Pharmacology of antimicrobials

DR JOSEPH EIGBEFOH
FWACS;FMCOG;FICS;D.MAS
• Antibiotics : Compounds synthesised by
microorganism which kills or inhibits the
growth of cells which produce diseases
• Chemotherapeutic
agents/substances(antimicrobial agents): all
compds (synthetic) are produced by living cells
to kill or inhibit the growth of cells which
produce dx in the body
• Bactericidal (antimicrobial agents) kills bacteria
eg penicillins, aminoglycosides
• Bacteriostatic : stop bacteria division (mitosis)
and bacteria is ultimately eliminated by host
defenses e.g tetracycline, erythromycin
• Bacteriocidal drugs are used when phagocytic
cells cant get to the site of infection eg
endocarditis,leucopenia. Co administration of
both drugs may be synergistic, additive or
antagonistic but usually no measurable
disadvantage occurs
 Classification of antimicrobial agents
(chemical structure)
• B-Lactam antibiotics(penicillins,
cephalosporins)
• Floroquinolones (ciprofloxacin,ofloxacins)
• Macrolides (erythromycin, azithromycin,
clarithomycin)
• Aminoglycosides(streptomycin,kanamycin,
gentamycin)
 Classification based of types of
organisms an antimicrobial is used
against
• Antibacterial agents
• Antifungal /antifungal agents
• Antiviral
• Antiprotozoa
• Antihelmithics
• Anticancer(antineoplastic, antimitotic)
 Spectrum of activity
• Narrow spectrum: penicillin G, Streptomycin,
erythromycin
• Broad spectrum: (I.e they can cover all organisms
e.g tetracycline, chroramphenicol. They kill both
pathogens and commensals (normal flora). s/e
superinfection
• Extended spectrum: penicillins, amoxicillin,
fluoroquinolones, clavunate, aminoglycosides,3rd
generation cephalosporins(ceftriaxone)
 Types of action
• Primarily bacteriostatic e,g sulphanamide,
tetracyclines, chloramphenicol
• Primarily bacteriocidal eg penicillin,
aminoglycoside,cephalosporins, trimethoprim,
cotrimoxazole
 Mechanism of action
• Inhibitors of cell wall synthesis e.g penicillin,
fluoroquinolones, cephalosporins, isoniazid,
cycloserine, vancomycin & vasitracin
Agents causing leakage thru bacterial
cell membrane(surface active agents )
• Polypeptide e.g polymycine, colistin,vasitracin
• Polyenes e.g amphotericin B, nystatin
 Inhibitors of protein synthesis
(ribosomal function)
• Reversible e,g tetracycline, chloramphenicol,
erythromycin, clindamycin
• Irreversible e.g aminoglycosides
 Inhibitors of DNA synthesis
• E.g DNA gyrase inhibitors (fluoroquinolones)
e.g metronidazole
• Inhibitors of RNA synthesis :DNA dependent
RNA polymerase e.g rifampicin
• Interference with metabolism e.g
sulphonamide, trimethoprim, pyrimethamine
• Binds to viral agents i.e altering replication
 Basic principle of prescribing
antibiotics
• Correct diagnosis of a bacterial infection
• Choose the drug that has the fewest adverse
effect for that patient so as to get maximum
benefits
• Choose drugs that have minimal effects on
commensals : limits spread of resistant
organism and maintain natural defence of
body
• Cost effective,convinient; adherence
• Factors of age, weight , hepatic and renal
function and severity of infection
Prescribe dose appropriate to the condition
• Route of administration: depends on severity
of infection. Severe life threatening inf. E.g
menigitis use iv. Avoid painful injection in
children
• Duration of therapy: tailor fit each regimen;
long therapy desirable in tb and chronic
osteomyelitis . To limit s/e and resistance
• Synergism : combination therapy in emprirical
and polymicrobial infection
• Prophylactic antibiotics : used to protect
healthy persons after invasion of some areas
of body
 Antihelmintic drugs
• Antihelmitics : acts locally to expel worms
froom GIT or sytemically to eradicate adult
helmiths or developmental forms that iinvade
organs/tissues
 Classifications
• Broad spectrum antehelmiths e.g
benzimedazole (albendazole, mebedazole)
• Narrow spectrum antehelmithic e.g
nermectin(mectizan) for public eradication for
filariasis and onchoceriasis
Drugs for treatment of nematodes
• Mebendazole
• Pyrantel pamoate (combantrin)
• Taiabendazole
• Diethy ccarbamazine (banocide)
• Ivermectin
 Drugs for trematode (trematode-
fluke)
• Praziquantel for schistosomiasis and hook
worm disease

