CHEMOTHERAPY (ANTIBIOTICS)

Chemotherapy can be defined as the use of chemicals in infectious diseases to destroy microorganisms
without damaging the host tissues.
Antibiotics are substances produced by microorganisms which suppress the growth of or destroy other
microorganisms.
CLASSIFICATION
1. Based on their mechanisms of action, anti-microbial are classified as follows.

2. ON THE BASIS OF MODE OF ACTION

Bacteriostatic - agents that suppress the growth of bacteria.
For example, Sulfonamides, tetracyclines, linezolid chloramphenicol, clindamycin.
Bactericidal - agents that kill the bacteria. For example, Penicillins, cephalosporins, aminoglycosides,
fluoroquinolones, rifampicin, metronidazole, vancomycin.
3. Antibacterial spectrum An antimicrobial may have a narrow or broad spectrum of activity.
Narrow spectrum -For example: Penicillin G - gram-positive Aminoglycosides - gram-negative
Broad spectrum- Tetracyclines, Chloramphenicol
Broad spectrum antibiotics are so called because, in addition to suppression of gram-positive and gram-
negative bacteria, they also inhibit the growth of other micro-organisms like Rickettsiae, Chlamydiae,
Mycoplasma and some protozoa.

MAHESH PATEL
MSC.N (CVS), PHARMACOLOGY
SULFONAMIDES
Sulfonamides were the first effective antibacterial agents to be used systemically in man. They are
synthetic agents that contain a sulfonamide group.
Antibacterial spectrum Sulfonamides inhibit gram-positive and some gram-negative bacteria, nocardia,
chlamydiae, Plasmodium falciparum and Toxoplasma gondii
Mechanism of Action
PABA

Folic acid synthetase ← Sulfonamides

Dihydrofolic Acid
Bacteria synthesize their own folic acid from p-amino benzoic acid (PABA) with the help of the enzyme
folic acid synthetase. Sulfonamides are structurally similar to PABA and competitively inhibit the enzyme
folic acid synthetase. This results in folic acid deficiency and injury to the bacterial cell.Human cells are
not affected because they require preformed folic acid supplied from the diet and cannot synthesize folic
acid by themselves. Sulfonamides are bacteriostatic.
Classification
Short-acting :- Sulfisoxazole, sulfadiazine
Intermediate-acting :- Sulfamethoxazole
Long-acting :- Sulfamethoxypyridazine, Sulfadoxine
Poorly absorbed :- Sulfasalazine
Topical :- Sulfacetamide, mefenide Silver sulfadiazine.

COTRIMOXAZOLE
The combination of trimethoprim and sulfamethoxazole is cotrimoxazole. Trime-thoprim is
effective against several gram-positive and gram -negative organisms. But when used as a
sole agent, resistance develops rapidly.
Mechanism of action Sulfonamides inhibit the conversion of PABA to dihydrofolic acid
(DHF) and trimethoprim inhibits dihydrofolate reductase (DHFR) and thus prevents the
reduction of DHF to tetrahydrofolic acid (THF). The two drugs thus block sequential steps in
folic acid synthesis and the combination in bactericidal.
 QUINOLONES
The quinolones are a group of synthetic antimicrobial agents. Nalidixic acid is the older agent in the group.
Oxalinic acid and cinoxacin are other quinolones.
Nalidixic acid is bactericidal against various gram-negative organisms like E. coli, Shigella, Proteus and
Klebsiella. Its mechanism of action is same as that of fluoroquinolones (see below). Nalidixic acid is well
absorbed orally. However, the plasma concentration of the drug is inadequate to have systemic effects but
it attains high concentrations in the urine.
FLUOROQUINOLONES
The quinolones were fluorinated to obtain compounds with a wider spectrum of activity, fewer side effects,
lesser chance of resistance and better tissue penetration when compared to quinolones. The fluoroqui-
nolones (FQs) include norfloxacin, ciprofloxacin, pefloxacin, ofloxacin, lomefloxacin and sparfloxacin—
many more are being added. The newer agents include trovafloxacin, gatifloxacin, moxifloxacin, and
clinafloxacin.
Mechanism of Action
Fluoroquinolones are bactericidal. They inhibit the bacterial enzyme DNA gyrase (topoisomerase II)
which is required for DNA replication and transcription. During DNA replication there is positive
supercoiling of the DNA. This is corrected by the enzyme DNA gyrase by introducing negative
supercoils and therefore this enzyme is necessary for DNA replication. By inhibiting the enzyme
DNA gyrase, fluoroquinolones inhibit DNA replication.

