GENERALCONSIDERATION,INTRODUCTION,CLASSIFICATION,AMINO GLYCOSIDE ANTIBIOTICS,BROAD-SPECTRUM ANTIBIOTICS

1. PRESENTED BY :- KINJAL S. GAMIT
DEPARTMENT OF PHARMACOLOGY
EN.NO :- 172280825005
M.PHARM
SEM -2
L.M.C.P.

2.  GENERALCONSIDERATION
 INTRODUCTION
 CLASSIFICATION
 AMINOGLYCOSIDE ANTIBIOTICS
 STREPTOMYCIN
 OTHER AMINOGLYCOSIDE ANTIBIOTICS
 BROAD-SPECTRUM ANTIBIOTICS
 TETRACYCLINES
 CHLORAMPHENICOL
 SUMMARIES
 REFERENCES
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3.  Chemotherapy means the use of chemicals (synthetic or
chemicals of indigenous origin) to destroy or inhibit
harmful parasites without disturbing the host tissue.
 Chemotherapy includes :
Antibiotics and
Chemotherapeutic agents
 Chemotherapeutic agents :
 They destroys or prevents the growth of microbes but
may or may not derived from the living organism.
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4.  Antibiotics : (anti: against & bios: life)
 These are substances produced by microorganisms,
which selectively suppress the growth of or kill other
microorganisms at very low concentrations.
 This definition excludes other natural substances which
also inhibit microorganisms but are produced by higher
forms (e.g. antibodies) or even those produced by
microbes but are needed in high concentrations (ethanol,
lactic acid, H2O2).
 All antibiotics are chemotherapeutics agents but all
chemotherapeutics agents need not be antibiotics.
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5.  Chemotherapy word given by Paul Ehrlich (FATHER OF
MORDEN CHEMOTHERAPY).
 Evolutionary period of Chemotherapy divided into 4
periods :
1. pre- Ehrlich era
2. Paul Ehrlich era
3. Modern era of chemotherapy
4. Golden era of antibiotics
Bacteriostatic: inhibit growth of bacteria
Bactericidal : kill the bacteria
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6.  Antimicrobial drugs can be classified in many ways:
A. Chemical structure
1.Sulfonamides and related drugs: Sulfadiazine and others,
Sulfones Dapsone (DDS),Paraaminosalicylic acid (PAS).
2.Diaminopyrimidines: Trimethoprim, Pyrimethamine.
3.Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin,
Gatifloxacin, etc.
4.β-Lactam antibiotics: Penicillins,
Cephalosporins,Monobactams, Carbapenems.
5.Tetracyclines: Oxytetracycline, Doxycycline, etc.
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7. 6.Nitrobenzene derivative: Chloramphenicol.
7.Aminoglycosides: Streptomycin, Gentamicin, Amikacin,
Neomycin, etc.
8.Macrolide antibiotics: Erythromycin, Clarithromycin,
Azithromycin, etc.
9.Lincosamide antibiotics: Lincomycin, Clindamycin.
10.Glycopeptide antibiotics: Vancomycin,Teicoplanin.
11.Oxazolidinone: Linezolid.
12.Polypeptide antibiotics: Polymyxin-B, Colistin,
Bacitracin, Tyrothricin.
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8. 13.Nitrofuran derivatives: Nitrofurantoin, Furazolidone.
14.Nitroimidazoles: Metronidazole, Tinidazole, etc.
15.Nicotinic acid derivatives: Isoniazid, Pyrazinamide,
Ethionamide.
16.Polyene antibiotics: Nystatin, Amphotericin-B, Hamycin.
17.Azole derivatives: Miconazole, Clotrimazole,
Ketoconazole, Fluconazole.
18.Others: Rifampin, Spectinomycin, Sod. fusidate,
Cycloserine, Viomycin, Ethambutol,Thiacetazone,
Clofazimine, Griseofulvin.
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9. B. Mechanism of action
1.Inhibit cell wall synthesis:
 Penicillins,Cephalosporins, Cycloserine, Vancomycin,
Bacitracin.
2. Cause leakage from cell membranes:
 Polypeptides:- Polymyxins, Colistin, Bacitracin.
 Polyenes:- Amphotericin B, Nystatin,Hamycin.
3. Inhibit protein synthesis:
 Tetracyclines,Chloramphenicol, Erythromycin,
Clindamycin,Linezolid.
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10. 4. Cause misreading of m-RNA code and affect
permeability:
 Aminoglycosides:-Streptomycin,Gentamicin, etc.
5. Inhibit DNA gyrase:
 Fluoroquinolones:- Ciprofloxacin and others.
6. Interfere with DNA function:
 Rifampin, Metronidazole.
7. Interfere with DNA synthesis:
 Acyclovir,Zidovudine.
8. Interfere with intermediary metabolism:
 Sulfonamides, Sulfones, PAS,
Trimethoprim,Pyrimethamine, Ethambutol.
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11. C. Type of organisms against which primarily active
1.Antibacterial:
 Penicillins, Aminoglycosides,Erythromycin, etc.
2. Antifungal:
 Griseofulvin, Amphotericin B,Ketoconazole, etc.
3. Antiviral:
 Acyclovir, Amantadine, Zidovudine,etc.
4. Antiprotozoal:
 Chloroquine, Pyrimethamine,Metronidazole, Diloxanide,
etc.
5. Anthelmintic:
 Mebendazole, Pyrantel, Niclosamide,Diethyl carbamazine,
etc.
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12. D. Spectrum of activity
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Narrow-spectrum Broad-spectrum
Penicillin G Tetracyclines
Streptomycin Chloramphenicol
Erythromycin

