CHEMOTHERAPY

1
General Principles of
Antimicrobial
Therapy
 Introduction
 Antimicrobials are among the most commonly
used and misused of all drugs

 Widespread and irrational use of antimicrobial

agents  Emergence of antibiotic-resistance

3
 Definition
 Antibiotics
 are antibacterial substances produced by various species
of microorganisms that suppress the growth of other
microorganisms.

 Commonly the term extends to include synthetic

antimicrobial agents, such as sulfonamides and
quinolones.

4
 Definitions…
• Chemotherapy
– Use of chemicals (drugs) against invading organisms
as well as cancerous cells.
• Antimicrobial Agent
– Use of chemicals against invading organisms.
• Antibiotic
– is a chemical that is produced by one microorganism
and has the ability to harm other microbes.
 Definition

• Bactericidal
Is directly lethal to bacterial at clinically ochievable
concentrations
• Bacteriostatic
seize microbial growth but does not cause cell death
• eliminiton of bacteria must ultematerly be accomplished
by host defenses
 Definition

• Minimal inhibitory concentration (MIC): Lowest

concentration of antimicrobial drug capable of inhibiting
growth of an organism in a defined growth medium

• Selective toxicity: More toxic to the invader than to the

host; a property of useful antimicrobial drugs
 Selective toxicity

• Is the ability of a drug to harm a target cell or target

organism with out injuring other cells or organisms with
which the target is in intimate contact.

• Antimicrobial drugs kill or suppress infecting microbes

with out causing injury to the host.

• If they were as harmful to the host as they are to

infecting organisms, antimicrobials would have no
therapeutic utility.
 Classification
 Based on chemical structure and proposed MOA
1. Cell wall synthesis inhibitors , e.g. -lactam antibiotics,
cycloserine, vancomycin, and bacitracin
2. Agents that act directly on the cell membrane of the
microorganism, e.g. Polymyxin, nystatin and amphotericin B,
daptomycin
3. Agents that affect ribosomal protein synthesis (e.g., CAF, TTCs,
erythromycin, clindamycin, aminoglycosides)
4. Agents that affect bacterial nucleic acid metabolism, such as
the rifamycins and the quinolones
5. The antimetabolites, including trimethoprim & sulfonamides
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 Susceptibility and Resistance
Antimicrobial therapy depends on the concentration of
antibiotic at the site of infection.
 Concentration should be sufficient to inhibit growth
 Intact and active host defence  bacteriostatic effect sufficient
 Impaired host defence  antibiotic-mediated killing required

 The concentration at the site of infection

 Inhibit the organism + remain below the level that is toxic to humans
 Susceptible
 If an inhibitory or bactericidal concentration exceeds that which can be
achieved safely in vivo, then the microorganism is considered resistant
to that drug.
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General mechanisms of bacterial resistance

 The drug does not reach its target

 The drug is not active

 The target is altered

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 Drug resistance may be acquired by
 Mutation and selection, with passage of the trait
vertically to daughter cells
 Horizontal transfer of resistance determinants from a
donor cell, often of another bacterial species, by
transduction, transformation, or conjugation.

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Antibiotics have three general uses
 Empirical (initial) therapy
Antibiotic should cover all the likely pathogens

Either combination therapy or a single broad-

spectrum agent

 Definitive therapy
Once the infecting microorganism is identified, a
narrow-spectrum, low-toxicity agent is instituted

 Prophylactic or preventive therapy

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 Factors that affect selection of
antibiotics
 Microbial sensitivity  Local Factors

 Pharmacokinetic factors  Age

 Route of Administration  Pregnancy

 Host Defense Mechanisms  Drug allergy

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 Combining Antimicrobial Agents
 Recommended in specifically defined situations
based on pharmacological rationale.

 Selection of an appropriate combination

 Understanding of the potential for interaction between the
antimicrobial agents.

 Interactions may affect either the microorganism or the

patient.
 May enhance or impair overall antimicrobial activity.

 May have additive or superadditive toxicities.

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 Indications for the Clinical Use of Combinations

of Antimicrobial Agents

 For empirical therapy of an infection in which the cause

is unknown

 For treatment of polymicrobial infections

 To enhance antimicrobial activity (i.e. synergism) for a

specific infection

 To prevent emergence of resistance.

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 Disadvantages of Combinations of
Antimicrobial Agents

 Increased risk of toxicity from two or more agents

 Selection of multiple-drug-resistant microorganisms

 Eradication of normal host flora with subsequent

superinfection

 Increased cost to the patient.

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 Super-infections
 Appearance of bacteriological and clinical evidence of a new infection
during the chemotherapy of a primary one

 Alterations in the normal microbial population of the intestinal, upper

respiratory, and genitourinary tracts

 Due to removal of inhibitory influence of normal flora

 The broader the antibacterial spectrum and the longer the period
of antibiotic treatment, the greater is the alteration in the normal
microflora, and the greater is the possibility that a single,
typically drug-resistant microorganism will become predominant,
invade the host, and produce infection.

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 Misuses of Antibiotics

Treatment of nonresponsive infections

Therapy of fever of unknown origin

Improper Dosage

Inappropriate reliance on chemotherapy alone

Lack of adequate bacteriological information

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SULFONAMIDES
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 Chemistry

 Has the basic sulfanilamide nucleus (which is

structurally similar to p-aminobenzoic acid)
 Derivatization: attaching substituents to the amido
group (–SO2–NH–R) or the amino group (–NH2)

 Sulfonamides tend to be much more soluble at

alkaline than at acidic pH.

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22
 Mechanism of action and resistance
 Susceptible microorganisms require extracellular PABA to
form dihydrofolic acid (Humans cannot synthesize folic acid
and must acquire it in the diet)
 Competitively inhibit dihydropteroate synthase (DHPS) and
block folic acid synthesis

 bacteriostatic

 Inhibit both G(+) and G(-) bacteria, nocardia, Chlamydia

trachomatis, Some enteric bacteria (E coli, klebsiella,
salmonella, shigella, and enterobacter), and some protozoa.
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24
25
 Mechanism of action and resistance
(cont’d)
 Resistance can be the result of
 Decreased bacterial permeability to the drug

 Increased production of PABA

 Production of an altered DHPS that exhibits low

affinity for sulfonamides.

 Active efflux of the sulfonamides

 Their inhibitory effect can be reversed by the presence of

pus, tissue fluids, and drugs that contain releasable
PABA.
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 Pharmacokinetics
 Divided into three major groups
1. Oral, absorbable
 Short-, medium-, or long-acting on the basis of their half-lives.
2. Oral, nonabsorbable
3. Topical

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 Clinical Uses
 Infrequently used as single agents.

 largely replaced by trimethoprim-sulfamethoxazole

(Co-trimoxazole).

 Many strains of formerly susceptible species are now

resistant.

 Can be useful for treatment of urinary tract

infections due to susceptible organisms

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 Clinical Uses…
 Urinary Tract Infections

 Nocardiosis

 Toxoplasmosis (combination of pyrimethamine

and sulfadiazine is the treatment of choice)

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 Rapidly Absorbed and Eliminated
Sulfonamides
 Sulfisoxazole
 Rapidly absorbed and excreted

 High solubility minimizes renal toxicity

 About 95% of a single dose is excreted by the

kidney in 24 hours

 Preferred when a rapidly absorbed and rapidly

excreted sulfonamide is indicated.
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 Sulfamethoxazole
 A close congener of sulfisoxazole with slower
rates of enteric absorption and urinary excretion

 Crystalluria may occur (high %age of the

acetylated, relatively insoluble form in the
urine).

 A component of the fixed-dose combination

cotrimoxazole (with trimethoprim)

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 Sulfadiazine
 Sulfadiazine given orally is absorbed rapidly
from the GI tract, and excreted quite readily by
the kidney in both the free and acetylated forms

 About 15% to 40% of the excreted sulfadiazine

is in acetylated form.

 Risk of crystal (ensure adequate fluid intake or

sodium bicarbonate)

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 Poorly Absorbed Sulfonamides
 Sulfasalazine
 Used in ulcerative colitis and regional enteritis
 Broken down by intestinal bacteria to sulfapyridine and
5-aminosalicylate
 5-Aminosalicylate effective in inflammatory bowel
disease, whereas sulfapyridine is responsible for most of
the toxicity.
 Toxic reactions include acute hemolysis in patients with
glucose-6-phosphate dehydrogenase deficiency, and
agranulocytosis. Nausea, fever.

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 Sulfonamides for Topical Use

 Sulfacetamide
 N1-acetyl-substituted derivative of sulfanilamide.

 Sodium salt solutions are used in ophthalmic infections.

 Very high aqueous concentrations are not irritating to the eye
and are effective against susceptible microorganisms.

 The drug penetrates into ocular fluids and tissues in high

concentration.

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 Silver Sulfadiazine
 Used topically to reduce microbial colonization and
the incidence of infections of wounds from burns
 It should not be used to treat an established deep
infection.
 Silver is released slowly from the preparation in
concentrations that are selectively toxic to the
microorganisms.
 One of the agents of choice for the prevention
of burn infection.
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 Long-Acting Sulfonamides
 Sulfadoxine
 Has long half-life (7 to 9 days)

 Used in combination with pyrimethamine (500

mg sulfadoxine plus 25 mg pyrimethamine as
FANSIDAR) for the prophylaxis and treatment of
malaria caused by mefloquine -resistant strains
of Plasmodium falciparum

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Adverse Reactions
 All sulfonamides and their derivatives are cross-
allergenic.

