CHEMOTHERAPY

• Chemotherapy involves treatment of infectious diseases using chemical substances –

(chemo: chemical agents, therapy: treatment). Antibiotic is any substance obtained from
microorganisms acting against microorganisms. Antimicrobial agent –is a synthetic
substances acting against microorganisms.

❑ IDEAL ANTIBIOTIC/antimicrobial agent

• Selectively toxic and should not trigger allergic and hypersensitive reactions

• Effective against broad range of bacteria (preferably bactericidal rather than bacteriostatic)

• Desired levels should be reached rapidly and maintained for adequate period of time

• Be free of interactions with other drugs

• Should be affordable and should not give rise to resistance 1

 CLASSIFICATION OF ANTIBACTERIAL AGENT
1. Spectrum of activity
▪ Broad spectrum: G– and G+ organisms e.g. Tetracycline, Chloramphenicol,
Cephalosporins
▪ Narrow spectrum; limited activity usually against particular species e.g.
Aminoglycoside, sulfonamides, Polymixin; Bactricin
2. Type of action
Bacteriostatic: sulfonamides, tetracycline, macrolides etc
Bacteriocidal: Aminoglycoside, penicillin, metronidazole, cephalosporin
3. Mechanism of action: i. Inhibitors of cell wall synthesis ii. Inhibitors of
protein synthesis iii. Inhibitors of nucleic acid synthesis iv. Inhibitors of cell
membrane function v. Inhibitors of folic acid synthesis
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Antibacterial agents

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 PENICILLINS
• Alexander Fleming (1928) -discovers a mold which inhibits the growth of staph. Penicillin
produced by Penicillium chrysogenum by fermentation. 6-APA (6-aminopenicillanic acid)
developed as semi-synthetic penicillin. They are β-lactams penicillin as Intact β-lactam ring
is essential for activity. Antibacterial activity is time dependent, so must maintain MIC
❑ Classifications of penicillin:
o A) Natural penicillin: e.g. Penicillin G (Benzyl penicillin), Penicillin V (Phenoxymethyl),
Procaine Penicillin G, Benzathine Penicillin G
o B) Penicillinase-resistant penicillin: Methicillin, Nafcillin, Oxacillin, Cloxacillin
o C) Aminopenicillins: Amoxicillin, Ampicillin, Bacampicillin HCL
o D) Extended-spectrum penicillin: Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin
o E) β-lactamase combination: Amoxicillin- clavulanic acid, Ampicillin-sulbactam.
Ticarcillin-clavulanic acid, Piperacillin-tazobactam. 4
❑ Spectrum of activity: ranges between - Good gram +, gram - ,
✓Penicillin G (effective but painful in IV or IM, has a bulky side chain, hence poor GI
penetration, resistant to β-lactamase
✓Penicillin V, (Acid resistant thus taken orally, however readily hydrolyzed by β-lactamase)
✓ Methicillin, Oxacillin, Cloxacillin etc. Penicillinase - Resistant thus IV & PO
✓Amoxicillin, Ampicillin inactivated by beta-lactamases = ineffective against Staphylococcus,