13. E. Type of action
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Primarily
bacteriostatic
Primarily
bactericidal
Sulfonamides Penicillins Cotrimoxazole
Erythromycin Cephalosporins Isoniazid
Tetracyclines Vancomycin Metronidazole
Chloramphenicol Polypeptides Pyrazinamide
Linezolid Aminoglycosides Ciprofloxacin
Ethambutol Nalidixic acid Rifampin
Clindamycin

14. F. Antibiotics are obtained from:
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Fungi Bacteria Actinomycetes
Penicillin Polymyxin B Aminoglycosides
Griseofulvin Tyrothricin Macrolides
Cephalosporin Colistin Tetracyclines
Aztreonam Polyenes
Bacitracin Chloramphenicol

15. 1. Toxicity
 (a) Local irritancy
 (b) Systemic toxicity
2. Hypersensitivity reactions
3. Drug resistance
 Natural resistance
 Acquired resistance
Resistance may be developed by mutation or
gene transfer.
4. Superinfection (Suprainfection)
5. Nutritional deficiencies
6. Masking of an infection
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16.  The Aminoglycosides are a group of antibiotics of
complex chemical structure, resembling each other in
antimicrobial activity, pharmacokinetic characteristics
and toxicity.
 The main agents are :
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Gentamicin
Streptomycin
Tobramycin
Amikacin
Neomycin

17.  These are a group of natural and semi synthetic
antibiotics having polybasic amino groups linked
glycosidically to two or more aminosugar (streptidine,2-
deoxy streptamine, garosamine) residues.
 These drugs effective against gram-negative bacteria.
 Streptomycin was the first member discovered in 1944 by
Waksman and his colleagues.
 It assumed great importance because it was active
against tubercle bacilli.
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18.  All Aminoglycosides are produced by soil actinomycetes
and have many common properties.
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Systemic
Aminoglycosides
Topical
Aminoglycosides
Streptomycin Neomycin
Amikacin Framycetin
Gentamicin
Sisomicin
Kanamycin
Tobramycin
Netilmicin

19.  Aminoglycosides inhibit bacterial protein synthesis.
 There are several possible sites of action.
 Their penetration through the cell membrane of the
bacterium depends partly on oxygen-dependent active
transport by a polyamine carrier system (which,
incidentally, is blocked by chloramphenicol) and they
have minimal action against anaerobic organisms.
 The effect of the aminoglycosides is bactericidal and is
enhanced by agents that interfere with cell wall synthesis
(e.g. penicillins).
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20.  All having the same general pattern of action
which may be described in two main steps:
(a) Transport of the aminoglycoside through the
bacterial cell wall and cytoplasmic membrane.
(b) Binding to ribosomes resulting in inhibition
of protein synthesis.
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21. 172280825005 (MPH SEM-2) 21