Beta-lactam Antibiotics
The β-lactam antibiotics have a β-lactam ring. Penicillins, cephalosporins, monobactams and carbapenems
are β-lactam antibiotics.
PENICILLINS - Sir Alexander Fleming discovered penicillin in 1928. Penicillins are one of the most
important groups of antibiotics. Penicillin is now obtained from the fungus Penicillium chrysogenum.
Mechanism of Action
The β-lactam antibiotics act by inhibiting the cell wall synthesis in the bacteria.
The rigid cell wall of the bacteria protects it from lysis. Peptidoglycan—a complex polymer, is an
important component of the cell wall. It consists of glycan chains which are cross-linked by peptide chains.
The synthesis of this peptidoglycan requires enzymes called transpeptidases. β-lactam antibiotics inhibit
these transpeptidases and thus inhibit the synthesis of the peptidoglycan, resulting in the formation of cell
wall deficient bacteria. Such bacteria undergo lysis. Thus penicillins are bactericidal.
Classification
A. Natural—Penicillin G
B. Semisynthetic
Acid resistant—Penicillin V
Penicillinase resistant— Methicillin, Oxacillin, Cloxacillin, Nafcillin
Aminopenicillins— Ampicillin, Bacampicillin, Amoxicillin
Antipseudomonal penicillins
Carboxypenicillins— Carbenicillin, Ticarcillin
Ureidopenicillins— Azlocillin, Mezlocillin, Piperacillin.

CEPHALOSPORINS
Cephalosporins are semisynthetic antibiotics with a beta-lactam ring related to penicillins. They are
derived from cephalosporin-C and have a wider spectrum of activity than penicillins.
Mechanism of action Cephalosporins inhibit the bacterial cell wall synthesis similar to penicillins
Cephalosporins are classified into 4 generations as follows:
 Parenteral Oral

First generation Cephalothin Cephalexin

Cefazolin Cefadroxil
Second
generation Cefamandole Cefachlor
Cefuroxime Cefuroxime
Cefotetan, axetil
Cefoxitin
Third generation Cefotaxime Cefixime
Ceftrioxone Cefpodoxime
Cefoperazone proxetil
Ceftizoxime Cefdinir
Ceftazidime Ceftibuten
Fourth
generation Cefepime
Cefpirome

CARBAPENEMS
Carbapenems contain a β-lactam ring fused with a five-membered penem ring. Carba-penems include
imipenem, meropenem and ertapenem.
Antibacterial spectrum – Carbapenems have a wide antibacterial spectrum and inhibit various gram-
positive, gram-negative organisms and anaerobes including streptococci, staphylococci, enterococci,
Listeria, enterobacteriaceae, Pseudomonas and B.fragilis.
Mechanism of Action
Carbapenems inhibit bacterial cell wall synthesis similar to penicillins (see page 270). Imipenem-is not
absorbed orally and is administered intravenously (250- 500 mg every 6-8 hours); it has good tissue
penetrability. Imipenem is inactivated quickly by a dehydropeptidase in the renal tubules. Hence it is
always combined with cilastatin, an inhibitor of dehydropeptidase in order to prolong its plasma half life.

