexpression of the target enzyme InhA. Cross resistance may occur between isoniazid and
ethionamide.
4. Pharmacokinetics:
Isoniazid is readily absorbed after oral administration. Absorption is impaired if isoniazid is taken with
food, particularly high-fat meals. The drug diffuses into all body fluids, cells, and caseous material
(necrotic tissue resembling cheese that is produced in tuberculous lesions). Drug concentrations in the
cerebrospinal fluid (CSF) are similar to those in the serum. Isoniazid undergoes N-acetylation and

hydrolysis, resulting in inactive products. [Note: Isoniazid acetylation is genetically regulated, with the
fast acetylators exhibiting a 90-minute serum half-life, as compared to 3 to 4 hours for slow acetylators
Excretion is through glomerular filtration and secretion, predominantly as metabolites. Slow acetylators
excrete more of the parent compound.
5. Adverse effects:
Hepatitis is the most serious adverse effect associated with isoniazid. If hepatitis goes unrecognized, and
if isoniazid is continued, it can be fatal. The incidence increases with age (greater than 35 years old),
among patients who also take rifampin, or among those who drink alcohol daily. Peripheral neuropathy
(manifesting as paresthesia of the hands and feet) appears to be due to a relative pyridoxine deficiency.
This can be avoided by supplementation of 25 to 50 mg per day of pyridoxine (vitamin B6). Central
nervous system (CNS) adverse effects can occur, including convulsions in patients prone to seizures.
Hypersensitivity reactions with isoniazid include rashes and fever. Because isoniazid inhibits the
metabolism of carbamazepine and phenytoin, isoniazid can potentiate the adverse effects of these drugs
(for example, nystagmus and ataxia)

B. Trimethoprim
A potent inhibitor of bacterial dihydrofolate reductase, exhibits an antibacterial spectrum similar to that of
the sulfonamides. Trimethoprim is most often compounded with sulfamethoxazole, producing the
combination called cotrimoxazole.
A. Mechanism of action
The active form of folate is the tetrahydro derivative that is formed through reduction of dihydrofolic acid
by dihydrofolate reductase. This enzymatic reaction is inhibited by trimethoprim, leading to a decreased
availability of the tetrahydrofolate cofactors required for purine, pyrimidine, and amino acid synthesis.
The bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme,
which accounts for the selective toxicity of the drug.
B. Antibacterial spectrum
The antibacterial spectrum of trimethoprim is similar to that of sulfamethoxazole. However, trimethoprim
is 20- to 50-fold more potent than the sulfonamides. Trimethoprim may be used alone in the treatment of
UTIs and in the treatment of bacterial prostatitis (although fluoroquinolone are preferred).
C. Resistance

Resistance in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has
a lower affinity for trimethoprim. Efflux pumps and decreased permeability to the drug may play a role.
D. Pharmacokinetics
Trimethoprim is rapidly absorbed following oral administration. Because the drug is a weak base, higher
concentrations of trimethoprim are achieved in the relatively acidic prostatic and vaginal fluids. The drug
is widely distributed into body tissues and fluids, including penetration into the cerebrospinal fluid.
Trimethoprim undergoes some O-demethylation, but 60% to 80% is renally excreted unchanged.
E. Adverse effects
Trimethoprim can produce the effects of folic acid deficiency. These effects include megaloblastic
anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having very poor
diets. These blood disorders may be reversed by the simultaneous administration of folinic acid, which
does not enter bacteria