22.  1. All are used as sulfate salts, which are highly water
soluble; solutions are stable for months.
 2. They ionize in solution; are not absorbed orally;
distribute only extracellularly; do not penetrate brain or
CSF.
 3. All are excreted unchanged in urine by glomerular
filtration.
 4. All are bactericidal and more active at alkaline pH.
 5. They act by interfering with bacterial protein synthesis.
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23.  6. All are active primarily against aerobic gram-negative
bacilli and do not inhibit anaerobes.
 7. There is only partial cross resistance among them.
 8. They have relatively narrow margin of safety.
 9. All exhibit ototoxicity and nephrotoxicity.
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24.  Resistance to aminoglycosides is becoming a problem.
 It occurs through several different mechanisms, the most
important being inactivation by microbial enzymes, of
which nine or more are known.
 Amikacin was designed as a poor substrate for these
enzymes, but some organisms can inactivate this agent
as well.
 Resistance as a result of failure of penetration can be
largely overcome by the concomitant use of penicillin
and/or vancomycin, at the cost of an increased risk of
severe adverse effects.
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25.  The aminoglycosides are effective against many aerobic
Gram-negative and some Gram-positive organisms.
 They are most widely used against Gram-negative enteric
organisms and in sepsis.
 They may be given together with a penicillin in
streptococcocal infections and those caused by Listeria
spp. and P. aeruginosa .
 Gentamicin is the aminoglycoside most commonly used,
although tobramycin is the preferred member of this
group for P. aeruginosa infections.
 Amikacin has the widest antimicrobial spectrum and can
be effective in infections with organisms resistant to
gentamicin and tobramycin.
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26.  The aminoglycosides are polycations and therefore highly
polar.
 They are not absorbed from the gastrointestinal tract and
are usually given intramuscularly or intravenously.
 They cross the placenta but do not cross the BBB,
although high concentrations can be attained in joint and
pleural fluids.
 The plasma half-life is 2–3 h. Elimination is virtually
entirely by glomerular filtration in the kidney, 50–60% of
a dose being excreted unchanged within 24 h.
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27.  Serious, dose-related toxic effects, which may increase
as treatment proceeds, can occur with the
aminoglycosides, the main hazards being ototoxicity and
nephrotoxicity.
 The ototoxicity involves progressive damage to, and
eventually destruction of, the sensory cells in the cochlea
and vestibular organ of the ear.
 The result, usually irreversible, may manifest as vertigo,
ataxia and loss of balance in the case of vestibular
damage, and auditory disturbances or deafness in the
case of cochlear damage.
 streptomycin and gentamicin are more likely to interfere
with vestibular function, whereas neomycin and amikacin
mostly affect hearing.
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28.  Ototoxicity is potentiated by the concomitant use of
other ototoxic drugs (e.g. loop diuretics) and
susceptibility is genetically determined via mitochondrial
DNA.
 The nephrotoxicity consists of damage to the kidney
tubules and may necessitate dialysis, although function
usually recovers when administration ceases.
 Nephrotoxicity is more likely to occur in patients with
pre-existing renal disease or in conditions in which urine
volume is reduced, and concomitant use of other
nephrotoxic agents (e.g. first-generation cephalosporins,
vancomycin) increases the risk.
 Plasma concentrations monitored regularly.
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29.  A rare but serious toxic reaction is paralysis caused by
neuromuscular blockade.
 This is usually seen only if the agents are given
concurrently with neuromuscular-blocking agents.
 It results from inhibition of the Ca2+ uptake necessary
for the exocytotic release of acetylcholine.
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30.  1. Avoid aminoglycosides during pregnancy: risk of foetal
ototoxicity.
 2. Avoid concurrent use of other ototoxic drugs,e.g. high
ceiling diuretics, minocycline.
 3. Avoid concurrent use of other nephrotoxic drugs, e.g.
amphotericin B, vancomycin,cyclosporine and cisplatin.
 4. Cautious use in patients past middle age and in those
with kidney damage.
 5. Cautious use of muscle relaxants in patients receiving
an aminoglycoside.
 6. Do not mix aminoglycoside with any drug in the same
syringe/infusion bottle.
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31.  It is the oldest aminoglycoside antibiotic obtained from
Streptomyces griseus; used extensively in the past, but
now practically restricted to treatment of tuberculosis.
 It is less potent (MICs are higher) than other
aminoglycosides.
 The antimicrobial spectrum of streptomycin is relatively
narrow: active primarily against aerobic gram-negative
bacilli, but potency is low.