amoxicillin has an extended spectrum of activity against many gram negative bacilli and is
acid resistant
❑ Therapeutic uses
✓Penicillin G benzathine Syphilis, rheumatic fever prophylaxis ,streptococcal pharyngitis
✓Penicillin V streptococcal pharyngitis
✓Methicillin, Oxacillin, Cloxacillin etc. used to treat penicillinase-producing Staph aureus.
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❑ Therapeutic uses (Amoxicillin, Ampicillin):
• H. Influenza infections (otitis media, sinusitis, chronic bronchitis, pneumonia, bacterial
meningitis), E. Coli infections (Urinary & biliary infections), samonella infections (typhoid
fever), shigella infections, gonococcal infections
• NB: Amoxicillin & ampicillin alone are readily destroyed by Staph. Penicillinase are
ineffective against P. aeruginosa
❖ Piperacillin, Ticarcillin etc. (Extended Spectrum Penicillin /Anti-pseudomonas Penicillin):
More resistant to β-lactamase than aminopenicillins, susceptible to degradation in the GIT
and not penicillinase resistant
❑ Therapeutic uses: Pseud. aeruginosa infections. For pseud. septicemia, give together with
an aminoglycoside ( e.g. Gentamicin ).
❖ β-lactamase Combination: These compounds act as suicide inhibitors of the b-
lactamases, they bind with beta-lactamase and prevent the enzyme from breaking down the
penicillin. The enzyme remains acylated
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❑ MOA: Penicillin inhibit the trans-peptidase catalyzed reaction thus hindering the formation
of cross-links essential for cell wall integrity. They are therefore cell wall synthesis
inhibitors
❑ Pharmacokinetics: Oral absorption mostly poor (Except: Penicillin V and Amoxicillin)
• Relatively insoluble in lipid. Hence, have poor penetration into cells and BBB
• Short half-lives (0.5-2 h) and must be given 3-4 times per day. Excreted mostly unchanged
in urine via tubular secretion. Probenecid blocks their secretion at the renal tubules.
• NB: Take on an empty stomach as Food slows their absorption, Acids in fruit juices or colas
could deactivate the drug
❑ Adverse Reactions
1. Hypersensitivity - mild or severe; urticarial rash most common, Fever, exfoliative
dermatitis, Stevens-Johnson syndrome and anaphylaxis
2. Superinfection - secondary infection when normal microbial flora of the body disturbed
during antibiotic Rx
3. Organ toxicity - esp. liver & kidneys
SS. nausea, vomiting, diarrhea, abdominal pain. Diarrhea is more common with ampicillin 7
 CEPHALOSPORINS
• Cephalosporins are semisynthetic derivatives from a fungus, Cephalosperium acremonium.
Cephalosporins are similar to penicillins but have a 6 member dihydrothiazine ring instead
of a 5 member thiazolidine ring. They share similar features of chemistry, mechanism of
action, pharmacologic, clinical effects and side effects with the other β-lactam drugs