 Skin rashes, urticaria, photosensitivity, arthritis,

conjunctivitis, hematopoietic disturbances,
hepatitis

 Precipitate in urine (at neutral or acid pH)

producing crystalluria, hematuria, or even
obstruction.
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 Trimethoprim
 Structural analogue of the pteridine portion of DHF
acid
 Competitively inhibits dihydrofolate reductase
(DHFR)
 The bacterial enzyme is 20,000 to 60,000 times more
sensitive than its mammalian enzyme
 Trimethoprim–sulfamethoxazole
 Synergistically and sequentially inhibit bacterial synthesis
of THF acid
 To delay development of bacterial resistance

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Antibacterial Spectrum & Resistance
 Trimethoprim exhibits broad-spectrum activity

 Active against most g(+) and g(-)

 Little activity against anaerobic bacteria

 Resistance can develop from

 Alterations in DHFR

 Bacterial impermeability to the drug

 Overproduction of DHFR

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Pharmacokinetics
 Usually given orally, alone or in combination with
sulfamethoxazole

 Absorbed efficiently from the gut and distributed

widely in body fluids and tissues, including CSF

 Trimethoprim (a weak base of pKa 7.2)

concentrates in prostatic and vaginal fluids, which
are more acid than plasma.

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Clinical use
 In acute urinary tract infections(100 mg twice daily)

 Most community-acquired organisms tend to be

susceptible to the high concentrations that are
found in the urine.

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 Trimethoprim 80mg-Sulfamethoxazole
400 mg (TMP-SMX)

 The combination shows synergistic effect as the

two affect different points in the folic acid
synthetic pathway
 The incidence of bacterial resistance is less than
that observed when the drugs are used
individually.

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 Oral preparation
 Effective for P. jiroveci pneumonia, shigellosis, systemic
salmonella infections, complicated UTI, prostatitis, many
respiratory tract pathogens (including the
pneumococcus, haemophilus species, Moraxella
catarrhalis, and Klebsiella pneumoniae)
 Useful alternative to -lactams in URTI and community-acquired
bacterial pneumonia

 Parentheral preparations
 Agent of choice for moderately severe to severe
pneumocystis pneumonia.
 If patient can not take the oral preparation
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 Pyrimethamine
 2,4- diaminopyrimidine derivative that inhibits DHFR

 Pyrimethamine is well absorbed after oral

administration

 Binds to tissues and has slow rate of renal excretion

 In combination with a sulphonamide

 Malaria

 Toxoplasmosis

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Adverse Effects
 TMP: antifolate adverse effects (megaloblastic
anemia, leukopenia, and granulocytopenia)
 Prevented by simultaneous administration of folinic acid

 Nausea and vomiting, drug fever, vasculitis, renal

damage

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QUINOLONES
46
 Introduction
 Nalidixic acid: the first quinolone
 Used for many years in treatment of UTIs

 Fluorinated 4-quinolones
 Broad antimicrobial activity

 Effective after oral administration for the treatment of a

wide variety of infectious diseases

 Relatively few side effects

 Microbial resistance does not develop rapidly

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48
 MOA
 The quinolone antibiotics target bacterial DNA
gyrase and topoisomerase IV

 DNA replication or transcription  double-helical

DNA separation  overwinding or excessive
positive supercoiling

 DNA gyrase introduces negative supercoils

 An ATP-dependent reaction requiring that both strands
of the DNA be cut to permit passage of a segment of
DNA through the break; the break then is resealed. 49
 Topoisomerase IV separates interlinked (catenated)
daughter DNA molecules that are the product of
DNA replication.

 Eukaryotic cells
 Do not contain DNA gyrase

 Have type II DNA topoisomerase

 Quinolones inhibit eukaryotic type II topoisomerase

only at much higher concentrations

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 Classification of quinolones
 Often classified into generations (1st through 4th)
with spectrum of specificity and unique
pharmacological properties
 First: nalidixic acid and cinoxacin;

 Second: norfloxacin, ciprofloxacin, ofloxacin, enoxacin,

and lomefloxacin;

 Third: levofloxacin, sparfloxacin, gatifloxacin;

 Fourth: trovafloxacin and moxifloxacin

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First-generation
 Oldest quinolones

 Exhibit limited Gm(-) activity

 Nalidixic acid and cinoxacin restricted to

therapy of bladder infections caused by urinary
pathogens, such as E. coli and Klebsiella and
Proteus spp.
 Use is restricted by resistance.

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Second-generation
 Demonstrate activity against Gm(-) organisms
including Enterobacteriaceae. Haemophilus
[Link] STD agents are also susceptible.
 The piperazine moiety is responsible for the
antipseudomonal activity of some of these
drugs

 Resistance is becoming more prevalent.

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The third and fourth generations possess
significantly greater activity against Gm(+),
such as S. pneumoniae

The fourth-generation quinolones also

possess activity against anaerobes.

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 Pharmacokinetics
 Fluoroquinolones are well absorbed (bioavailability
of 80–95%) After oral administration

 Distributed widely in body fluids and tissues.

 Oral absorption is impaired by divalent cations

 Most are eliminated by renal mechanisms (tubular

secretion or GF. Dose adjustment required in renal
impairment.

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 Mechanism of Resistance
 Via mutations in the bacterial chromosomal genes
encoding DNA gyrase or topoisomerase IV or by
active transport of the drug out of the bacteria.

 No quinolone-modifying or -inactivating activities

have been identified in bacteria

 Resistance has increased in Pseudomonas,

staphylococci, Salmonella, N. gonorrhoeae, and S.
pneumoniae 56
 Clinical Uses
 UTI by even MDR bacteria, eg, Pseudomonas.
 Norfloxacin, ciprofloxacin, and ofloxacin

 Also for bacterial diarrhea caused by shigella,

salmonella, E coli, or campylobacter.

 Infections of soft tissues, bones, and joints and in

intra-abdominal and RTI
– All fluoroquinolones except norfloxacin,

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 Clinical Uses (cont’d)
 Gonococcal infection (Ciprofloxacin and ofloxacin)

 Chlamydial urethritis or cervicitis (ofloxacin).

 Occasionally in the treatment of TB (Ciprofloxacin or

levofloxacin)

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 Adverse Effects
 Extremely well tolerated.
 Most common: nausea, vomiting, and diarrhea
 Occasionally, headache, dizziness, insomnia, skin rash, or
abnormal liver function tests develop.
 Acute hepatitis and hepatic failure (Trovafloxacin)
 Photosensitivity (lomefloxacin and pefloxacin)
 QT prolongation
 Arthropathy
 They should be avoided during pregnancy in the absence of
specific data documenting their safety.

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 -LACTAM
ANTIBIOTICS

60
 Introduction
 The drugs share a common structure and mechanism of
action, inhibition of synthesis of the bacterial peptidoglycan
cell wall.

 Include penicillins, cephalosporins, -lactamase

inhibitors, carbapenems and monobactam.

 Mechanisms of resistance against -lactam antibiotics

 Production of -lactamases

 Alterations in or acquisition of novel penicillin-binding proteins

 Decreased entry and/or active efflux of the antibiotic

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62
 PENICILLINS
 Chemistry
 The basic structure of the penicillins consists
 A thiazolidine ring (A) connected to

 A -lactam ring (B) to which is attached a side chain (R)

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 Mechanism of action
 The -lactam antibiotics structurally resemble the terminal
D-alanyl-D-alanine (D-Ala-D-Ala) in the pentapeptides on
peptidoglycan (murein).

 Bacterial transpeptidases covalently bind -lactam

antibiotics at the enzyme active site, and the resultant acyl
enzyme molecule is stable and inactive.

 The -lactam ring modifies the active serine site on

transpeptidases and blocks further enzyme function.

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65
 In addition, penicillins bind to penicillin-binding
proteins (PBPs), which function as transglycosylases
and carboxypeptidases.

 PBPs are involved with assembly, maintenance, or

regulation of peptidoglycan cell wall synthesis.

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67
68
 Classification
 Currently penicillins are divided in to 4 groups
based on the spectra of activity
 Natural penicillins
 Penicillin G, Penicillin V
 Penicillinase-resistant penicillins
 Dcloxacillin, Nafcillin, Oxacillin
 Aminopenicillins
 Amoxicillin, Ampicillin
 Extended-spectrum penicillins
 Carbenicillin, Piperacillin, Ticarcilllin

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70
71
 A. Natural Penicillins
 Produced by fermentation of of Penicillium chrysogenium.

 Different side chains at R are produced by altering the composition

of the culture media of Penicillium

 Penicillins F, G, N, O, V, X

 Are acid labile and -lactamase sensitive

 Active against most Gm(+) and Gm(-) aerobic cocci, some Gm(+)
aerobic and anaerobic bacilli, and most spirochetes.
 Many bacteria have developed resistance.

 Most streptococci are susceptible

 More than 90% of staphylococcal strains are now resistant

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 Penicilin G
 Non-suitable for oral administration (IM or IV)

 The drug distributes to most tissues

 Excreted by the kidneys (90% of renal elimination occurs via
tubular secretion and 10% by glomerular filtration.
 Probenecid blocks tubular secretion and has been used to
prolong the half-life of penicillins).
 Depot IM formulations of penicillin G (procaine penicillin
and benzathine penicillin) have decreased solubility,
delayed absorption, and a prolonged t½
 IV penicillin G is among the antibiotics of first choice in
meningitis caused by susceptible Streptococcus
pneumoniae 73
 Penicillin G potassium and Penicillin G sodium
 Aqueous, crystalline Pen G and are used IV

 Used when rapid and high serum concentrations are

required
 Septicemia, meningitis, pericarditis, endocarditis, severe
pneumonia

 Penicillin G procaine and penicillin G benzathine

 Used only
 For treatment of moderately severe infections susceptible to low
concentrations

 Prophylaxis of infections caused by these organisms

 Or maintenance therapy to IM or IV Penicillin G 74

Penicillin V
 Phenoxymethyl congener of penicillin G

 More stable in acidic media and is better absorbed

from the GIT

 Have similar antibacterial spectrum as penicillin G.

 Used to treat streptococcal infections when oral

therapy is appropriate and desirable.

