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General consideration
GENERAL CONSIDERATIONS
Antimicrobial
drugs
are
the
greatest
contribution
of
the
20th
century
to
therapeutics. They are one of the most
frequently used as well as misused drugs.
All three groups of scientists Domagk, FlemingChain-Florey and Waksman received Nobel Prize
of infection :
State
of host defense :
Surgical
Determination
Use
of a specific, narrow-spectrum
antibiotic
Use
Patients
drug history:
Use
Use
Cost
of antibiotics:
Proper
Proper
dose:
time interval
Proper
route of administration:
Combination
antibiotic therapy:
to treatment
If
Route of administration.
Dose.
Patient compliance.
Correct antibiotic.
Causes
of failure in treatment of
infection:
Development
of adverse reactions
Superinfection
and recurrent
infection
Principles of Therapeutic
uses of antibiotics
As
CLASSIFICATION:
Chemical structure :
Diaminopyrimidines: Trimethoprim,
Pyrimethamine.
Mechanism of action :
Penicillin G
Tetracyclines
Streptomycin
Chloramphenicol
Erythromycin
Type of action :
Primarily bacteriostatic
sulfonamides, Erythromycin, Tetracycline Ethambutol,
Chloramphenicol.
Primarily bactericidal:
Penicillins, Cephalosporins, Aminoglycosides,
Vancomycin, Polypeptides, Nalidixic acid, Rifampin,
Ciprofloxacin, Cotrimoxazole
Antibiotics obtained from :
Bacteria:Polymyxin-B,Tyrothricin, Colistin,
Aztreonam, Bacitracin.
Actinomycetes:Aminoglycosides, Macrolides,
Tetracyclines, Polyenes,Chloramphenicol.
Cross resistance:
Acquisition of resistance to one AMA conferring
resistance to another AMA, to which the organism has
not been exposed, is called cross resistance.
Use
6.
Masking of an infection:
Failure of chemotherapy :
Florey and chain with Fleming got Nobel Prize in 1945 in medicine
Cephalosporins
Carbapenems
Monobactams
Carbacephems
-lactam ring
Increased resistance.
Mutations in Penicillin binding proteins lower their affinity for lactam antibiotics:
Mutation
Transformation
PENICILLINS
Classification
1.Natural penicillins
Procaine penicillin-G
Benzathine penicillin-G
2.Acid resistant penicillins
3. Cloxacillin
6. Nafcilin
1. Ampicillins
2. Amoxycillins
3. Talampicillin
4. Pivampicillin
5.Extended spectrum penicillins
Carboxy penicillins a) Cerbenicillin b) Ticarcillin
Uridopenicillins
a) Piperacillin
b) Mezlocillin
Amidinopenicillins a) Mecillinam
b) Pivmecillinam
6.Penicillins with betalactamase inhibitors
Penicillin G
Penicillin V
Adverse effects:
Minor reactions
Nausea, Vomiting, inflammatory reaction at the site of
injection (pain, aching), Diarrhea
Local reaction-Erythema, Induration
Prolonged injury-Thrombophlebitis
Accidental IV procaine PnG-Anxiety, Mental disturbances,
Parasthesia
Major reactions:
Allergy and anaphylaxis, Jarish herxheimer reaction, Super
infection
Hyperkalemia, Acute non-allergic reactions,
Palpitation,Hypertension,
Twitchings, Auditory and visual
disturbances,Headache,Dizziness
If insoluble procaine particles deposited in the lungs
produce small pulmonary infarcts
Large doses of PnG may cause irritation of CNS
Convulsions,Encephalopathy
PnG large doses if injected in uremic patients
neurotoxicity
BENZYLPENICILLIN
Available in the form of its water soluble Na+ and K+ salts
Dry state Stable for years
Aqueous solution
IM or I/V
Rapidly absorbed
Peak plasma level is reached within 15 to 30 minutes and drug disappears
from plasma by 3 to 6 hours
BBB blood brain barrier is not readily crossed by the drug but
therapeutically enough drugs are passed in meningeal infections,
trasverses the placental barrier.
In plasma
60% bound to albumin bacteriologically inactive & 40% Free form
30% parental dose metabolized in the body and small amounts
appear in bile, milk and saliva major portion is eliminated by the
kidneys.