 Sensitive organisms are—H. ducreyi, Brucella, Yersinia
pestis,Francisella tularensis, Nocardia, Calym.granulomatis,M.
tuberculosis.
 Only few strains of E. coli, H. influenzae, V. cholerae, Shigella,
Klebsiella, enterococci and some gram-positive cocci are now
inhibited, that too at higher concentrations.
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32.  Many organisms develop rapid resistance to
streptomycin, either by one-step mutation or by
acquisition of plasmid which codes for inactivating
enzymes.
 In the intestinal and urinary tracts, resistant organisms
may emerge within 2 days of therapy. E. coli., H.
influenzae, Str. pneumoniae, Str. pyogenes, Staph.aureus
have become largely resistant.
 If it is used alone, M. tuberculosis also become resistant.
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33. Streptomycin dependence
 Certain mutants grown in the presence of streptomycin
become dependent on it.
 Their growth is promoted rather than inhibited by the
antibiotic.
 This occurs when the antibiotic induced misreading of
the genetic code becomes a normal feature for the
organism.
 This phenomenon is probably significant only for use of
streptomycin in tuberculosis.
Cross resistance
 Only partial and often unidirectional cross resistance
occurs between streptomycin and other aminoglycosides.
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34.  Streptomycin is highly ionized.
 It is neither absorbed nor destroyed in the g.i.t. However,
absorption from injection site in muscles is rapid.
 It is distributed only extracellularly: volume of
distribution (0.3 L/kg) is nearly equal to the extracellular
fluid volume.
 Low concentrations are attained in serous fluids like
synovial, pleural, peritoneal.
 Concentrations in CSF and aqueous humour are often
nontherapeutic, even in the presence of inflammation.
 Plasma protein binding is clinically insignificant.
 Streptomycin is not metabolized—excreted unchanged in
urine.
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35.  Glomerular filtration is the main channel: tubular
secretion and reabsorption are negligible.
 The plasma t½ is 2–4 hours, but the drug persists longer
in tissues.
 Half-life is prolonged and accumulation occurs in
patients with renal insufficiency, in the elderly and
neonates who have low g.f.r.
 Reduction in dose or increase in dose-interval is essential
in these situations.
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36.  About 1/5 patients given streptomycin 1 g BD i.m.
experience vestibular disturbances.
 Auditory disturbances are less common.
 Streptomycin has the lowest nephrotoxicity among
aminoglycosides; probably because it is not concentrated
in the renal cortex.
 Hypersensitivity reactions are rare; rashes, eosinophilia,
fever and exfoliative dermatitis have been noted.
 Anaphylaxis is very rare.
 Topical use is contraindicated for fear of contact
sensitization.
 Superinfections are not significant.
 Pain at injectionsite is common. Paraesthesias and
scotoma are occasional.
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37.  1. Tuberculosis
 2. Subacute bacterial endocarditis (SABE): Streptomycin
(now mostly gentamicin) is given in conjunction with
penicillin. A 4–6 weeks treatment is needed.
 3. Plague: It effects rapid cure (in 7–12 days), may be
employed in confirmed cases, but tetracyclines have been
more commonly used for mass treatment of suspected
cases during an epidemic.
 4. Tularemia: Streptomycin is the drug of choice for this
rare disease: effects cure in 7–10 days.
 Oral use of streptomycin for diarrhoea is banned in India.
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38.  It was obtained from Micromonospora purpurea in 1964;
has become the most commonly used aminoglycoside for
acute infections.
 Gentamicin : plasma t½ of 2–4 hours after i.m. injection
are the same as streptomycin, but there are following
differences:
 (a) It is more potent (MIC for most organisms is 4–8 times
lower.)
 (b) It has a broader spectrum of action:
 effective against Ps. aeruginosa and most strains of
Proteus, E. coli, Klebsiella, Enterobacter, Serratia.
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39.  (c) It is ineffective against M. tuberculosis, Strep.
pyogenes and Strep. pneumoniae, but inhibits many
Strep. faecalis and some Staph. aureus.
 (d) It is relatively more nephrotoxic.
 Dose: The dose of gentamicin must be precisely
calculated according to body weight and level of renal
function.
 For an average adult with normal renal function
(creatinine clearance > 100 ml/min) 3–5 mg/kg/day i.m.
either as single dose or divided in three 8 hourly doses is
recommended.
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40.  The daily dose of gentamicin (and other aminoglycosides)
should be reduced in patients with impaired renal
function according to measured creatinine clearance.
 A general guideline is:
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guideline for dose adjustment of
gentamicin in renal insufficiency
CLcr (ml/min) % of daily dose
70 70% daily
50 50% daily
30 30% daily
20–30 80% alternate day
10-20 60% alternate day
<10 40% alternate day