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Penicillin G Uses
 Gm(+) aerobic bacterial infections
Drugs of choice for many streptococcal infections and
non-penicillinase producing staphylococcal infections
Drugs of first or second choice for the treatment of
many infections caused by susceptible Gm(+) aerobic
bacilli (Bacillus anthracis, Corynebacterium diphtheria..)
 Gm(-) aerobic bacterial infections
Treatment of a variety of infections by susceptible cocci
(Neisseria meningitidis)
Drugs of choice in infections caused by pasteurella
Generally not useful in the treatment of infections
caused by other Gm(-) aerobic bacteria
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Penicillin G Uses (cont’d)
 Anaerobic bacterial infection
Drugs of choice for the treatment of many infections
including those caused by

Actinomyces, Peptococcus, Peptostreptococcus,

and some strains of Bacterioides, Clostridia,
Eubacterium, and Fusobacterium

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 B. Penicillinase-resistant penicillins
 Also Known As antistaphylococcal penicillins
 Semi-synthetic antibiotics resistant to staphylococcal
penicillinase (hence effective against streptococci and
most community-acquired penicillinase- producing
staphylococci)
 Are relatively stable in acidic medium
 Have bulky side chains at R on the 6-APA
 Results in steric hindrance for the binding of penicillinases to the
-lactam ring
 Generally less active against Pen G susceptible organisms
than other penicillins
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 Methicillin-resistant S. aureus (MRSA): emerging
 Resistance of bacteria to all the penicillinase-resistant
penicillins and cephalosporins
 Vancomycin considered drug of choice for MRSA

 Nafcillin and oxacillin

 Parentheral

 Cloxacillin and dicloxacillin

 Oral

 Methicillin: no more in clinical use

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 C. Aminopenicillins
 Semisynthetic penicillins with enhanced activity against
Gm(-) bacteria compared to natural and penicillinase-
resistant penicillins
 Are stable in acidic media
 Amoxicillin & Ampicillin
 Used orally for the treatment of infections of upper & lower
RTI, GIT, skin and skin structures, genitourinary tract, & otitis
media caused by susceptible organisms.
 IM or IV for the treatment of meningitis, endocarditis, or severe
RT, GIT, bone and joint, or genitourinary tract infections by
susceptible organisms.
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Aminopenicillins are used for the treatment of
 infections caused by susceptible Gm(-) aerobic
bacilli
Haemophilus influenzae, E. coli, Salmonella

 Susceptible Gm(+) aerobic cocci

Enterococci, Streptococcus pneumonia, non-
penicillinase-producing S. aureus)

 Gm(+) bacilli
Listeria monocytogenes
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 Amoxicillin is absorbed more rapidly and
completely from the GIT than is ampicillin (the
major difference between the two drugs)

 Both have essentially identical spectrum of

antimicrobilal action, except that amoxicillin is less
effective than ampicillin for shigellosis.

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 D. Extended-spectrum penicillins
 Semisynthetic penicillins with wider spectra of
activity than the other penicillins.

 Are active against some isolates of P. aeruginosa and

certain Proteus spp. that are resistant to ampicillin
and its congeners.

 Sensitive to destruction by -lactamases and are

generally less effective against Gm(+) infections than
the other penicillins
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 Two different sub-groups

 -carboxypenicillins
Carbenicillin, Ticarcillin

 Acylaminopenicillins
Mezlocillin, Piperacillin

 Their use is generally limited to treatment of serious

infections caused by susceptible Gm(-) bacilli or
mixed aerobic-anaerobic infections
84
 Mechanism of Resistance
 Decreased affinity PBPs

 Inability to penetrate to the site of action

 Difference in susceptibility of Gm(-) Gm(+) bacteria

 Active efflux mechanisms (P. aeruginosa, E. coli, and

Neisseria gonorrhoeae.)
 Enzymatic destruction of the -lactam ring

85
 Untoward effects
 Hypersensitivity reactions
 0.7% and 4% of all treatment courses
 Maculopapular rash, urticarial rash, fever, bronchospasm,
vasculitis, serum sickness, exfoliative dermatitis, Stevens-
Johnson syndrome, and anaphylaxis

 Other adverse reactions

 bone marrow depression, granulocytopenia, and hepatitis
 Pain and sterile inflammatory reactions at the sites of
intramuscular injections
 Nausea, vomiting, diarrhea

 Superinfection
86
Cephalosporins

87
 Introduction
 Are derivatives of 7-aminocephalosporanic acid

 Act in the same manner as penicillins

 Are relatively stable in dilute acid and are highly

resistant to penicillinase

88
 General Features of the Cephalosporins
 Many are absorbed readily after oral administration
while some are administered parenterally
 Excretion primarily by the kidney (dosage adjustment in
renal insufficiency)
 Probenecid slows tubular secretion

 Several cephalosporins penetrate into CSF in sufficient

concentration, cross the placenta, relatively good
penetration into the aqueous humor but is poor into
the vitreous humor
89
90
 Classification
 Classified into four based on their spectrum of activity

 First generation
 Cefadroxil, cefazolin, cephalexin, Cephalothin

 Second generation
 Cefaclor, Cefprozil, Cefuroxime, Cefoxitin (a cephamycin)

 Third generation
 Cefdinir, Cefixime, Cefotaxime, Cefpodoxime, Ceftazidime,
Ceftibuten, Ceftriaxone, Cefditoren

 Fourth generation
 Cefepime, Cefpirome
91
 First Generation Cephalosporins
 Active in vitro against
 Gm(+) cocci including Penicillinase-producing and
nonpenicillinase producing Staphylococcal strains,
streptococcus pyogens, S. pneumonia

 Have limited activity against Gm(-) bacteria (some

strains of E. coli, Klebsiella, Shigella are inhibited in
vitro)

 Inactive against
 Enterococci, MRSA, Listeria monocytogenes 92
 Second generation cephalosporins
 Have greater stability against -lactamase
 Active, in vitro, against
 Bacteria susceptible to 1st GC
 Most strains of Haemophilus influenza (anaerobes)
 Gm(-) bacteria (2nd GC are more active than 1st GC)
 May be active against Enterobacter, [Link], Klebsiella,
Neisseria that are resistant to 1st GC

 Inactive against
 Enterococci, MRSA, and Pseudomononas
93
 Third generation cephalosporins
 Higher -lactamase stability

 Less active in vitro against susceptible staphylococci than 1st

GC

 Expanded spectrum of activity against Gm(-)

 Active in vitro against

 Gm(-) susceptible to 1st and 2nd G.C.s

 Most are active against enterobacter, E. coli, Klebsiella, Neisseria.. That

may be resistant to 1st and 2nd G.C.

 Some are active against Pseudomonas

 Inactive against MRSA and generally are inactive against

enterococci and Listeria monocytogenes 94
 Fourth generation cephalosporins
 More resistant to inactivation by -lactamases

 Expanded spectrum of activity against Gm(-)

 Active against some Gm(-) including Pseudomonas
aeruginosa and certain Enterobacteriaceae, that are
generally resistant to 3rd GC

 More active against Gm(+) than most 3rd GCs

 Inactive against MRSA, enterococci, and Listeria

monocytogenes
95
 Mechanisms of Bacterial
Resistance to the Cephalosporins
 Resistance to the cephalosporins may be related to
 Inability of the antibiotic to reach its sites of action

 Alterations in the penicillin-binding proteins (PBPs)

 Destruction of the cephalosporins by hydrolysis of

the -lactam ring (by -lactamases)

96
 Adverse reaction
Hypersensitivity
 Anaphylaxis, bronchospasm, and urticaria

 Cross-reactivity with penicillin allergy (in 20%)

Nephrotoxicty, Diarrhea, disulfiram-like

reaction,

97
 Therapeutic Uses
 Skin and soft tissue infections due to S. aureus and S.
pyogenes (1st GCs)
 Colorectal surgery, where prophylaxis for intestinal
anaerobes is desired (2nd GCs)

 Generally 2nd GCs displaced by 3rd GCs

 Oral 2nd GCs can be used to treat RTI

 In situations where facultative Gm(-) and anaerobes are involved

(intra-abdominal infections, pelvic inflammatory disease, and
diabetic foot infection)

98
 Therapeutic Uses (cont’d)
 3rd GCs (with or without aminoglycosides)
 Drugs of choice for serious infections caused by Klebsiella, Enterobacter,
Proteus, Serratia, and Haemophilus spp.
 Ceftriaxone is the therapy of choice for all forms of gonorrhea and for
severe forms of Lyme disease.

 Drugs of choice for the treatment of meningitis caused by H. influenzae,

sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric
bacteria

 Treatment of Pseudomonas meningitis infection

 Treatment of community-acquired pneumonia

99
 Therapeutic Uses (cont’d)
4th GCs
 Empirical treatment of nosocomial infections
where antibiotic resistance owing to extended-
spectrum -lactamases or chromosomally induced
-lactamases are anticipated

100
Other -lactam antibiotics

101
 Carbapenems
 Carbapenems are -lactam antibiotics that contain a
fused -lactam ring and a five-membered ring
system that differs from the penicillins in being
unsaturated and containing a carbon atom instead of
the sulfur atom.

 Has a broader spectrum of activity than do most

other -lactam antibiotics.

102
 Imipenem
 Marketed in combination with cilastatin, a drug that
inhibits the degradation of imipenem by a renal
tubular dipeptidase
 Derived from a compound produced by Streptomyces
cattleya. The compound thienamycin is unstable, but
imipenem is stable
R=CH2CH2NHCH=NH

103
 Mechanism of Action

 Binds to penicillin-binding proteins, disrupts bacterial

cell wall synthesis, and causes death of susceptible
microorganisms.

 It is very resistant to hydrolysis by most -lactamases.

104
 Antimicrobial Activity
 Active against
 Streptococci (including pen-resistant), enterococci (excluding E.
faecium and non--lactamase-producing pen-resistant strains),
staphylococci (including penicillinase-producing strains), and Listeria

 Most MRSA strains are resistant

 Excellent Activity against the Enterobacteriaceae, including

organisms that are cephalosporin-resistant

 Most strains of Pseudomonas and Acinetobacter are inhibited.