MONOBACTAMS

Monobactams are monocyclic beta-lactams, i.e they contain a single ring–the beta-lactam
ring. Aztreonam is the monobactam available. It is active against gram - negative bacilli
including Pseudomonas aeruginosa but is not effective against gram-positive organisms and
anaerobes. Aztreonam acts by inhibiting cell wall synthesis like penicillins. It is given
parenterally (IM/IV 1-2 G every 6-8 hrs). Aztreonam can be used in patients allergic to
penicillins because there is no cross allergenicity with other β-lactams. The only reported
adverse effects are occasional skin rashes. Aztreonam is used in pseudomonas infections
especially nosocomial and in other gram-negative infections.
Broad Spectrum Antibiotics
TETRACYCLINES
Tetracyclines are antibiotics with four cyclic rings (hence the name) obtained from the soil actinomycetes.
In addition to gram-positive and gram-negative bacteria, tetracyclines also inhibit the growth of other
micro-organisms like Rickettsiae, Chlamydiae, Mycoplasma and some protozoa. Therefore they are called
broad spectrum antibiotics.
The tetracyclines include-
Tetracyclines Semisynthetic derivatives
Chlortetracycline Demeclocycline
Tetracycline Methacycline
Oxytetracycline Doxycycline
Minocycline
Mechanism of action Tetracyclines are taken up by the susceptible microorganisms by active transport.
The bacterial ribosome (Fig. 38.1) consists of 50S and 30S subunits. The tRNA carries amino acids to the
ribosome for protein synthesis. The ribosome has three binding sites viz. A, P and E sites. Tetracyclines
bind to 'A' site and prevent the binding of tRNA to this site. Thus they prevent protein synthesis and are
bacteriostatic.
Antibacterial spectrum is broad including gram-positive and gram-negative organisms like
Streptococci, Staphylococci,Gonococci, Meningococci, H. influenza, Brucella, V. cholerae,
Campylobacter, Y.pestis and many anaerobes.They also inhibit rickettsiae, chlamydiae,
mycoplasma, actinomyces, E. histolytica and plasmodia. Many organisms have now become
resistant.
CHLORAMPHENICOL
Chloramphenicol is a broad spectrum antibiotic first obtained from Streptomyces venezuelae in 1947.
Mechanism of action Chloramphenicol is bacteriostatic but to some organisms it is bactericidal. It binds to
50S ribosomal subunit and inhibits protein synthesis - by inhibiting transpeptidation reaction.
Antibacterial spectrum is broad and includes gram-negative organisms, some gram-positive organisms,
anaerobic bacteria, Rickettsiae, Chlamydiae and Mycoplasma. Thus H. influenzae, Salmonella, Shigella,
Bordatella, Brucella, gonococci, mening-ococci, streptococci, staphylococci, Clostri-dium, E.coli and
Klebsiella—are inhibited apart from Rickettsiae, Chlamydiae and Mycoplasma.

Aminoglycosides
Aminoglycosides are antibiotics with amino sugars in glycosidic linkages. They are derived from the soil
actinomycetes of the genus streptomyces (streptomycin, kana-mycin, tobramycin, neomycin) and the
genus micromonospora (gentamicin and netilmicin) hence the difference in spelling. Amikacin and
netilmicin are semisynthetic products.
Mechanism of action Aminoglycosides, being water-soluble penetrate the bacterial cell membrane
through aqueous pores and from there they are taken up by an active transport process. Inside the cell, (Fig.
39.1) amino-glycosides bind to 30S ribosomes and inhibit bacterial protein synthesis - block initiation of
protein synthesis, cause termination of protein synthesis and cause addition of incorrect amino acids
resulting in the synthesis of abnormal proteins. Amino-glycosides are bactericidal. Higher the
concentration, greater is the bactericidal effect. A residual bactericidal effect— postantibiotic effect—
remains even after the plasma levels of aminoglycosides fall. Hence, even though they have a short t½,
they can be given once a day