41.  Gentamicin is the cheapest (other than streptomycin) and
the first line aminoglycoside antibiotic. However, because
of low therapeutic index, its use should be restricted to
serious gramnegative bacillary infections.
 1.Gentamicin is very valuable for preventing and treating
respiratory infections in critically ill patients; in those
with impaired host defence (receiving anticancer drugs or
high-dose corticosteroids; AIDS; neutropenic), patients in
resuscitation wards, with tracheostomy or on respirators;
postoperative pneumonias; patient with implants and in
intensive care units. It is often combined with a
penicillin/cephalosporin or another antibiotic in these
situations.
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42.  Aminoglycosides should not be used to treat community
acquired pneumonias caused by gram-positive cocci and
anaerobes.
 Gentamicin is often added to the peritoneal dialysate to
prevent or treat peritonitis.
 2. Pseudomonas, Proteus or Klebsiella infections: burns,
urinary tract infection, pneumonia, lung abscesses,
osteomyelitis, middle ear infection, septicaemia, etc. are
an important area of use of gentamicin.
 It may be combined with piperacillin or a third generation
cephalosporin for serious infections.
 Topical use on infected burns and in conjunctivitis is
permissible.
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43.  3. Meningitis caused by gram-negative bacilli: in addition
to the usual i.m. dose, 4 mg intrathecal injection may be
given daily, but benefits are uncertain.
 Because this is a serious condition, drug combinations
including an aminoglycoside are used.
 The third generation cephalosporins alone or with a
aminoglycoside are favoured for this purpose.
 4. SABE: gentamicin is more commonly used.
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44.  It is a semisynthetic derivative of kanamycin to which it
resembles in pharmacokinetics, dose and toxicity.
 The outstanding feature of amikacin is its resistance to
bacterial aminoglycoside inactivating enzymes.
 Thus, it has the widest spectrum of activity, including
many organisms resistant to other aminoglycosides.
 Relatively higher doses are needed for Pseudomonas,
Proteus and Staph. infections.
 It is recommended as a reserve drug for hospital acquired
gram-negative bacillary infections where
gentamicin/tobramycin resistance is high.
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45.  It is effective in tuberculosis, but rarely used for this
purpose.
 More hearing loss than vestibular disturbance occurs in
toxicity.
 Dose: 15 mg/kg/day in 1–3 doses;
urinary tract infection 7.5 mg/kg/day.
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46.  It was obtained from S. tenebrarius in the 1970s.
 The antibacterial and pharmacokinetic properties,as well
as dosage are almost identical to gentamicin, but it is 2–4
times more active against Pseudomonas and Proteus,
including those resistant to gentamicin.
 It is not useful for combining with penicillin in the
treatment of enterococcal endocarditis.
 It should be used only as a reserve alternative to
gentamicin. Serious infections caused by Pseudomonas
and Proteus are its major indications.
 Ototoxicity and nephrotoxicity is probably lower than
gentamicin.
 Dose: 3–5 mg/kg day in 1–3 doses.
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47.  Obtained from S. kanamyceticus (in 1957), it was the
second systemically used aminoglycoside to be
developed after streptomycin.
 It is similar to streptomycin in all respects including
efficacy against M. tuberculosis and lack of activity on
Pseudomonas.
 It is more toxic, both to the cochlea and to kidney.
 Hearing loss is more common than vestibular
disturbance.
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48.  Because of toxicity and narrow spectrum of activity,it has
been largely replaced by other aminoglycosides for
treatment of gram-negative bacillary infections.
 It is occasionally used as a second line drug in resistant
tuberculosis.
 Dose: 0.5 g i.m. BD–TDS:
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49.  Introduced in 1980s, it is a natural aminoglycoside from
Micromonospora inyoensis that is chemically and
pharmacokinetically similar to gentamicin, but somewhat
more potent on Pseudomonas, a few other gram-
negative bacilli and β haemolytic Streptococci.
 It is moderately active on faecal Streptococci—can be
combined with penicillin for SABE.