 Anaerobes, including B. fragilis, are highly susceptible.

105
 Pharmacokinetics
 Not absorbed orally

 Hydrolyzed rapidly by dipeptidase in renal tubule

 Approximately 70% of administered imipenem is

recovered in the urine as the active drug

 Adverse Reactions
 Nausea and vomiting (most common), Seizures, patients
allergic to other -lactam antibiotics may have
hypersensitivity reactions

106
 Therapeutic Uses
 Especially useful for the treatment of infections caused by
cephalosporin-resistant nosocomial bacteria

 For empirical treatment of serious infections in hospitalized

patients who have recently received other -lactam

 Imipenem should not be used as monotherapy for infections

caused by P. aeruginosa because of the risk of resistance
developing during therapy

107
Meropenem
 Not sensitive to renal dipeptidase.
 Similar toxicity to imipenem (less likely to cause
seizures)
 It is therapeutically equivalence to imipenem.

Ertapenem
 Have larger serum t½ that allows once-daily
dosing
 Inferior activity against P. aeruginosa &
Acinetobacter spp. 108
 Monobactams
Aztreonam
 A monocyclic -lactam compound (a
monobactam) isolated from Chromobacterium
violaceum

109
 Mechanism of Action and
antimicrobial activity
 Acts in the same way as other -lactam antibiotics
 Aztreonam is resistant to many of the -lactamases
elaborated by most Gm(-)
 Its antimicrobial activity differs from those of other
-lactams and resembles that of aminoglycosides.
 No activity against Gm(+) bacteria & anaerobic
organisms
 Excellent activity against Enterobacteriaceae and P.
aeruginosa.
110
 Therapeutic Uses
 Little allergic cross-reactivity with -lactam
antibiotics (possible exception of ceftazidine)

 Aztreonam is useful for treating g(-) infections that

normally would be treated with a -lactam antibiotic
were it not for the history of a prior allergic reaction.

111
 -Lactamase Inhibitors
 -Lactamase inhibitors are most active against
plasmid-encoded -lactamases, but are inactive at
clinically achievable concentrations against -
lactamases induced in Gm(-) bacilli by treatment
with 2nd and 3rd GCs

 They resemble -lactam molecules but have very

weak intrinsic antibacterial action.

112
 A "suicide" inhibitor that irreversibly binds -
lactamases produced by a wide range of gram-
positive and gram-negative microorganisms

 Used in combination with -lactam antibiotics to

increase their spectrum of activity.
 Amoxicillin + clavulanate (augmentin)

 Ticarcillin + clavulanate (Timentin)

113
AMINOGLYCOSIDES
114
 Introduction
 Gentamicin, Tobramycin, Amikacin, Netilmicin,
Kanamycin, Streptomycin, Neomycin

 Primarily used to treat infections caused by aerobic

gram-negative bacteria

 Streptomycin: in the treatment of tuberculosis

 Have bactericidal activity

115
 Chemistry
 The aminoglycosides consist of
 A hexose (aminocyclitol) nucleus [either streptidine
(found in streptomycin) or 2-deoxystreptamine (found in
all other available aminoglycosides)]

 Amino sugars attached through glycosidic linkages to

the aminocyclitols

 Are water-soluble, stable in solution, and more

active at alkaline than at acid pH

116
Streptomycin

117
 Mechanism of action

 Aminoglycosides
 Are rapidly bactericidal

 Have a post-antibiotic effect (their killing action

continues when their plasma levels have declined below
measurable levels)

 Penetration through the outer bacterial membrane

 Outer membrane disruption

 Diffusion through outer membrane porins.

118
 Mechanism of action (cont’d)
 Transport across the cytoplasmic membrane depends
on electron transport
 Requirement for a membrane electrical potential (interior
negative) to drive permeation

 Is rate-limiting and can be blocked or inhibited by divalent

cations (e.g., Ca2+ and Mg2+), hyperosmolarity, a reduction
in pH, and anaerobic conditions.

 Antimicrobial activity reduced in the anaerobic environment

of an abscess and in hyperosmolar acidic urine
119
 Mechanism of action (cont’d)
 Inside the cell
 Aminoglycosides bind to ribosomes and interfere with
protein synthesis
 misreading and premature termination of mRNA translation
 Hence, aberrant proteins produced and may be inserted
into the cell membrane, leading to altered permeability
 Bind to 30S ribosomal subunit and disrupt the
normal cycle of ribosomal function by
 blocking formation of initiation complex
 Misreading of the mRNA template
 Incorporating incorrect AA to growing polypeptide chains
 inhibiting translocation 120
 Mechanism of Resistance
 Resistance could be due to
 Failure to penetrate intracellularly

 Low affinity of the drug for the bacterial ribosome

 Inactivation of the drug by microbial enzymes

 Aminoglycoside-modifying enzymes phosphorylate, adenylate,
or acetylate specific hydroxyl or amino groups

 The metabolites may compete with the parent drug for transport
across the inner membrane, but are incapable of binding to
ribosomes

121
 Antibacterial Spectrum
 Primarily active against aerobic Gm(-) bacilli

 Have little activity against anaerobic microorganisms

or facultative bacteria under anaerobic conditions.

 Limited action against most gram-positive bacteria

 Produce synergistic bactericidal effect in vitro (against
enterococci, streptococci, and staphylococci) when
combined with a cell wall-active agent

122
 Pharmacokinetics
Absorption
 Very poorly absorbed from the GIT.

 Absorbed rapidly from IM sites of injection.

 In critically ill patients, especially those in shock,
absorption of drug may be reduced from
intramuscular sites because of poor perfusion

123
 Distribution
 Do not penetrate into most cells and has negligible plasma
albumin binding (Except for streptomycin)
 Vd  the volume of extracellular fluid
 High concentrations are found in renal cortex and inner ear
(likely contributor to the nephrotoxicity and ototoxicity)
 Streptomycin and tobramycin can cause hearing loss in
children born to women who receive the drug during
pregnancy.
 Recommendation: use with caution during pregnancy and only for
strong clinical indications in the absence of suitable alternatives.

 Elimination.
 The aminoglycosides are excreted almost entirely by
glomerular filtration,
124
Dosing
 Total daily dose as a single injection or two or three
equally divided doses

 Total daily dose as a single injection is associated

with less toxicity and is just as effective as multiple-
dose regimens
More drug accumulates with higher plasma
concentrations, particularly at trough, and with prolonged
periods of exposure.
125
 Untoward effects
 Vestibular & auditory ototoxicity
 Vestibular and auditory dysfunction can follow the
administration of any of the aminoglycosides

 Nephrotoxicity

 Neuromuscular Blockade
 And the associated apnea

 Decreasing potency for blockade: neomycin,

kanamycin, amikacin, gentamicin, and tobramycin.
126
 Streptomycin
 Is generally less active than other members of the
class
 Administered by deep IM or IV
 Dose adjustment in renal impairment
 Therapeutic Uses
 Bacterial Endocarditis
 Streptomycin and penicillin in combination

 Tularemia
Streptomycin (or gentamicin) is the drug of choice
 Plague
 Tuberculosis
127
 Gentamicin
 First choice due to low cost and reliable activity against
all but the most resistant g(-) aerobes.
 Available for parenteral, ophthalmic, and topical
 Therapeutic Uses (Gentamicin, tobramycin, amikacin,
and netilmicin)
 Urinary Tract Infections
 Pneumonia
 Meningitis
 Bacterial Endocarditis
 Sepsis
128
 Tobramycin
 Therapeutic Uses
 Same as those for gentamicin
 The preferred aminoglycoside for treatment of
serious infections caused by P. aeuroginosa (usually
in combination with an antipseudomonal -lactam
antibiotic)
 Poor activity in combination with penicillin against
many strains of enterococci.
 Ineffective against mycobacteria
129
 Amikacin
 Broadest spectrum of activity in the group
 Resistant to many of the aminoglycoside-inactivating
enzymes
 Therapeutic Uses
 The preferred agent for the initial treatment of serious
nosocomial Gm(-) bacillary infections in hospitals
 Active against the majority of aerobic g(-) bacilli in the
community and the hospital
 Less active than gentamicin against enterococci
 It is active against M. Tuberculosis
130
MACROLIDES
131
 Introduction
 Contain a large 14 or 15 membered lactone ring to
which one or more deoxy sugars are attached.
 Include erythromycin, clarithromycin, azithromycin,
and oleandomycin
 Clarithromycin differs from erythromycin only by
methylation of the hydroxyl group at the 6 position,
 Azithromycin differs by the addition of a methyl-
substituted nitrogen atom into the lactone ring.
 Improve acid stability and tissue penetration and broaden the
spectrum of activity
132
133
 Antibacterial Activity
 Erythromycin usually is bacteriostatic, but may be
bactericidal in high concentrations

 The antibiotic is most active in vitro against aerobic

gram-positive cocci and bacilli.

 Macrolide resistance is common among streptococci.

 Cross-resistance among macrolides is complete

 Staphylococci are not reliably sensitive to

erythromycin.
134
 Antibacterial Activity (cont’d)
 Erythromycin is inactive against most aerobic
enteric Gm-negative bacilli.

 Macrolides are active against Campylobacter jejuni.

 Erythromycin is active against M. Pneumoniae and

Legionella pneumophila

135
 Antibacterial Activity (cont’d)
 Clarithromycin is more potent than erythromycin against
sensitive strains of streptococci and staphylococci, and
has modest activity against H. influenzae and N.
gonorrhoeae.
 Azithromycin: less active than erythromycin against Gm(-)
organisms and slightly more active against H. influenzae
and Campylobacter spp.
 Azithromycin & clarithromycin have enhanced activity
against M. avium-intracellulare & some protozoa (e.g., T.
gondii, Cryptosporidium, and Plasmodium spp.). 136
 Mechanism of Action
 Inhibit protein synthesis by binding reversibly to
50S ribosomal subunit

 Inhibits the translocation step where in a newly

synthesized peptidyl tRNA molecule moves from
the acceptor site on the ribosome to the peptidyl
donor site.