50% of drugs elimination occurs within 1st hour
Plasma half life 30 minutes.
20% of oral penicillin detected in urine
Prolonged plasma levels seen in neonates and infants.
Probenecid an uricosruric agent, competes with penicillin for
tubular transport and can promote higher blood levels by
delaying its excretion.
Preparation & dosage:
Benzylpenicillin (penicllin G) injection contains 5,00,000 units of
drug per ml 0.5mu im/iv 6-12 hourly Benzyl penicillin 0.5
IM units
Repository preparation:
Procaine benzylpenicillin injection available in powder form to be
suspended in distilled water prior to injection.
Dose 6,00,000 units daily by IM injection.
Aqueous solution are stable for many months at temperature
below 25C
Forfitied benzylpenicillin forfied PP inj. 3 + 1 lakh unit Inj. contain
a mixture of 3,00000 units of procaine benzyl penicillin and
1,00000 units of benzyl penicillin per ml.
Benzithine penicillin (penidure, benapen)
A dose of 1.2 million units produce detectable blood levels of upto 3 weeks.
Probenicid:
When administered orally in the dose of 29mg/day in divided along
with penicillin raises its plasma level to two fold to 4 fold.
Therapeutic plasma levels of penicillin are maintained for
approximately twice as long with Probencid. Probencid is capable
of producing allergic reactions, so not recommended in children
under 2 years of age.
Therapeutic use:
Pneumococcal pneumonia
Pneumococcal empyema and pericarditis
Penumococal meninigitis
Streptococcal infections
Pharyngitis
Acute otitis media
Streptococcal osteomyelitis and arthritis
Streptococcal SABE
Staphylococcal infections
Meningococcal meningitis
STDs-Syphilis
Neurosyphilis
Gonorrhea
Actinomycosis
Anthrax
Penicillin prophylaxis
Rheumatic fever and streptococcal infections
SEMISYNTHETIC PENICLLIN
ACID RESISTANT PENICILLIN
Potassium phenoxymethyl penicillin (penicillin V)
Given in less serious condition due to penumococci and streptococci and in infections which
require a prolonged treatment.
Less active than penicillin G against gonococci H-influenzae species and hence not used in
gonorrhea.
METHICILLIN:
Must be injected
CLOXACILLIN:
It has a side chain, has weak antibacterial activity & acid resistant
than benzyl penicillin-G. Food interferes with absorption.
peak plasma level occurs within an hour and persists for 4-6
hours.
Drug distributed throughout the body but highest concentration
in the kidney and 90-95% bound to plasma proteins 30% of single
dose excreted in the urine.
Over 95% of the 24 hour urinary excretion occurs within first 6
hours
Significant amounts are excreted in the bile
Less active against penicillin G sensitive organism
More active against penicillinase producing organisms but not
against MRSA
Adverse effect:
Similar to penicillin
Skin rashes, Diarrhea common with oral administration
Therapeutic uses:
1. UTI:
2. Respiratory tract infection
3. Meningitis and SABE
4. Biliary tract and intestinal infections
5. Miscellaneous:
AMOXICILLIN:
3. Meningitis
4. Salmonella infections
Carbenicilin:
It is inactivated by penicillinase
Drug can cause CCF because of large Na+ content of the drug and
bleeding because of abnormal platelet aggregation.
Piperacillin:
Beta-lactamase
inhibitors:
acid
Clavulanic
Sulbactam
It is a semisynthetic -lactamase
inhibitor
Absorption of sulbactam is inconsistent.
Therefore, it is preferably given
parenterally
Indications are:
PPNG; sulbactam per se inhibits N.
gonorrhoea
Mixed aerobic-anaerobic infections, tooth
abscess, intra-abdominal, gynaecological,
CEPHALOSPORINS
CLASSIFICATION BY
GENERATION
First
Generation Cephalosporins.
Second
Generation
Cephalosporins.
Third
Generation Cephalosporins.
Fourth
Generation Cephalosporins.
Very
Moderate
Do
Excretion
Parenteral
Oral
Occasionally
SECOND GENERATION(CEFOXITIN)
Extended
Several
Poor
Dosage
failure.
Variety
THIRD GENERATION
Ceftriaxone and ceftazidime
Expanded
gram-negative coverage.