Aminoglycosides Doses Routes

Streptomycin (STREPTONEX) 1-2 g/day IM

Gentamicin (GARAMYCIN) 3-5 mg/kg/day in 3 divided doses IM/IV
Tobramycin (TOBRANEG) 3-5 mg/kg/day in 3 divided doses IM/IV
Amikacin (AMICIN) 15 mg/kg/day in 2-3 divided doses IM/IV
Netilmicin (NETROMYCIN) 4-6 mg/kg/day in 2-3 divided doses IM/IV
Macrolides and Antibacterial Agents and
Chemotherapy of Urinary Tract Infections
Macrolides are antibiotics with a macrocyclic lactone ring to which sugars are attached.
Erythomycin and its semisynthetic deri-vatives roxithromycin, clarithromycin and
azithromycin are macrolides.
ERYTHROMYCIN
Erythromycin is obtained from Streptomyces erythreus.
Antibacterial spectrum Erythromycin has a narrow spectrum and is effective against aerobic gram- positive
bacteria and a few gram-negative organisms. Streptococci, pneumococci, staphylococci, gonococci, C.
diphtheriae, C. jejuni, Mycoplasma, Chlamydiae and some atypical mycobacteria are sensitive.
Mechanism of Action
Erythromycin is bacteriostatic at low and cidal at high concentrations. It binds to 50S ribosomes and
inhibits bacterial protein synthesis. Chloramphenicol and clindamycin also bind to 50 S ribosomes and the
three may inhibit each others activity. Hence the combination should be avoided.

Drug Dose (oral) and duration

Erythromycin stearate 250-500 mg QID

(ERYTHROCIN) 7-14 days

Erythromycin estolate 250-500 mg QID

(ALTHROCIN) 7-14 days
Erythromycin gluceptate 500-1000 mg 6 hrly for 10-14 days

Roxithromycin 150 mg BD
(ROXID) (to be taken 30 minutes before food)

Clarithromycin 250-500 mg BD
(CLARIBID) 7-14 days

Azithromycin Ist day 500 mg OD

(AZITHRAL) 250 mg OD for next 3-4 days
(to be taken 1 hr before or 2 hrs after food)
Tuberculosis and Leprosy
Tuberculosis is a chronic granulomatous disease caused by Mycobacterium tuberculosis
Drugs Used in Tuberculosis
1. First line drugs Isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin.
2. Second line drugs Ethionamide, thia-cetazone, para aminosalicylic acid (PAS), amikacin,
ciprofloxacin, capreomycin, cycloserine, rifabutin, kanamycin.
Based on antitubercular activity, drugs may be grouped as:
Tuberculocidal agents–Isoniazid, rifam-picin, streptomycin, pyrazinamide, capreomycin, kanamycin,
ciprofloxacin.
Tuberculostatic agents–Ethambutol, ethio-namide, thiacetazone, cycloserine PAS.
Isoniazid
Mechanism of action INH inhibits the synthesis of mycolic acids which are the important components of
the mycobacterial cell wall.INH enters the mycobacteria where it is converted to an active metabolite. This
metabolitie binds the enzymes necessary for mycolic acid synthesis. Thus the synthesis of mycolic acid is
inhibited.
Rifampicin
Mechanism of action Rifampicin binds to DNA dependent RNA polymerase and inhibits RNA synthesis
in the bacteria.
Pyrazinamide
Pyrazinamide is tuberculocidal, being more active in acidic pH. Mechanism of action is not
known. It is effective against intracellular bacilli. If used alone resistance develops. It is well-
absorbed (achieves good con-centration in CSF). Hepatotoxicity is the most common adverse
effect. Hyperuricaemia (due to ↓ excretion of uric acid may result in gouty arthritis),
arthralgia, anorexia, vomit-ing and rashes may be seen
Streptomycin
Streptomycin is tuberculocidal, acts only against extracellular organisms due to poor penetrating power. It
has to be given IM. When used alone resistance develops. Because of these disadvantages and its
toxicity(ototoxicity and nephrotoxicity), streptomycin is the least preferred of the first line drugs.
Ethambutol
is tuberculostatic and acts on fast multiplying bacilli in the cavities. It is also effective against atypical
mycobacteria. It inhibits the incorporation of mycolic acids into the mycobacterial cell wall.
Optic neuritis resulting in ↓ visual acuity and inability to differentiate red from green is an important
adverse effect which needs withdrawal of the drug. Colour vision should be monitored during treatment.
Ethambutol is to be avoided in children because their ability to differentiate red from green cannot be
reliably tested. Other adverse effects include nausea, anorexia, headache, fever and allergic reactions.
Drugs Doses
Isoniazid (INH) 300-400 mg
Ethambutol (E) 800-1000 mg
Rifampicin (R) 450-600 mg
Streptomycin (S) 750-1000 mg
Pyrazinamide (Z) 1200-1500 mg
Thiacetazone (T) 150 mg