 Increased antimicrobial activity at alkaline pH

(more permeabillity of the un-ionized form)
137
 Mechanism of resistance
 Resistance to macrolides usually results from
1. Drug efflux by an active pump mechanism
2. Ribosomal protection by inducible or constitutive
production of methylase enzymes, which modify
the ribosomal target and decrease drug binding
3. Macrolide hydrolysis by esterases produced by
Enterobacteriaceae
4. Chromosomal mutations that alter a 50S ribosomal
protein
138
 Pharmacokinetics
 Absorbed from the intestinal tract,

 Presence of food interferes with absorption (Azithromycine)

 Erythromycin is relatively more acid labile

 Serum levels of clarithromycin and azithromycin are low, but

they concentrate in tissue and reach high levels.

 Erythromycin and azithromycin are excreted primarily in bile

 Clarithromycin is metabolized to the biologically active 14-

OH metabolite and is eliminated largely by the kidney.

 t½ : erythromycin (1.4 hours), clarithromycin (3 to 7),

azithromycin (68 hours). 139
 Clinical uses
 Mycoplasma pneumonia infections
 A macrolide or TTC is the drug of choice
 Legionnaires’ Disease
 Azithromycin or a fluoroquinolone
 Chlamydial Infections
 Can be treated effectively with any of the
macrolides
Diphtheria
 erythromycin
Pertussis
 Drug of choice for treatment & prophylaxis 140
 Clinical uses (cont’d)
 Streptococcal infections
 Alternatives in patients who are allergic to penicillin.
Penicillin-resistant strains of S. Pneumoniae are very
likely to be resistant to macrolides

 Staphylococcal infections

 Campylobacter infections
 largely replaced by Fluoroquinolones in adults

 Erythromycin remains useful for treatment of

Campylobacter gastroenteritis in children.
141
 Clinical uses (cont’d)
 Tetanus
 Erythromycin may be given to eradicate Clostridium
tetani in patients allergic to penicillin
 Mycobacterial Infections
 Clarithromycin or azithromycin is recommended as first-
line therapy for prophylaxis and treatment of
disseminated infection caused by M. avium-
intracellulare in AIDS patients and for treatment of
pulmonary disease in non-HIV-infected patients

142
143
144
 Adverse Effects
 The incidence of side effects associated with erythromycin
therapy is very low.
 Mild GI upset with nausea, diarrhea, and abdominal pain (more
common)
 Rashes are seen infrequently
 Thrombophlebitis may follow IV administration
 Transient impairment of hearing.
 Cholestatic hepatitis (characterized by fever, enlarged and
tender liver, hyperbilirubinemia, dark urine, eosinophilia,
elevated serum bilirubin, and elevated transaminase levels)
 The drugs inhibits hepatic microsomal enzymes and
interfere with the actions of various drugs
145
 KETOLIDES (Telithromycin)
 are semisynthetic derivatives of erythromycin,
differing from erythromycin by substitution of a 3-
keto group for the neutral sugar L-cladinose

 This renders ketolides less susceptible to methylase-

mediated and efflux-mediated mechanisms of
resistance.

 Ketolides therefore are active against many

macrolide-resistant g(+) strains.
146
Antibacterial Activity
 Have similar antibacterial properties with
macrolides

 Telithromycin is active against staphylococci,

streptococci, S. pneumoniae, Haemophilus spp.,
Moraxella catarrhalis, mycoplasma, chlamydia,
and Legionella

 It is slightly more active by weight than

erythromycin.
147
 Pharmacokinetics
 Oral formulated (well absorbed, 60% bioavailability)

 t½ 9.8 hours (once daily administration)

 60% to 70% bound by serum protein

 Penetrates well into most tissues

 Telithromycin is concentrated into macrophages and

white blood cells

 Primarily cleared by hepatic metabolism

148
Therapeutic Uses
 Approved for treatment of RTI, including acute
exacerbation of chronic bronchitis, acute
bacterial sinusitis (5-day regimen), and
community-acquired pneumonia.

149
 Untoward Effects
 Telithromycin generally is well tolerated

 Nausea, vomiting, and diarrhea (most common side

effects)

 Visual disturbances, reversible hepatic dysfunction,

pseudomembranous colitis, reports of disease
exacerbation in patients with myasthenia gravis

 Clinically significant QTc prolongation

 Telithromycin has several clinically significant drug

interactions similar to those for erythromycin. It is both a
substrate and a strong inhibitor of CYP3A4. 150
TETRACYCLINES
(TTC)

151
 Introduction
 Produced by different species of Streptomyces
 OxyTTC is a natural product elaborated by Streptomyces
rimosus
 TTC is a semisynthetic derivative of chlorTTC
 Demeclocycline is the product of a mutant strain of
Strep. Aureofaciens
 Methacycline, doxycycline, and minocycline are
semisynthetic derivatives.

 Chlortetracycline, the prototype of the class, was

introduced in 1948
152
153
 Effects on Pathogenic Microorganisms

 Are bacteriostatic antibiotics active against a wide

range of aerobic and anaerobic Gm(+) & Gm(-)
bacteria

 Are also effective against Rickettsia, Coxiella

burnetii, Mycoplasma pneumoniae, Chlamydia
spp., Legionella spp., Ureaplasma, some atypical
mycobacteria, and Plasmodium spp., that are
resistant to cell-wall-active antimicrobial agents
154
 Effects on Intestinal Flora
 Many of the TTCs are incompletely absorbed from
the GIT, and high concentrations in the bowel can
alter enteric flora.

 Sensitive aerobic & anaerobic coliform

microorganisms & Gm(+) spore-forming bacteria
are markedly suppressed

 Overgrowth of TTC-resistant microorganisms

(yeasts (Candida spp.), enterococci, Proteus, &
Pseudomonas) 155
 Mechanism of Action
 TTCs inhibit bacterial protein synthesis by binding to the
30S bacterial ribosome and preventing access of aminoacyl
tRNA to the acceptor (A) site on the mRNA-ribosome
complex

 TTCs enter Gm(-) bacteria by passive diffusion through the

porin channels of the outer cell membrane and by active
transport via an energy-dependent system that pumps all
TTCs across the cytoplasmic membrane

 Entry into Gm(+) bacteria requires metabolic energy, but is

not as well understood
156
M.O.A. TTC
Resistance to the Tetracyclines
The main resistance mechanisms
1. Decreased accumulation of tetracycline as a
result of either decreased antibiotic influx or
acquisition of an energy-dependent efflux
pathway;

2. Production of a ribosomal protection protein

that displaces tetracycline from its target

3. Enzymatic inactivation of tetracyclines

158
 Pharmacokinetics
 Absorption
 Partially absorbed from the stomach and upper GIT
 Impaired by Food (all except doxycycline and minocycline)
 TTCs form insoluble chelates with calcium, magnesium, and other
metal ions  interfere with absorption
 Distribution
 Distributed throughout body tissues and fluids
 Minocycline and doxycycline (highest lipid solubility), oxyTTC (the least)

 Ellimination
 TTCs are excreted mainly in bile and urine
 Ten to 50 % of various TTCs is excreted into the urine.
 Doxycycline is eliminated by nonrenal mechanisms TTC of choice
in renal insufficiency.
159
 Classification
Based on serum half-lives, TTCs are Classified
 Short-acting
Serum half-life of 6-8 hours
ChlorTTC, TTC, oxyTTC
 Intermediate-acting)
Serum half-life of 12 hours
Demeclocycline and methacycline
 long-acting
Serum half-life of 16-18 hours
Doxycycline and minocycline
Almost complete absorption and slow excretion of
these drugs allow for once daily dosing.
160
 Therapeutic Uses
 Rickettsial Infections
 Doxycycline is the drug of choice
 Mycoplasma Infections
 Chlamydial infections
 Trachoma
 Sexually Transmitted Diseases
 Because of resistance, doxycycline no longer is
recommended for gonococcal infections
 Anthrax
 Doxycycline: for prevention or treatment of
anthrax
161
 Therapeutic Uses (cont’d)
 Bacillary Infections
 Brucellosis
Tetracyclines in combination with rifampin or
streptomycin
 Tularemia
TTCs are effective, though streptomycin is preferable
 Cholera
Doxycycline
 Other Bacillary Infections
 Ineffective in infections caused by Shigella, Salmonella, or
other Enterobacteriaceae

162
 Therapeutic Uses (cont’d)
 Coccal Infections
 Resistance restricts their use in staphylococcal,
streptococcal, or meningococcal infections.
 Community strains of MRSA often are susceptible to TTC,
doxycycline, or minocycline
 Doxycycline effective for empirical therapy of community-
acquired pneumonia
 Are generally drugs of choice in infections with
Mycoplasma pneumoniae, chlamydiae, rickettsiae,
and some spirochetes
 Are sometimes employed in the treatment of
protozoal infections (Entamoeba histolytica,
Plasmodium falciparum)
163
164
 Cont’d tetracycline

2/9/2025 165
 Adverse effects
Gastrointestinal Adverse Effects
 Nausea, vomiting, and diarrhea
 modification the normal flora with overgrowth
of pseudomonas, proteus, staphylococci,
resistant coliforms, clostridia, and candida

Bony Structures and Teeth

 Deposition in calcium deposited in newly
formed bone or teeth
166
 Adverse effects (cont’d)
Liver Toxicity
 Especially during pregnancy

Kidney Toxicity
 Aggravate azotemia in patients with renal
disease

Photosensitization

Vestibular Reactions
 Dizziness, vertigo, nausea, and vomiting 167
Contraindications
 In pregnant women
 Children under the age of 8 years

Therapeutic selection
 Little difference in clinical response among the
various TTCs.
 The selection of an agent, therefore, is based on
Tolerance
Ease of administration, and
Cost
168
CHLORAMPHENICOL
169
 Introduction
 Crystalline chloramphenicol is a neutral, stable
compound

 Contains a nitrobenzene moiety and is a

derivative of dichloroacetic acid.
 The biologically active form is levorotatory.
170
 Mechanism of Action
 It inhibits protein synthesis in bacteria, and to a
lesser extent, in eukaryotic cells.
 Binds reversibly to the 50S ribosomal subunit

 Although binding of tRNA at the codon recognition site

on the 30S ribosomal subunit is undisturbed, the drug
apparently prevents the binding of the amino acid-
containing end of the aminoacyl tRNA to the
acceptor site on the 50S ribosomal subunit.