• Cephalosporins are classified into four groups called “generations” based on their parallel
chronological development & Their antimicrobial spectrum

• Later generations generally become more effective against Gram (-) bacteria due to an
increasing number of polar groups. Ceftazidime (3rd gen) in particular can cross blood
brain barrier and is used to treat meningitis.

• Later generations are often the broadest spectrum and are reserved against penicillin
resistant infections to prevent the spread of cephalosporin resistant bacteria.
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❑ 1st Gen: e.g. cefadroxil & cephalexin (PO); Cefazolin & cephalothin (IM)
• Good gram-positive coverage, poor gram-negative coverage, Cephalexin has the highest
therapeutic index. Nephrotoxic to a certain degree
• Used for skin/skin structure infections, penicillinase productive S. aureus, surgical
prophylaxis, resp, GI, bone, & joint infections, community-acquired infections, URIs, otitis
media
❑ 2nd Gen: cefaclor (PO), cefoxitin, cefuroxime (PO), cefotetan (IM, IV), cefprozil etc.,
• Good gram+ve coverage and better gram-ive coverage than first generation
• Used for: otitis media, respiratory infections, UTIs, LRTIs, mixed infections (peritonitis,
pelvic infections), sinusitis. Cefuroxime does not kill anaerobes; but the only member that
crosses the BBB – used for meningitis 9
❑ 3rd Gen: cefixime, ceftizoxime, cefpodoxime, ceftriaxone, ceftazidime, cefotaxime.
• The broadest spectrum, most potent against G+ve and least active against G-ve
• Highest resistance to β-lactamase, best penetration of the BBB, no nephrotoxicity, long half-
life, so once-a-day dosing for some
• Used for ambulatory patients, UTI, LRTI, Septicemia, cellulitis, typhoid fever, gonorrhea
o Cefixime: Only oral 3rd-Gen and best oral cephalosporins against
gram-negative (Tablet and suspension)
o Ceftriaxone – IM and IV, long half-life, once-a-day dosing (Easily passes meninges and
diffused into CSF to treat CNS infections, Not advised in neonates (↑ bilirubin).
o Ceftazidime – IV and IM, used for difficult-to-treat organisms such as Pseudomonas spp.
Excellent spectrum of coverage, Eliminated renally instead of biliary rout
❑ 4th Gen: cefepime (IV or IM), cefpirome (Newest)
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❖ Pharmacokinetics: Relatively lipid insoluble do not penetrate cells or the CNS, except 3rd
gen. Mostly excreted unchanged by the kidney (glomerular & tubular secretion ), except,
ceftazidime, cefoperazone, and ceftriaxone (biliary tract)
• Probenecid slows their elimination and prolong their half-live (except ceftazidime &
cefoperazone), Half-life 30-90 min; ceftriaxone 4-7 hr. (the longest in cephalosporins)
❖ Therapeutic uses: Alternative to penicillin in allergic patients, URTI and otitis media (e.g
cefaclor, cefuroxime, cefprozil, cefixime), septicemia caused by G- bacteria ( P.
aeruginosae), urinary tract infections -E.coli ( cefuroxime, cefixime), prophylaxis in
surgery: Appendectomy, Obstetrical & gynecological, urological, orthopedic procedures, etc,
Meningitis- N. Meningitidis, Gonococcal infections
❖ Adverse effects: Hypersensitivity reactions (most common), thrombophlebitis ( i.v.
administration), superinfections, diarrhea when use oral cephalosporins.
• cefoperazone may cause: bleeding disorders (hypothrombinemia), flushing, tachycardia,
vomiting with alcohol intake
• Elevation of liver enzymes (5-10%), disulfiram-like reaction and displacement of bilirubin
from albumin binding sites - theoretical problem in neonates (ceftriaxone & cefoperazone)
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 AMINOGLYCOSIDES
• E.g. Streptomycin, Gentamicin, Netilmicin, Amikacin, Tobramycin etc. Streptomycin (from
genus Streptomyces), Gentamicin (from micromonospora); or semi synthetic e.g. netilmicin.
Antibacterial activity is concentration dependent, i.e more effective if higher blood
concentration are reached periodically.

• Post antibiotic effect: A persistent suppression of bacterial growth seen even when
concentration of drug falls below MIC. A feature seen with aminoglycosides, this explains
why these drugs can be given in a single daily dose even though they have a short half life (1-
3) Hrs.

• Spectrum of activity: broad gram negative coverage including Pseudomonas, Enterobacter,