C. Fluoroquinolone
Nalidixic acid is the predecessor to all fluoroquinolones, a class of man-made antibiotics. Over 10,000
fluoroquinolone analogs have been synthesized, including several with wide clinical applications.
Fluoroquinolone in use today typically offer greater efficacy, a broader spectrum of antimicrobial activity,
and a better safety profile than their predecessors. Unfortunately, fluoroquinolone use has been closely
tied to Clostridium difficile infection and the spread of antimicrobial resistance in many organisms (for
example, methicillin resistance in staphylococci). The unfavorable effects of fluoroquinolone on the
induction and spread of antimicrobial resistance are sometimes referred to as collateral damage, a term
which is also associated with third-generation cephalosporin (for example, ceftazidime). The
fluoroquinolones and other antibiotics discussed in this chapter are listed in.
A. Mechanism of action
Fluoroquinolones enter bacteria through poor in channels and exhibit antimicrobial effects on DNA
gyrase (bacterial topoisomerase II) and bacterial topoisomerase IV. Inhibition of DNA gyrase results in
relaxation of supercoiled DNA, promoting DNA strand breakage. Inhibition of topoisomerase IV impacts
chromosomal stabilization during cell division, thus interfering with the separation of newly replicated
DNA.
In gram-negative organisms (for example, Pseudomonas aeruginosa), the inhibition of DNA gyrase is
more significant than that of topoisomerase IV, whereas in gram-positive organisms (for example,

Streptococcus pneumoniae), the opposite is true. Agents with higher affinity for topoisomerase IV (for
example, ciprofloxacin) should not be used for S. pneumonia infections, while those with more
topoisomerase II activity (for example, moxifloxacin) should not be used for P. aeruginosa infections.
B. Antimicrobial spectrum
Fluoroquinolones are bactericidal and exhibit area under the curve/minimum inhibitory concentration
(AUC/MIC)dependent killing. Bactericidal activity is more pronounced as serum drug concentrations
increase to approximately 30-fold the MIC of the bacteria. In general, fluoroquinolone are effective
against gram-negative organisms (Escherichia coli, P. aeruginosa, Haemophilus influenza), atypical
organisms (Legionellaceae, Chlamydiaceae), gram-positive organisms (streptococci), and some
mycobacteria (Mycobacterium tuberculosis). Fluoroquinolones are typically not used for the treatment of
Staphylococcus aureusor enterococcal infections. They are not effective against syphilis and have limited
utility against Neisseria gonorrhoeaedue to disseminated resistance worldwide. Levofloxacin and
moxifloxacinare sometimes referred to as respiratory fluoroquinolones, because they have excellent
activity against S. pneumoniae, which is a common cause of community-acquired pneumonia (CAP).
Moxifloxacin also has activity against many anaerobes. Fluoroquinolones are commonly considered
alternatives for patients with a documented severe -lactam allergy. Fluoroquinolone may be classified
into generations based on their antimicrobial targets. The nonfluorinated quinolone nalidixic acid is
considered to be first generation, with a narrow spectrum of susceptible organisms. Ciprofloxacin and
norfloxacin are second generation because of their activity against aerobic gram-negative and atypical
bacteria. In addition, these fluoroquinolones exhibit significant intracellular penetration, allowing therapy
for infections in which a bacterium spends part or all of its life cycle inside a host cell (for example,
chlamydia, mycoplasma, and mycobacteria). Levofloxacin is classified as third generation because of its
increased activity against gram-positive bacteria. Lastly, the fourth generation includes only moxifloxacin
because of its activity against anaerobic and gram-positive organisms.
C. Examples of clinically useful fluoroquinolones
1. Norfloxacin:
Norfloxacin is infrequently prescribed due to poor oral bioavailability and a short half-life. It is effective
in treating nonsystemic infections, such as urinary tract infections (UTIs), prostatitis, and infectious
diarrhea (unlabeled use).
2. Ciprofloxacin:

Ciprofloxacin is effective in the treatment of many systemic infections caused by gram-negative bacilli
(Figure 40.2). Of the fluoroquinolones, it has the best activity against P. aeruginosa and is commonly used
in cystic fibrosis patients for this indication. With 80% bioavailability, the intravenous and oral
formulations are frequently interchanged. Travelers diarrhea caused by E. coli as well as typhoid fever
caused by Salmonella typhi can be effectively treated with ciprofloxacin. Ciprofloxacin is also used as a
second-line agent in the treatment of tuberculosis. Although typically dosed twice daily, an extendedrelease formulation is available for once-daily dosing, which may improve patient adherence to treatment.
3. Levofloxacin:
Levofloxacin is the l-isomer of ofloxacin and has largely replaced it clinically. Due to its broad spectrum
of activity, levofloxacin is utilized in a wide range of infections, including prostatitis, skin infections,
CAP, and nosocomial pneumonia. Unlike ciprofloxacin, levofloxacin has excellent activity against
S.pneumonia respiratory infections. Levofloxacin has 100% bioavailability and is dosed once daily.
4. Moxifloxacin:
Moxifloxacin not only has enhanced activity against gram-positive organisms (for example, S.
pneumoniae) but also has excellent activity against many anaerobes, although resistance to
Bacteroidesfragilis has been reported. It has poor activity against P. aeruginosa. Moxifloxacin does not
concentrate in urine and is not indicated for the treatment of UTIs.
D. Resistance
Although plasmid-mediated resistance or resistance via enzymatic degradation is not of great concern,
high levels of fluoroquinolone resistance have emerged in gram-positive and gram-negative bacteria,
primarily due to chromosomal mutations. Cross-resistance exists among the quinolones. The mechanisms
responsible for this resistance include the following:
1. Altered target:
Chromosomal mutations in bacterial genes (for example, gyrA or parC) have been associated with a
decreased affinity for fluoroquinolone at their site of action. Both topoisomerase IV and DNA gyrase may
undergo mutations.
2. Decreased accumulation:
Reduced intracellular concentration is linked to 1) poor in channels and 2) efflux pumps. The former
involves a decreased number of poor in proteins in the outer membrane of the resistant cell, thereby

impairing access of the drugs to the intracellular topoisomerases. The latter mechanism pumps drug out of
the cell.
E. Pharmacokinetics
1. Absorption:
Only 35% to 70% of orally administered norfloxacin is absorbed, compared with 80% to 99% of the other
fluoroquinolones (Figure 40.3). Intravenous and ophthalmic preparations of ciprofloxacin, levofloxacin,
and moxifloxacin are available. Ingestion of fluoroquinolone with sucralfate, aluminum- or magnesium
containing antacids, or dietary supplements containing iron or zinc can reduce the absorption. Calcium
and other divalent cation also interfere with the absorption of these agents (Figure 40.4).
2. Distribution:
Binding to plasma proteins ranges from 10% to 40%. The fluoroquinolone distribute well into all tissues
and body fluids, which is one of their major clinical advantages. Levels are high in bone, urine (except
moxifloxacin), kidney, and prostatic tissue (but not prostatic fluid), and concentrations in the lungs exceed
those in serum. Penetration into cerebrospinal fluid is relatively low except for ofloxacin.
Fluoroquinolones also accumulate in macrophages and polymorphonuclear leukocytes, thus having
activity against intracellular organisms.
3. Elimination:
Most fluoroquinolone are excreted renally. Therefore, dosage adjustments are needed in renal
dysfunction. Moxifloxacin is excreted primarily by the liver, and no dose adjustment is required for renal
impairment.
F. Adverse reactions
In general, these agents are well tolerated. Like most antibiotics, the most common adverse effects of
fluoroquinolone are nausea, vomiting, and diarrhea. Headache and dizziness or lightheadedness may
occur. Thus, patients with central nervous system (CNS) disorders, such as epilepsy, should be treated
cautiously with these drugs. Peripheral neuropathy and glucose dysregulation (hypoglycemia and
hypoglycemia) have also been noted. Fluoroquinolone can cause phototoxicity, and patients taking these
agents should be advised to use sunscreen and avoid excess exposure to sunlight. If phototoxicity occurs,
discontinuation of the drug is advisable. Articular cartilage erosion has been observed in immature
animals exposed to fluoroquinolones. Therefore, these agents should be avoided in pregnancy and
lactation and in children under 18 years of age. [Note: Careful monitoring is indicated in children with

cystic fibrosis who receive fluoroquinolones for acute pulmonary exacerbations.] An increased risk of
tendinitis or tendon rupture may also occur with systemic fluoroquinolone use. Moxifloxacin and other
fluoroquinolone may prolong the QTc interval and, thus, should not be used in patients who are
predisposed to arrhythmias or those who are taking other medications that cause QT prolongation.
Ciprofloxacin can increase serum levels of theophylline by inhibiting its metabolism. Quinolones may
also raise the serum levels of warfarin, caffeine, and cyclosporine.