 The interaction between peptidyltransferase and its

amino acid substrate cannot occur, and peptide bond
formation is inhibited
171
Steps in bacterial protein synthesis and
targets of (1) chloramphenicol; (2)
macrolides, clindamycin, and type B
streptogramins; and (3) tetracyclines
172
 Pharmacokinetics
 Crystalline CAF is rapidly and completely absorbed
After oral administration

 widely distributed to virtually all tissues and body

fluids, including the CNS and CSF s

 It penetrates cell membranes readily

 Most of the drug is inactivated either by

conjugation with glucuronic acid or by reduction
to inactive aryl amines
173
 Antimicrobial Actions
 Broad spectrum antimicrobial activity

 Effective against Gm(+) and Gm(-) bacteria,

including Rickettsia, Mycoplasma, and Chlamydia spp.

 Also effective against most anaerobic bacteria,

including Bacteroides fragilis.

174
 Resistance to Chloramphenicol

Resistance is caused due to

 Plasmid-encoded acetyltransferase that
inactivates the drug (Acetylated derivatives fail
to bind to bacterial ribosomes)

 Decreased permeability of the drug

 Ribosomal mutation.

175
 Therapeutic Uses
 Typhoid Fever
 3rd GC and quinolones are drugs of choice
 Bacterial meningitis
3rd GC have replaced CAF
An alternative in patients allergic to -lactams and in
developing countries
 Rickettsial Diseases
The TTCs are the preferred agents
In patients allergic to TTCs, in reduced renal function,
in pregnant women, and in children younger than 8
years of age who require prolonged or repeated
courses of therapy, CAF is the drug of choice
 Brucellosis
 When a TTC is contraindicated CAF is recommended.
176
 Untoward effects
 CAF inhibits the synthesis of proteins of the inner
mitochondrial membrane, probably by inhibiting the
ribosomal peptidyltransferase.

 These include subunits of cytochrome c oxidase,

ubiquinone-cytochrome c reductase, and the proton-
translocating ATPase critical for aerobic metabolism.

 Much of the toxicity observed with this drug can be

attributed to these effects.
177
 Untoward effects (cont’d)
 Newborn infants cannot adequately conjugate CAF
to form the glucuronide
High levels of free CAF cause the gray baby syndrome.
 Abdominal distention, vomiting, progressive cyanosis, irregular
respiration, hypothermia, and vasomotor collapse

 Effects on hematopoietic system: manifested by bone

marrow depression or idiosyncratic aplastic anemia.
 Bone marrow depression is dose related and is
characterized by anemia, leukopenia or thrombocytopenia,
but it is reversible on discontinuation of CAF.
 Aplastic anemia is usually fatal. The mechanism is not
known, but it occurs most frequently with oral or
ocular administration. 178
 Drug Interactions
 CAF inhibits hepatic CYP450s and prolongs the t½ of
drugs metabolized by this system (warfarin,
dicumarol, phenytoin, chlorpropamide, antiretroviral
protease inhibitors, rifabutin, and tolbutamide)

 Phenobarbital, rifampin potently induce CYPs and

shorten the t½ of CAF

179
MISCELLANEOUS
ANTIBIOTICS
180
Vancomycin

181
 Introduction
 A glycopeptide antibiotic of molecular weight 1500
daltons produced by Streptococcus orientalis.

 With the single exception of flavobacterium, it is

active only against gram-positive bacteria,
particularly staphylococci.

 It is water-soluble and quite stable.

182
 Antibacterial Activity
 a narrow-spectrum agent active against Gm(+)
organisms

 Bacteriostatic against staphylococci, streptococci, and

enterococci.

 G(+) rods, such as Bacillus anthracis, Corynebacterium

diphtheriae, Clostridium tetani, and Clostridium
perfringens, are also susceptible
 Not effective against Gm(-) rods, mycobacteria, or
183
fungi.
 Mechanism of Action
 Cell wall synthesis inhibitor
 Binds firmly to the D-Ala-D-Ala terminus of nascent
peptidoglycan pentapeptide . This inhibits the
transglycosylase, preventing further elongation of
peptidoglycan and cross-linking.

 The peptidoglycan is thus weakened and the cell becomes

susceptible to lysis.

 The cell membrane is also damaged, which contributes to

the antibacterial effect.
184
 Mechanism of Resistance

 Resistance to vancomycin in enterococci and

vancomycin-resistant S aureus strains is due to
 modification of the D-Ala-D-Ala binding site of the
peptidoglycan building block in which the terminal D-
Ala is replaced by D-lactate.

185
 Pharmacokinetics
 Poorly absorbed from the GIT and should be orally
administered only for the treatment of antibiotic-
associated enterocolitis caused by Clostridium difficile
 Parenteral doses must be administered IV
 The drug has a serum elimination half-life of about 6 hours.
 Appears in various body fluids, including the CSF when the
meninges are inflamed
 About 90% is excreted by glomerular filtration (dosage
adjustments in renal impairment)

186
 Clinical Uses
 Should be employed only to treat serious infections
 is particularly useful in the management of infections due to
MRSA, and in severe staphylococcal infections in patients
who are allergic to penicillins and cephalosporins.
 Effective and convenient when there is disseminated
staphylococcal infection or localized infection of a shunt in a
patient with irreversible renal disease who is being
maintained by hemodialysis or peritoneal dialysis
 Treatment of infections caused by Corynebacterium spp.
 Important in the management of known or suspected
penicillin-resistant pneumococcal infections

187
Clindamycin

188
189
 Mechanism of Action and Resistance
 Clindamycin inhibits protein synthesis by interfering with
the formation of initiation complexes and with aminoacyl
translocation reactions.
 The binding site for clindamycin on the 50S subunit of the
bacterial ribosome is identical with that for erythromycin.
 Resistance to clindamycin, which generally confers cross-
resistance to other macrolides, is due to
i. mutation of the ribosomal receptor site
ii. modification of the receptor by a constitutively expressed
methylase
iii. Enzymatic inactivation of clindamycin
 Gm(-) aerobic species are intrinsically resistant because of
poor permeability of the outer membrane.

190
 Mechanism of Action and
Resistance (cont’d)
Macrolide resistance due to ribosomal methylation
may produce resistance to clindamycin.

However, because clindamycin does not induce the

methylase, there is cross-resistance only if the
enzyme is produced constitutively.

Clindamycin is not a substrate for macrolide efflux

pumps
191
 Antibacterial Activity
 Streptococci, staphylococci, and pneumococci are
inhibited by clindamycin

 Enterococci and Gm(-) aerobic organisms are

resistant (in contrast to their susceptibility to
erythromycin).

 Bacteroides species and other anaerobes, both

Gm(+) and Gm(-), are usually susceptible.

 Clostridium difficile is resistant.

192
 Pharmacokinetics
 Absorption
 Nearly completely absorbed following oral administration
 Food in the stomach does not reduce absorption significantly
 Distribution
 Widely distributed in many fluids and tissues
 Readily crosses the placental barrier
  90% is bound to plasma proteins
 Excretion
 10% is excreted unaltered in the urine, and small quantities are
found in the feces.
 Inactivated by metabolism to N-demethylclindamycin and
clindamycin sulfoxide, which are excreted in the urine and bile

193
 Therapeutic Uses
 Treatment of severe anaerobic infection caused by
bacteroides and other anaerobes that often participate in
mixed infections.
 In combination with aminoglycoside or cephalosporin,
 To treat penetrating wounds of the abdomen and the gut

 Clindamycin plus primaquine is an effective alternative to co-

trimoxazole for moderate to moderately severe Pneumocystis
carinii pneumonia in AIDS patients.
 Also used in combination with pyrimethamine for AIDS-
related toxoplasmosis of the brain.

194
 Untoward Effects
 Diarrhea (in 2% to 20% subjects)
 Pseudomembranous colitis caused by the toxin from C.
difficile
 Characterized by abdominal pain, diarrhea, fever, and mucus and blood
in the stools.
 It may be lethal
 Discontinuation of the drug, combined with administration of
metronidazole orally or intravenously usually is curative
 Skin rashes, Stevens-Johnson syndrome, impaired liver
function, granulocytopenia, thrombocytopenia, and
anaphylactic reactions
 Local thrombophlebitis with IV administration
 Can inhibit neuromuscular transmission and may potentiate
the effect of a neuromuscular blocking
195
Spectinomycin

196
 Introduction
 Spectinomycin is an antibiotic produced by
Streptomyces spectabilis.
 It is an aminocyclitol with the following structural
formula

197
 Antibacterial Activity and Mechanism

 Active against a number of Gm(-) bacterial species,

but it is inferior to other drugs to which such
microorganisms are susceptible.