Serratia, Proteus, Acinetobacter, Klebsiella, others. Used in combination with another
antibiotic such as beta-lactam to extend coverage, provide synergy, and because may not be
effective alone outside of the urinary tract (due to tissue hypoxia, WBC debris , local
acidosis, etc.) 12
• MOA: Ribosomes are involved in protein synthesis by bacteria, Aminoglycosides crosses
outer bacterial membrane by passive diffusion via porin channels and bind to 30S ribosomal
units of bacteria and prevent formation of initiation complex. Which is prerequisite for
peptide synthesis. Lack of formation of initiation complex causes 30S subunit to misread
genetic code on mRNA. Incorrect amino acids (nonsense peptides) are thus incorporated
into growing peptide chain which are of no use for bacterial growth.
• Clinical uses: Serious, life-threatening G-ve infection, complicated skin, bone or soft tissue
infection, complicated urinary tract infection, sepsis, peritonitis and other severe intra-
abdominal infections, severe pelvic inflammatory disease, endocarditis, mycobacterium
infection, neonatal sepsis, ocular infections (topical), otitis externa (topical)
❖ Gentamicin: most widely used, effective for both G+ve (although resistance occurs) and
G-ves. Therapeutic Applications: UTI, pneumonia (nosocomial), peritonitis, meningitis and
sepsis. IM, IV; Topical and Ophthalmic
❖ Streptomycin: (IM), 2nd line for tuberculosis in combination with other agents
❖ Amikacin: (IV, IM); Used for resistant bacteria 13
❖Neomycin: Limited to topical and oral use e.g. bowel prep for surgery. Paromomycin:
For intestinal amebiasis, hepatic coma; Oral. Netilmicin; Similar to gentamicin and
tobramycin, but may be more active against resistant strains, IV, IM
❑ Adverse effects:
• Nephrotoxicity: Reversible renal failure (acute tubular necrosis) Risk factors: elderly,
renal dysfunction, dehydration, hypotension, liver disease, concomitant use of other
nephrotoxins, > 5 days of therapy (limit therapy to 2 weeks if possible). Somewhat depends
on the aminoglycoside, most nephrotoxic include neomycin, tobramycin and gentamicin
• Ototoxicity: Both vestibular (2/3 of ototoxicity; manifests as vertigo, ataxia, loss of
balance, tinnitus) and Cochlear: (1/3 of ototoxicity; manifests as high frequency hearing
loss, deafness is unusual). Often irreversible e.g. Neomycin, kanamycin, amikacin are most
ototoxic
• Other effects: Neuromuscular blockade (very high doses given too fast resulting in
respiratory paralysis), hypersensitivity (rare)
• Question: Gentamicin has a short half-life of 1-3 Hrs. but is most a times prescribed once
daily. Explain the reason for that? 14
 TETRACYCLINES
• Natural agents: (Tetracycline, oxytetracyclin isolated from Streptomyces), Aureomycin,
Terramycin, Panmycin
• Synthetic agents: Doxycycline, Minocycline, Methacycline, Demeclocycline
• At present, for many reasons such as toxicity, drug resistance, the development of more
effective agents, the uses of tetracyclines have largely declined. Tetracycline is limited for a
few infections and is being gradually substituted by some semisynthetic tetracyclines such as
minocycline (most active) and doxycycline.

MOA: Sensitive bacteria pump tetracyclines into the

cell by energy dependent system; TCN bind to the 30S
ribosomal subunit at a site that blocks binding of
charged tRNA to the "A" site of the ribosome;
This prevents addition of amino acids to the growing
peptide, resulting in inhibition of protein synthesis.

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• TCN can inhibit mammalian protein synthesis, but because they are "pumped" out of most
mammalian cells, they do not usually reach concentrations needed to significantly reduce
mammalian protein synthesis.
• Broad-spectrum bacteriostatic antibiotics. Include G+ and G– aerobe and anaerobe, ricketts
organism, spirochete, mycoplasma, chlamydia and some protozoan. But no activity to
Enterococci, Proteus and Pseud. aeruginosa.
• They are weaker than penicillin and cephalosporins, aminoglycosides and chloramphenicol
• administered orally, chelated and inactivated by calcium (milk), magnesium, aluminum
(antacids) and iron, and should be taken on empty stomach. Doxycycline is less avidly
chelated and can be taken with a meal.
Widely distributed in body, Bind in tissues undergoing
calcification (teeth, bones), cross placenta and concentrate
in fetal bones and teeth so contraindicated in pregnancy
Concentrate in liver and partially metabolized, Secreted
into bile and excreted in urine, Doxycycline and
minocycline largely excreted in feces (Used in renal
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insufficiency)
• Adverse Effects of TCN: : GI discomfort (Anorexia, epigastric pain, abdominal distention,
nausea, vomiting, diarrhea, sore mouth, perianal irritation)- take with full glass of water
while standing up. Hepatic injury, kidney toxicity (Nephrotoxicity), Teeth discoloration and
depression of bone growth, Photosensitization (Severe sunburn in sun;
doxy/demeclocycline). Contraindications: pregnancy, children, renal insufficiency, TCN may
interfere with the bactericidal action of penicillin. Concurrent use of tetracycline may render