 It is susceptible to aminoglycoside inactivating enzymes
and offers no advantage in terms of ototoxicity and
nephrotoxicity.
 It can be used interchangeably with gentamicin for the
same purposes in the same doses.
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50.  This semisynthetic derivative of sisomicin has a broader
spectrum of activity than gentamicin.
 It is relatively resistant to aminoglycoside inactivating
enzymes and thus effective against many gentamicin-
resistant strains.
 It is more active against Klebsiella, Enterobacter and
Staphylococci, but less active against Ps. aeruginosa.
 Pharmacokinetic characteristics and dosage of netilmicin
are similar to gentamicin.
 hearing loss occurs, though fewer cases of vestibular
damage.
 Dose: 4–6 mg/kg/day in 1–3 doses;
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51.  Obtained from S. fradiae, it is a wide-spectrum
aminoglycoside, active against most gramnegative bacilli
and some gram-positive cocci.
 Pseudomonas and Strep. pyogenes are not sensitive.
 Neomycin is highly toxic to the internal ear (mainly
auditory) and to kidney.
 It is, therefore, not used systemically.
 Absorption from the g.i.t. is minimal.
 Oral and topical administration does not ordinarily cause
systemic toxicity.
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52.  1. Topically (often in combination with polymyxin,
bacitracin, etc.) for infected wound, ulcers, burn, external
ear infections, conjunctivitis, but like other topical
antiinfective preparations, benefits are limited.
 2. Orally for:
(a) Preparation of bowel before surgery: (3 dosesof 1.0 g
along with metronidazole 0.5 g on day before surgery)
may reduce postoperative infections.
(b) Hepatic coma: Normally NH3 is produced by colonic
bacteria.
 This is absorbed and converted to urea by liver.
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53.  In severe hepatic failure, detoxication of NH3 does not
occur, blood NH3 levels rise and produce
encephalopathy.
 Neomycin, by suppressing intestinal flora, diminishes
NH3 production and lowers its blood level; clinical
improvement is seen within 2–3 days.
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54. Applied topically
 Neomycin has low sensitizing potential. However, rashes
do occur.
Applied Oral
 neomycin has a damaging effect on intestinal villi—
prolonged treatment can induce malabsorption syndrome
with diarrhoea and steatorrhoea.
 It can decrease the absorption of digoxin and many other
drugs, as well as bile acids.
 Due to marked suppression of gut flora, superinfection
by Candida can occur.
 Small amounts that are absorbed from the gut or topical
sites are excreted unchanged by kidney.
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55.  This may accumulate in patients with renal
insufficiency—cause further kidney damage and
ototoxicity.
 Neomycin is contraindicated if renal function is impaired.
 Applied to serous cavities (peritoneum), it can cause
apnoea due to muscle paralysing action.
 Neomycin containing antidiarrhoeal formulations are
banned in India.
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56.  Obtained from S. lavendulae, it is very similar to
neomycin.
 It is too toxic for systemic administration and is used
topically on skin, eye, ear in the same manner as
neomycin.
 SOFRAMYCIN, FRAMYGEN 1% skin cream, 0.5% eye drops
or oint.
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57.  Broad spectrum antibiotics, as the name suggests are
those effective against a wide range of micro-organisms
gram +ve to gram –ve, rickettsia, fungi or even protozoa.
 Tetracycline
 Chloramphenicol
 These both are effective against large number of bacteria
and also rickettsia and even protozoa.
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58.  The tetracyclines are broad-spectrum antibiotics.
 All are obtained from soil actinomycetes.
 The first to be introduced was chlortetracycline in 1948
under the name aureomycin (because of the golden
yellow colour of S.aureofaciens colonies producing it).
 It contrasted markedly from penicillin and streptomycin
(the other two antibiotics available at that time) in being
active orally and in affecting a wide range of
microorganisms—hence called ‘broad spectrum
antibiotic’.
 Oxytetracycline and others were produced later, either
from mutant strains or semi synthetically.
 All tetracyclines are slightly bitter solids which are weakly
water soluble.
172280825005 (MPH SEM-2) 58