 Its only therapeutic use is in the treatment of

gonorrhea caused by strains resistant to first-line
drugs, or if there are contraindications to the use of
these drugs

198
 Mechanism of Action and Resistance
 Spectinomycin selectively inhibits protein synthesis in
Gm(-) bacteria.
 It binds to and acts on the 30S ribosomal subunit.
 Its action is similar to that of the aminoglycosides, but
spectinomycin is not bactericidal and does not cause
misreading of mRNA.
 Bacterial resistance may be mediated by mutations in the
16S ribosomal RNA or by modification of the drug by
adenylyltransferase
199
Pharmacokinetics
 Rapidly absorbed after IM injection.
 It is not significantly bound to plasma protein
 All of an administered dose is recovered in the
urine within 48 hours.
Therapeutic Uses
 Recommended in the treatment uncomplicated
gonococcal infection as an alternative regimen in
patients who are intolerant or allergic to -lactam
antibiotics and quinolones.
200
 Untoward Effects
Urticaria, chills, and fever, dizziness, nausea,
and insomnia.

Rarely Nephrotoxicity and anemia

Pain at the site of injection

201
 Polymixin B & Colistin
 The polymyxins, discovered in 1947,

 Produced by various strains of Bacillus polymyxa.

 Colistin is produced by Bacillus (Aerobacillus)

colistinus.
 Are cationic detergents

 are relatively simple, basic peptides with

molecular masses of about 1000 daltons.

202
 Antibacterial Activity and Mechanism of Action
 Activity is restricted to Gm(-) bacteria, including Enterobacter,
E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, Shigella,
most strains of P. aeruginosa.
 Proteus spp. are intrinsically resistant.

 Polymyxins are surface-active, amphipathic agents. They

interact strongly with phospholipids and disrupt the structure
of cell membranes.

 Sensitivity to polymyxin B apparently is related to the

phospholipid content of the cell wall-membrane complex.

 The cell walls of certain resistant bacteria may prevent access

of the drug to the cell membrane. 203
 Pharmacokinetics
 Both are not absorbed when given orally and are poorly
absorbed from mucous membranes and the surfaces of
large burns.
 Cleared renally (dose adjustment in renal impairment)
 Therapeutic Uses
 Colistin may be useful as a salvage regimen for
treatment of infections caused by MDR organisms such
as Stenotrophomonas maltophilia, Acinetobacter spp.,
or P. aeruginosa,
 Infections of the skin, mucous membranes, eye, and ear
due to sensitive microorganisms

204
 Untoward Effects
 Muscle weakness and apnea (interference with
neurotransmission at the neuromuscular junction)

 Vertigo, and slurred speech.

 Polymyxins are nephrotoxic, and administration with

aminoglycosides should be avoided if possible

205
ANTITUBERCULOSIS
DRUGS

206
 Characteristics of mycobacteria that make the
diseases chronic & necessitate prolonged treatment
 Mycobacteria grow slowly and may be dormant in the host
for long periods
 Many antibacterials do not penetrate mycobacterial cell
walls, and a portion reside inside macrophages
 Mycobacteria are agile in developing resistance to single
chemotherapeutic agents
 Consequence  effective therapy requires a
prolonged course of multiple drugs
 Patient compliance, drug toxicity, drug interactions,
concurrence of other diseases

207
 Tuberculosis
 Two species of Mycobacterium cause tuberculosis:
M. tuberculosis and M. bovis
 M. tuberculosis is transmitted by inhalation of
infective droplets coughed or sneezed into the air
by a patient with tuberculosis.

 M. bovis is transmitted by milk from diseased cows

and first produces intestinal or tonsillar lesions.

208
 Drugs for
Tuberculosis

209
First-line drugs are superior in efficacy and possess
an acceptable degree of toxicity.
 Include isoniazid, rifampin, pyrazinamide, ethambutol,
and streptomycin (Controvertial)
 Most patients with tuberculosis can be treated
successfully with these drugs.
 Second-line drugs are more toxic and less effective
 Indicated only when the M. tuberculosis organisms are
resistant to the first-line agents.
 Include cycloserine, ethionamide, aminosalicylic acid,
rifabutin, quinolones, capreomycin, viomycin, and
thiacetazone.
210
First-line drugs for
tuberculosis

211
 Isoniazid (isonicotinic acid
hydrazide, INH)
Chemistry
 Isoniazid is the hydrazide of isonicotinic acid
 Structurally similar to pyridoxine
 A small, simple molecule freely soluble in water

212
 Antibacterial Activity
 The most active drug for the treatment of tuberculosis
caused by susceptible strains
 Is bacteriostatic for "resting" bacilli, but is
bactericidal for rapidly dividing microorganisms
 Remarkably selective for mycobacteria
 Minimum tuberculostatic concentration = 0.025 to 0.05 mg/ml
 The growth of other microorganisms is inhibited with
concentrations in excess of 500 mg/ml
 Penetrates cells with ease and is just as effective against
bacilli growing within cells as it is against those
growing in culture media (Effective intracellular activity)
213
 Mechanism of Action
 Mycobacterial catalase-peroxidase (katG encoded) converts isoniazid
into an active metabolite
 A primary action of isoniazid is to inhibit the biosynthesis of mycolic
acids (MA)
 Resistance can be mapped to mutations in at least five different
genes: katG, inhA, ahpC, kasA, and ndh.
 Catalase-peroxidase-activated isoniazid binds enoyl-ACP reductase of
fatty acid synthase II, which converts 2-unsaturated fatty acids to
saturated fatty acids in the mycolic acid biosynthetic pathway.
 It also inhibits mycobacterial catalase-peroxidase, which may increase
the likelihood of damage to the mycobacteria from reactive oxygen
species and H2O2
214
 Bacterial Resistance
 Mutations in catalase-peroxidase (katg) (most common).

 Mutation in the mycobacterial inhA and KasA genes involved

in mycolic acid biosynthesis

 Mutations in NADH dehydrogenase (ndh)

 Cross-resistance between isoniazid and other antituberculosis

agents (except ethionamide) does not occur.

 Approximately 1 in 106 tubercle bacilli are genetically resistant

to isoniazid

215
 Pharmacokinetics
 Water soluble, well absorbed from oral & parenteral sites
 Does not bind to serum proteins, diffuses readily into all body
fluids and cells
 Caseous tuberculous lesions.
 Pleural and ascitic fluids, saliva and skin
 Concentrations in CNS & CSF are similar to those in plasma
during meningeal inflammation
 INH is acetylated to acetyl INH by N-acetyltransferase
 Genetic polymorphism in the rate of acetylation.
 Slow or rapid acetylation is rarely important clinically, although
slow inactivators tend to develop peripheral neuropathy more
readily.
216
 Clinical Uses
 Isoniazid is the safest and most active mycobactericidal

 Considered the primary drug for use in all therapeutic and

prophylactic regimens for susceptible tuberculosis infections

 As a single agent for treatment of latent tuberculosis, which is

usually determined by a positive tuberculin skin test.

217
 Adverse Reactions
 Allergic Reactions
 Fever, skin rashes, Drug-induced systemic lupus
erythematosus
 Direct Toxicity
 Hepatitis (greater risk in alcoholics & pregnancy and is a
contraindication to further use of the drug).
 Peripheral neuropathy due to a relative pyridoxine
deficiency (more likely in slow acetylators, malnutrition,
alcoholism, diabetes, AIDS)
 Minimized by administration of pyridoxine

 CNS toxicity (memory loss, psychosis, and seizures)

 May respond to pyridoxine

218
 Rifampin and other rifamycins
 The rifamycins (rifampin, rifabutin, rifapentine) are a group
of structurally similar, complex macrocyclic antibiotics
produced by Amycolatopsis mediterranei

 Rifampin is a semisynthetic derivative of rifamycin B.

 Rifampin is soluble in organic solvents and in water at

acidic pH.

219
 Antibacterial Activity
 Rifampin inhibits the growth of M. tuberculosis in
vitro.
 It also inhibits the growth of nontuberculous
mycobacteria
 Rifampin inhibits the growth of most Gm(+) bacteria
as well as many Gm(-) microorganisms such as E. coli,
Pseudomonas, Proteus, and Klebsiella.

220
 Mechanism of Action
 Rifampin binds DNA-dependent RNA polymerase and forms
stable drug-enzyme complex, leading to suppression of
initiation of chain formation (but not chain elongation) in
RNA synthesis.
 Nuclear eukaryotic RNA polymerases are unaffected
 High concentrations can inhibit RNA synthesis in
mammalian mitochondria, viral DNA-dependent RNA
polymerases, and reverse transcriptases.
 Bactericidal for both intracellular and extracellular
microorganisms.

221
 Bacterial Resistance
 Occurence: 1 in 107 to 108 tubercle bacilli

 Due to an alteration of the DNA-dependent RNA

polymerase,
 Mutations between codons 507 and 533 of the
polymerase rpoB gene
 Reduced binding of the drug to the polymerase

 It should not be used alone since resistance develops very fast

222
 Pharmacokinetics
 Well absorbed after oral administration and excreted
mainly through the liver into bile.
 Undergoes enterohepatic recirculation
 Intestinal reabsorption is reduced by food
 Small amount excreted in urine
 Distributed widely in body fluids and tissues
 Rifampin is relatively highly protein-bound,
 Adequate CSF concentrations are achieved only in the
presence of meningeal inflammation
223
 Clinical Uses
 A first-line antitubercular drug used in the treatment
of all forms of pulmonary and extrapulmonary TB

 Alternative to INH in the treatment of latent TB

infection

 In combination with antileprosy agent for the

treatment of leprosy

 Also used in MRSA infections

224
 Adverse Reactions
 Imparts orange color to urine, sweat, tears

 Rashes, thrombocytopenia, and nephritis,

cholestatic jaundice and occasionally hepatitis

 It is a strong inducer of most cytochrome P450

isoforms
 Increases the elimination of numerous drugs including
methadone, anticoagulants, some anticonvulsants,
protease inhibitors, and contraceptives

225
 Ethambutol
Ethambutol is a synthetic, water-soluble,
heat-stable compound

226
 Antibacterial Activity
 Nearly all strains of M. tuberculosis and M.
kansasii as well as a number of strains of MAC are
sensitive

 Ethambutol has no effect on other bacteria.