CHLORAMPHENICOL
oral contraceptives less
• Initially obtained from Streptomyces venuzuelae, broad spectrum. effect on G+ and G–
bacteria (including anaerobes), Salmonella typhi, ricketts organism, spirochete, chlamydia,
mycoplasma. Excellent BBB penetration, antibacterial activity because of nitrobenzene
substitution in their chemical structure.
• MOA: blocks proper binding of aminoacyl moiety to "A" site. Failure to properly align
prevents peptidyl transferase enzyme from transferring the growing chain from the "P" site
to the bound charged tRNA in the "A" site. This stops protein synthesis.
• CP binds 50S subunit and block elongation by inhibiting the formation of initiation
complexes and peptidyltransferase; binding site of CP overlaps with that of macrolides and
clindamycin. 17
• CP is primarily bacteriostatic, but it may be bactericidal to
some strains of microorganisms even at lower concentration
(H. influenzae, N. meningitidis and N. gonorrhoeae)
• Rapidly absorbed, well distributed, (esp. meningitis), 90%
eliminated by glucuronyl transferase.Resembles tetracycline
in usage, except more serious hazard so limit use
• Adverse reaction: Dose dependent reversible bone marrow
depression, toxicity for newborn infants (Gray-baby
syndrome) when given relatively large doses of CP;
cyanosis, respiratory irregularities, abdominal distention,
loose green stool, and an ashen-gray color.
• Mainly due to the immature hepatic conjugating mechanism
for the degradation and detoxification of CP in neonates
(inadequate renal elimination mechanism and the inactive
metabolites).
• Drug interaction: Inhibits microsomal CYP450 enzymes.,
e.g. dicumarol, phenytoin, tolbutamide, chlorpropamide 18
 MACROLIDES QUINOLONES
✓ MOA: Inhibit bacterial protein synthesis by ❑ MOA: Inhibit bacterial DNA gyrase,
bindng to 50 S subunits of ribosomes topoisomerase II and DNA synthesis.
✓ E.g. Erythromycin, Azithromycin, Interferes with DNA synthesis by inhibiting
Clarithromycin, Roxithromycin topoisomerase II, (or DNA gyrase), an
✓ Pharmacokinetics: Well absorbed orally enzyme involved in DNA replication.
even in presence of food, distributed readily • It is bactericidal
to most tissues and partly metabolized,
eliminated entirely by the bile. They are ❑ Classification: into generations based on
microsomal enzyme inhibitor, hence produces their antibacterial spectra.
toxicity if given with some drugs ✓1st Gen: cinoxacin, oxalinic acid
✓ Indications: As an alternative for penicillin • 2nd Gen: ciprofloxacin, lomefloxacin,
allergic individuals, bronchitis, chancroid, ofloxacin, pefloxacin, norfloxacin
diphtheria, legionella infections, pertussis • 3rd Gen: levofloxacin, sparfloxacin,
(Whooping cough) temafloxacin, balofloxacin
✓ Side effects: Epigastric distress, nausea, • 4th Gen: trovafloxacin, alatrofloxacin,
vomiting and diarrhea, jaundice, ototoxicity gatifloxacin, moxifloxacin 19
❑ Pharmacokinetics: rapidly absorbed (delayed in presence of food), first pass metabolism,
high tissue penetrability and excreted primarily in urine
❑ Indications UTI, typhoid fever, gonorrhea, gastroenteritis, bacterial gastroenteritis,
respiratory infection, tuberculosis
❑ Contraindications: pregnancy, children, nursing mothers
❑ Side effects: Nausea, vomiting, insomnia, restlessness, seizure (rarely)