59.  But their hydrochlorides are more soluble. Aqueous
solutions are unstable.
 All have practically the same antimicrobial activity (with
minor differences).
 The group includes :
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Natural: from Streptomuces
aureofaciens & S. rimosus.
Semi Synthetic: from
Oxytetracycline & Chlortetracycline
Oxytetracycline Minocycline
Chlortetracycline Tigecycline
Rolitetracycline
Clomocycline
Doxycycline
Demeclocycline
Lymecycline
methacycline

60.  These are a class of antibiotics having a nucleus of four
cyclic rings.
172280825005 (MPH SEM-2) 60

61. 172280825005 (MPH SEM-2) 61
 Bacteriostatic action
 inhibit protein synthesis by binding to 30S ribosomes in
susceptible organism.
 Subsequent to such binding, attachment of amino acyl-t-
RNA to the mRNA-ribosome complex is interferred. As a
result, the peptide chain fails to grow.
 The sensitive organisms have an energy dependent active
transport process which concentrates tetracyclines
intracellularly.
 In gram negative bacteria tetracyclines diffuse through
porin channels.

62. 172280825005 (MPH SEM-2) 62
 The more lipid-soluble members (Doxycycline ,
Minocycline) enter by passive diffusion (this is partly
responsible for their higher potency).
 The carrier involved in active transport of tetracyclines is
absent in the host cells.
 Moreover, protein synthesizing apparatus of host cells is
less sensitive to tetracyclines.
 These two factors are responsible for the selective
toxicity of tetracyclines for the microbes.

63. 172280825005 (MPH SEM-2) 63

64.  Gram +ve and Gram –ve bacteria highly sensitive to
tetracyclines are pneumococcai, gonococci, streptococci,
clostridium, vibrio comma, donovania granulomatus, H.
influenza, pertussis, brucella and klebsiella.
 E. coli, aerobacteria, salmonella, shigella, bacillus
anthrax, pasteurella and listeria monocytogens are
moderately sensitive to tetracyclines.
 They are highly effective against rickettsial and
chlamydial organism.
 They are effective against E. histolytica but higher
concentration are required.
172280825005 (MPH SEM-2) 64

65.  The tetracyclines are generally given orally but can also
be administered parenterally.
 Minocycline and doxycycline are well absorbed orally.
 The absorption of most other tetracyclines is irregular
and incomplete but is improved in the absence of food.
 Because tetracyclines chelate metal ions (calcium,
magnesium, iron, aluminium), forming non-absorbable
complexes, absorption is decreased in the presence of
milk, certain antacids and iron preparations.
172280825005 (MPH SEM-2) 65

66.  The use of tetracyclines declined because of widespread
drug resistance, but has staged a comeback, e.g. for
respiratory infections, as resistance has receded with
reduced use.
 Doxycycline is given once daily and may be used in
patients with renal impairment.
 Uses (sometimes in combination with other antibiotics)
include:
 rickettsial and chlamydial infections, brucellosis, anthrax
and Lyme disease
172280825005 (MPH SEM-2) 66

67.  as useful second choice, for example in patients with
allergies, for several infections, including mycoplasma
and leptospira
 respiratory tract infections (e.g. exacerbations of chronic
bronchitis, community-acquired pneumonia)
 acne
 inappropriate secretion of antidiuretic hormone (e.g. by
some malignant lung tumours), causing hyponatraemia:
demeclocycline inhibits the action of this hormone by an
entirely distinct action from its antibacterial effect.
172280825005 (MPH SEM-2) 67

68.  The commonest unwanted effects are gastrointestinal
disturbances caused initially by direct irritation and later
by modification of the gut flora.
 Vitamin B complex deficiency can occur, as can
suprainfection. Because they chelate Ca2+, tetracyclines
are deposited in growing bones and teeth, causing
staining and sometimes dental hypoplasia and bone
deformities. They should therefore not be given to
children, pregnant women or nursing mothers.
 Another hazard to pregnant women is hepatotoxicity.
 Phototoxicity (sensitisation to sunlight) has also been
seen, particularly with demeclocycline.
172280825005 (MPH SEM-2) 68

69.  Minocycline can produce vestibular disturbances
(dizziness and nausea).
 High doses of tetracyclines can decrease protein
synthesis in host cells, an antianabolic effect that may
result in renal damage.
 Long-term therapy can cause disturbances of the bone
marrow.
172280825005 (MPH SEM-2) 69

70. 172280825005 (MPH SEM-2) 70
 Chloramphenicol was initially obtained from
Streptomyces venezuelae in 1947.
 It is a yellowish white crystalline solid, aqueous solution
is quite stable, stands boiling, but needs protection from
light.
 It has a nitrobenzene substitution, which is probably
responsible for the antibacterial activity and its intensely
bitter taste.

71. 172280825005 (MPH SEM-2) 71
 It inhibits bacterial protein synthesis by interfering with
‘transfer’ of the elongating peptide chain to the newly
attached aminoacyl-tRNA at the ribosome-mRNA
complex.
 It specifically attaches to the 50S ribosome and thus may
hinder the access of aminoacyl-tRNA to the acceptor site
for amino acid incorporation.
 Probably by acting as a peptide analogue, it prevents
formation of peptide bonds.
 At high doses, it can inhibit mammalian mitochondrial
protein synthesis as well.
 Bone marrow cells are especially susceptible.

72. 172280825005 (MPH SEM-2) 72

73. 172280825005 (MPH SEM-2) 73
 Chloramphenicol has a wide spectrum of antimicrobial
activity, including Gram-negative and Gram-positive
organisms and rickettsiae.
 It is bacteriostatic for most organisms but kills H.
influenzae.
 Resistance, caused by the production of chloramphenicol
acetyltransferase, is plasmid-mediated.