 It suppresses the growth of most INH-and

streptomycin-resistant tubercle bacilli.

 Resistance to ethambutol develops very slowly in

vitro.
227
 Mechanism of Action and
Resistance
 Inhibits arabinosyl transferases involved in cell wall
biosynthesis.

 The enzyme is involved in the polymerization

reaction of arabinoglycan, an essential component
of the mycobacterial cell wall.

 Bacterial resistance to the drug develops via single

amino acid mutations in the embA gene when
ethambutol is given in the absence of other effective
agents 228
 Pharmacokinetics

 Well absorbed from the GIT

 About 20% of the drug is excreted in feces and

50% in urine in unchanged form (dose adjustment
in renal impairment)

 Is widely distributed in all body fluids

 It crosses the BBB only if the meninges are inflamed.

229
 Clinical Uses
 Has replaced aminosalicylic acid as a first-line
antitubercular drug.

 Commonly included as a 4th drug, along with INH,

pyrazinamide, and rifampin, in patients infected with
MDR strains.

 Also used in combination in the treatment of M.

aviumintracellulare infection in AIDS patients.

230
 Adverse Reactions

 Hypersensitivity, loss of visual acuity and red-green

color blindness (most serious side-effects)

 Ethambutol is relatively contraindicated in children

too young to permit assessment of visual acuity and
red-green color discrimination.

231
 Streptomycin
 An aminoglycoside antibiotic and was the first drug
to reduce tuberculosis mortality.

 It is bactericidal against M. Tuberculosis in vitro

but is inactive against intracellular organisms.

 Most M. tuberculosis strains and nontuberculosis

species, such as M. kansasii and M.
Aviumintracellulare,are sensitive.

232
 Antibacterial Activity
 Bactericidal in vitro.

 Suppressive activity in vivo

 Most M. tuberculosis strains and nontuberculosis

species, such as M. kansasii and M.
aviumintracellulare, are sensitive
 It penetrates into cells poorly, and is active
mainly against extracellular tubercle bacilli

233
 Mechanism of action and resistance
 Prokaryotic ribosomal protein synthesis inhibitor

 Spontaneous resistance occurs in approximately 1 in

106 tubercle bacilli,

 Resistance is related to a point mutation that

involves the gene (rpsl or rrs) that encodes for
ribosomal proteins and binding sites

 About 80% of strains that are resistant to INH and

rifampin are also resistant to streptomycin.
234
 Clinical Use in TB
 As a fourth drug in combination with INH, rifampin,
and pyrazinamide in patients at high risk for drug
resistance

 Employed when an injectable drug is needed or

desirable, (severe, possibly life-threatening forms of
TB, and in treatment of infections resistant to other
drugs)

 Other drugs are always given simultaneously to

prevent emergence of resistance 235
 Pyrazinamide
 Synthetic pyrazine analog of nicotinamide

 It is stable, slightly soluble in water, and quite

inexpensive.

 At neutral pH, it is inactive in vitro, but at pH

5.5 it inhibits tubercle bacilli

 Drug is taken up by macrophages and exerts its

activity against intracellular organisms residing
within acidic environment.
236
 Mechanism of Action and Resistance
 Exact MOA unknown, although its target appears to be the
mycobacterial fatty acid synthetase involved in mycolic acid
biosynthesis.

 It is a prodrug activated to the active pyrazinoic acid by the

mycobacterial enzyme pyrazinamidase

 Mutation in the gene (pncA) that encodes pyrazinamidase is

responsible for drug resistance

 Resistance develops fairly readily, but there is no cross-

resistance with INH or other antimycobacterial drugs.

237
 Pharmacokinetics
 Pharmacokinetics
 Well absorbed from the GIT and widely distributed in
body tissues, including inflamed meninges

 Clinical uses
 An important front-line drug used in conjunction
with INH and rifampin in short-course (ie, 6-month)
regimens as a "sterilizing" agent active against
residual intracellular organisms that may cause
relapse.
238
 Adverse effects

Hepatotoxicity (in 1–5%), nausea, vomiting,

drug fever, and hyperuricemia (occurs
uniformly and may provoke acute gouty
arthritis)

239
• Category I
• It includes those new patients who have smear-positive
Pulmonary TB and those who seriously ill patients with
smear-negative Pulmonary and Extra-pulmonary TB..
• The treatment regimen for this category is 2 (RHZE) / 6
(EH) or OR 2 (RHZE) / 4RH
• Category II
• This category is applied to a group of TB patients:
▫ Who relapsed after being treated and declared free
from the disease, OR

Please refer the TB guide line for dosages and regimen

▫ In those patients who are previously treated for more
than one month with SCC or LCC, and found to be
smear positive upon return, OR
▫ Who still remain smear positive while under treatment
,at month five and beyond
▫ The treatment regimen for this category is: 2 SE (RHZ) /
1E (RHZ) / 5 E3 (RH)3.
• Category III
• This refers to patients who have smear negative Pulmonary
TB, Extra-pulmonary TB and TB in Children.
• The regimen consists of 8 weeks of treatment with,
Ethambutol, Rifampicin, Isoniazid and Pyrazinamide during
the intensive phase followed by Ethambutol and Isoniazid
six months [2(RHZE/)/6(EH)]
• Category IV
• Treatment of chronic cases
• those cases that continue to be smear-positive after
completion of a fully supervised (initial phase and
continuation phase) treatment with the treatment regimen
Alternative Second-Line Drugs
for Tuberculosis

243
 Quinolones
 The fluoroquinolones are highly active against M. tb as well
as nontuberculous mycobacteria

 important components of treatment regimens of MDR TB

 C-8-methoxy-fluoroquinolones (gatifloxacin and

moxifloxacin) are the most active

 Cross-resistance within the entire class is common

 To prevent development of resistance, the most active

fluoroquinolones should be used, and only in combination
with other antimycobacterial agents

244
 Ethionamide
 A derivative of isonicotinic acid and is chemically
related to isoniazid.

 A secondary agent used in combination when

primary agents are ineffective or contraindicated

 It is a bacteriostatic antituberculosis agent.

245
Mechanism of Action
 EtaA, an NADPH-specific, FAD-containing
monooxygenase, converts ethionamide to a
sulfoxide, and then to 2-ethyl-4-aminopyridine

 Inhibits the activity of the inhA gene product,

the enoyl-ACP reductase of fatty acid synthase II
Inhibition of mycolic acid biosynthesis and
consequent impairment of cell-wall synthesis.

246
 Pharmacokinetics
 Well absorbed following oral administration

 Rapidly and widely distributed to all body tissues and

fluids, including the cerebrospinal fluid.

 Cleared by hepatic metabolism; it inhibits the

acetylation of isoniazid in vitro.

 Less than 1% of the drug is eliminated in the urine

unchanged.

247
 Therapeutic Uses
 A secondary agent, used concurrently with other drugs
only when therapy with primary agents is ineffective or
contraindicated.

 Untoward Effects
 Anorexia, nausea and vomiting, gastric irritation, and a
variety of neurologic symptoms. Severe postural
hypotension, mental depression, drowsiness, convulsions,
peripheral neuropathy.
 Pyridoxine (vitamin B6) relieves the neurologic symptoms
 Metallic taste
248
 P-Aminosalycilic acid
 Folate synthesis antagonist that is active almost
exclusively against M. tb.

 It is structurally similar to p-aminobenzoic acid

(PABA) and to the sulfonamides

249
 Mechanism of Action
 It is a folate synthesis antagonist that interferes with the
incorporation of PABA into folic acid.
 PAS is bacteriostatic
 Therapeutic Uses
 A second-line agent
 Untoward Effects
 GI problems(anorexia, nausea, epigastric pain, abdominal
distress, and diarrhea)
 Patients with peptic ulcers tolerate the drug poorly
 Hypersensitivity reactions
 Hematological abnormalities (leukopenia, agranulocytosis,
eosinophilia, lymphocytosis, thrombocytopenia).

250
 Cycloserine
 Cycloserine is a broad-spectrum antibiotic produced
by Streptomyces orchidaceus.

 It is structural analogue of D-alanine

 Antibacterial Activity
 No cross-resistance between cycloserine and other
tuberculostatic agents.

 D-alanine blocks the antibacterial activity of cycloserine

 Inhibitory to M. tb and active against E. coli, S. aureus, and

Enterococcus,Nocardia, and Chlamydia spp.
251
 Mechanism of Action
 Cycloserine and D-alanine are structural analogs; thus,
cycloserine inhibits reactions in which D-alanine is
involved in bacterial cell-wall synthesis
 Pharmacokinetics
 Rapidly absorbed When given orally (70% to 90%)
 Distributed throughout body fluids and tissues
 CSF concentrations are approximately the same as those
in plasma
 About 65% of a parenteral dose is excreted unchanged
in the urine in the first 72 hours.

252
 Therapeutic Uses
 In the treatment of MDR tuberculosis and is useful in renal
tuberculosis, since most of the drug is excreted unchanged in
the urine
 Untoward Effects
 CNS (headache, tremor, vertigo, confusion, nervousness,
irritability, psychotic states with suicidal tendencies, paranoid
reactions, catatonic and depressed reactions, visual
disturbances, seizures)

 Contraindicated in individuals with a history of epilepsy and

should be used with caution in individuals with a history of
depression, as suicide is a risk.
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 Other drugs
 Kanamycin & Amikacin
 Aminoglycoside antibiotics
 Amikacin is indicated for treatment of tb suspected or known to be
caused by streptomycin-resistant or MDR strains

 Capreomycin
 A polypeptide antibiotic derived from Streptomyces capreolus.
 It is bacteriostatic against most strains of M. tuberculosis, including
the MDR strain.
 Used as a second-line agent in combination with other drugs.
Particularly useful in multidrug regimens for the treatment of drug
resistant tb (esp with streptomycin resistance)
 Capreomycin is associated with ototoxicity and nephrotoxicity
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