ANTI-METABOLITES: Sulfonamides and Trimethoprim

• SULFONAMIDES
• Prontosil - Red-dye (Prodrug), discovery of sulfonamide: a milestone in the discovery of
antimicrobial agents (AMAS).
• Sulfonamide- Active component of prontosil, have a common chemical nucleus
resembling PABA (Antagonizes PABA), competitively inhibits condensation of PABA with
dihydropteridine to form dihydopteroic acid

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 Inhibitors of Folate Synthesis
• The mechanism of action of involves selective inhibition
of plasmodial dihydrofolate reductase, a key enzyme in
the pathway for the synthesis of folate. Sulphonamides
and sulphones inhibit another enzyme in the folate
pathway dihydropteroate synthase
• Dihydrofolate reductase which converts DHF to THF,
deficiency of which inhibits plasmodial cell division.
• Bacteriostatic but in high conc act as bacteriocidal
• Cmax: 15-200 mcg/L; Half-life: 4-17h; Protein binding:
25% to 95%, primarily metabolized by acetylation
• Primarily used to prevent urinary tract infection
• CLINICAL USES: Sulfisoxazole, sulfamethoxazole
(urinary tract infection) Sulfadiazine, sulfasalazine plus
pyrimethamine plus folic acid (toxoplasmosis),
Sulfadoxine + Pyrimetrine (treatment of malaria)
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• Sulfasalazine (ulcerative colitis, enteritis, other inflammatory bowel disease)
• Sulfacetamide (ophthalemic), Mafenide & silver sulfadiazine (topically)
• Adverse reaction: Hypersensitivity rection (Stevens-Johnson syndrome), urinary tract
disturbances, crystalluria, hematuria, obstruction, Hematopoietic disturbance (Hemolytic or
aplastic anemia, Granulocytopenia, thrombocytopenia, leukmoid reaction, Hemolysis in G-
6PDH deficient patients)
• TRIMETHOPRIM
• A diaminopyrimidine related to pyrimethamine (folic acid antagonist) which selectively
inhibits bacterial dihydrofolate reductase (DHFRase)
• Is is concentrated in acidic prostate tissue and vaginal fluids via ion trapping, so it is useful
for the treatment of bacteria prostitis and vaginitis. It is a selective inhibitor of bacterial
dihydrofolate reductase. Prevent the active form of bacteria THFA. A bacteriostatic
antibiotic. Active against many aerobic gram-negative bacilli and a few gram positive
organisms
• Pharmacokinetic: orally, fully absorbed in the GIT, and widely distributed in tissues and
body fluids, t1/2 = 10 hrs, high concentration in lungs and kidneys, Partly metabolised in
liver and excreted unchained in the urine 22
• Clinical uses: trimethoprim (Acute urinary infection), trimethoprim-sulfamethoxazole (P.
jiroveci pneumonia, shigellosis, systemic salmonella infection, complicated urinary tract
infection), respiratory pathogens, pneumocystis pneumonia, Shigllosis, typhoid fever.
Pryrimethamine with sulfanamide with sulfadiazine (Leishmaniasis, toxoplasmosis), with
sulfadoxine (malaria)
Toxicity: megaloblastic anaemia, leukopenia, and granulocytopenia (effects ameliorated by
supplementary folinic acid).
CO-TRIMOXAZOLE
• Fixed dose combination of trimethoprim and sulfamethoxazole (TMP-SMX). Introduced in
1969 to block the sequential bacterial folate metabolism
• Sulfonamide and trimethoprim are bacteriostatic, but the combination becomes bacteriocidal
against many organism, maximum synergism is seen when the organism is sensitive to both
compounds
• TMP-SMX is effective against P. jiroveci pneumonia, shigellosis, systemic salmonella
infections, UTI, prostatitis, respiratory pathogens pneumococcus, H. influenzae and
Moraxella catarrhalis. TMP-SMX is also the drug of choice in nocardiosis, 23