74. 172280825005 (MPH SEM-2) 74
 Being orally active, broad-spectrum and relatively cheap,
chloramphenicol has high incidence of resistance among
many gram-positive and gram-negative bacteria
especially in developing countries.
 In many areas, highly chloramphenicol resistant S. typhi
have emerged due to transfer of R factor by conjugation.
 Resistance among gram-negative bacteria is generally
due to acquisition of R plasmid encoded for an acetyl
transferase an enzyme which inactivates
chloramphenicol.
 Acetyl-chloramphenicol does not bind to the bacterial
ribosome.
 In many cases, this plasmid has also carried resistance to
ampicillin and tetracycline.

75. 172280825005 (MPH SEM-2) 75
 Multidrug-resistant S. typhi have arisen.
 Decreased permeability into the resistant bacterial cells
(chloramphenicol appears to enter bacterial cell both by
passive as well as facilitated diffusion) and lowered
affinity of bacterial ribosome for chloramphenicol are the
other mechanisms of resistance.
 Partial cross resistance between chloramphenicol and
erythromycin/ clindamycin has been noted, because all
these antibiotics bind to 50S ribosome at adjacent sites.
 Some cross resistance with tetracyclines also occurs,
though the latter binds to 30S ribosome.

76. 172280825005 (MPH SEM-2) 76
 Given orally, chloramphenicol is rapidly and completely
absorbed and reaches its maximum concentration in the
plasma within 2 h.
 It can also be given parenterally.
 The drug is widely distributed throughout the tissues and
body fluids including the CSF.
 Its half-life is approximately 2 h.
 About 10% is excreted unchanged in the urine, and the
remainder is inactivated in the liver.

77. 172280825005 (MPH SEM-2) 77
 Systemic use should be reserved for serious infections in
which the benefit of the drug outweighs its uncommon
but serious haematological toxicity.
 Such uses may include: –
 infections caused by Haemophilus influenzae resistant to
other drugs
 meningitis in patients in whom penicillin cannot be used
 typhoid fever, but ciprofloxacin or amoxicillin and co-
trimoxazole are similarly effective and less toxic.
 Topical use safe and effective in bacterial conjunctivitis.

78. 172280825005 (MPH SEM-2) 78
 Chloramphenicol inhibits metabolism of tolbutamide,
chlorpropamide, warfarin, cyclophosphamide and
phenytoin.
 Toxicity can occur if dose adjustments are not done.
Phenobarbitone,phenytoin, rifampin enhance
chloramphenicol metabolism → reduce its
concentration→ failure of therapy may occur.
 Being bacteriostatic, chloramphenicol can antagonize the
cidal action of β-lactams/aminoglycosides on certain
bacteria.

79. 172280825005 (MPH SEM-2) 79
 The most important unwanted effect of chloramphenicol
is severe, idiosyncratic depression of the bone marrow,
resulting in pancytopenia (a decrease in all blood cell
elements) – an effect that, although rare, can occur even
with low doses in some individuals.
 Chloramphenicol must be used with great care in
newborns, with monitoring of plasma concentrations,
because inadequate inactivation and excretion of the
drug can result in the ‘grey baby syndrome’ – vomiting,
diarrhoea, flaccidity, low temperature and an ashen-grey
colour – which carries 40% mortality.
 Hypersensitivity reactions can occur, as can
gastrointestinal disturbances secondary to alteration of
the intestinal microbial flora.

80. 172280825005 (MPH SEM-2) 80

81. 172280825005 (MPH SEM-2) 81

82. 172280825005 (MPH SEM-2) 82
NO DRUGS ROUTE OF ADMINISTRATION
1 STREPTOMYCIN i.m.
Orally (banned in India)
2 GENTAMICIN i.m./i.v.
3 AMIKACIN i.m./i.v.
4 TOBRAMYCIN i.m./i.v.
5 KANAMYCIN i.v.
6 SISOMICIN i.m./i.v./1-hr.infusion
7 NETILMICIN i.m./i.v.
8 NEOMYCIN Oral /Topical
9 FRAMYCETIN Topical
(Skin cream, Eye drops or Ointment)
10 TETRACYCLINES Orally/Parenterally
11 CHLORAMPHENICOL Orally/i.v.

83. 1) Elements of pharmacology by R.K.Goyal
2) Essentials of pharmacology by K.D.Tripathi
3) Goodman & Gilman's the pharmacological basis of
therapeutics (12th edition)
4) RANG AND DALE’S Pharmacology
172280825005 (MPH SEM-2) 83