Cefoperazone
Cross
Half-lives
Most
In
FOURTH GENERATION
-Cefepime
Similar
Good
Cleared
Therapeutic
SULFONAMIDES,
COTRIMOXAZOLE AND
QUINOLONES
Pharmacokinetics :
Adverse effects :
Nausea, vomiting and epigastirc pain.
Crystalluria is dose related.
Hypersensitivity reactions occur in 2-5% patients.
Steven-johnson syndrome and exfoliative dermatitis are more
common with long acting agents.
Contact sensitization.
Sulfonamides cause haemolysis & Kernicterus.
Interactions :Sulfonamides inhibit the metabolism of phenytoin,
tolbutamide and warfarin enhance their action.
Uses :
Systemic use of sulfonamides alone is rare now.
COTRIMOXAZOLE :
The fixed dose combination of trimethoprim and sulfamethoxazole
is called cotrimoxazole. selectively inhibits bacterial dihydrofolate
reductase (DHFRase).
Spectrum of action ;
Antibacterial spectra of trimethoprim and sulfonamides
overlap considerably.
Additional organisms covered by the combination are-S.
typhi, Serratia, Klebsiella, Enterobacter, Pneumocystic
carnii and many sulfonamide resistant strains of Staph
aureus, Strep, pyogenes, Shigella, enteropathogenic E.
coli, H. influenzae, gonococci and meningococci.
Resistance : Bacteria are capable of acquiring
resistance to trimethoprim mostly through mutational
or plasmid mediated acquisition. Slow to develop
compared to either drug along. Widespread use of the
combination has resulted in reduced responsiveness of
over 20% originally sensitive strains.
Adverse effects :
Nausea, vomiting, stomatitis, headache and rashes
Blood dyscrasias occur rarely.
It should not be given during pregnancy :
Patients with renal disease may develop uremia.
A high incidence of fever, rash and bone marrow
hypoplasia due to cotrimoxazole has been reported
among AIDS patients with Pneumocystis carinii
infection.
The elderly are also at greater risk of bone marrow
toxicity from cotrimoxazole.
Diuretics given with cotrimoxazole have produced a
higher incidence of thrombocytopeina.
QUINOLONES :
Nalidixic acid:
Mechanism of action:
The FQs inhibit the enzyme bacterial DNA gyrase. The DNA gyrase
consists of two A and two B subunits; FQs bind to A subunit with
high affinity and interfere with its strand cutting and resealing
function..
Greater affinity for topoisomerase IV may confer higher potency
against gram positive bacteria.
The bactericidal action probably results from digestion of DNA by
exonucleases whose production is signaled by the damaged DNA.
Mechanism of resistance : Resistance noted so far is due to
chromosomal mutation producing a DNA gyrase or topoisomerase
IV with reduced affinity for FQs, or due to reduced permeability /
increased efflux of these drugs across bacterial membranes.
ciprofloxacin :
It is the most potent first generation FQ active against a broad
range of bacteria; the most susceptible ones are the aerobic gram
negative bacilli, especially the enterobacteriaceae and Neisseria.
gram positive bacteria are inhibited at relatively higher
Pharmacokinetics :
Ciprofloxacin is rapidly absorbed orally, but food delays absorption,
and first pass metabolism occurs.
The most prominent feature of ciprofloxacin is high tissue
penetrability: concentration in lung, sputum, muscle, bone,
prostate and phagocytes exceeds that in plasma, but CSF and
aqueous levels are lower.
It is excreted primarily in urine.
Adverse effects: Ciprofloxacin has good safety record
nausea, vomiting, bad taste, anorexia.
dizziness, headache, restlessness, anxiety, insomnia, impairment
of concentration
rash, pruritus, photosensitivity, urticaria.
Interactions :
Plasma concentration of theophylline, caffeine and warfarin are
increased by ciprofloxacin due to inhibition of metabolism : toxicity
of these drugs can occur.
NSAIDs may enhance the CNS toxicity of FQs.
Antacids, sucralfate and iron salts given concurrently reduce
absorption of FQs.
References:
Basic & Clinical Pharmacology 12th ed :
Katzung
Oral & Maxillofacial Infections 4th ed :
Topazian
Essential of medical pharmacology 5th ed :
Tripathi
The pharmacological basis of therapeutics
10th ed : Goodman & gilman
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