• Drugs for cestodes (tapeworms): albendazole,

niclosamide
 Tetracyclines
• Broad spectrum antibiotics. Nuclueus of 4
rings obtained from soil actinomyces
 Classes
• Class I: Short acting (6 – 8hrs duration of
action); chlortetracycline, oxytetracycline
• Class II: Intermediate acting T1/2 = 12hrs e.g
Demeclocycline, Methacycline
• Class III: Long acting 16-18hrs e.g
Doxycline(tetradox), Minocycline,
Tigecycline(36hrs)
 Mechanism of action
• Inhibit protein synthesis by binding to the 30s
ribosome. Blocks attachment of aminoacyl-
transfer RNA to the receptor site on the Mrna
ribosomal complex.
• This inhibits the amino acids RNA anticodon
from recognising the codon hence the
photosynthesis stops
 Pharmacokinetics
Oral absorbtion is good
• Chortetracycline 30%
• Tcn/oxyTCN: 60-70%
• Doxycycline and minoxycline 95%. Newer
better than older.
• Absortion on empty stomach better with older
• With new: irrespective of food
• Bufferred TCN preparations are formulated for
iv admin.
• Tcn has chelating property properties- forms
insoluble and unabsorbable complexes with
calcium/metals
• Milk , fe preparations, oral antacids (mg, al)
and sucrafate decrease absorbtion
• Widely distributed in body
• Concentrated in liver and spleen, bone and
teeth.
• Csf conc, is ¼ of plasma
• Excreted by glomerular filteration
• Significant amount enters bile and breast milk
• Phenytoin/phenobarbiitone carbamezepin <
Absorbtion
Resistance to TCN
• Cross over resistance to other antibiotics
• <intracelular accumulation(plasmid mediated
transfer of R- factors, ribosome
production,enzyme induction)
 Adverse effects
• Irritating effects: nausea vomiting , diarrhea,
esophageal efffects(doxy), thromboplebitis(iv)
and pain(im)
• Dose related toxicity: liver damage; fatty
degeneration and jaundice(doxy,TCN have a
reduced s/e).
Other dose related effects: kidney damage
except doxycyline/tigamycine
• Photosensitivity: demethacycline
• Ca 2+ TCN deposited in developing
teeth/bones/decidous teeth: brownish
discolouration
• Childhood- 5yrs: temporary suppresion of bone
growth
• < protein synthesis
• Diabetes insipidus
• Vestibular toxicity
 Non dose toxicity
• Hypersensitivity
• Superinfection
 Uses
• Infection of ENT, resp tract
• GIT
• GUT(STD)
• Rickettsia infections e.g typhus fever, rocky
mountain spotted fever, Q- fever
• Mycoplasma-LGV
• Granuloma inguinale
• Chlamydia- topical in neonatal eye infection
• STIs – non specific urethritis
• Bacillary dysentery; cholera plague
• H.pylori
• Adjuvant for eradication of P.falciparum
• Atypical mycobacteria infection
• Acne vulgaris infection
 Chloramphenicol
• 1st completely synthetic A/B(1947), from
streptomyces Venezuela (1949)
• Bacteriotatic broad spectrum A/B active
against aerobi, anaerobic, gram +ve, -ve org,
(salmonella,H.influenza, mycoplasma,
rickettsia but not chlamydia)
• Inhibits proteosynthesis by reversible to the
bacteria 50s ribosomal subunits which
prevents peptide bound formation(peptidyl
transferase step of proteosynthesis). It inhibits
peptidyl transferase
• Well absorbed orally > parenteral
 Metabolism
• Liver conjugation with glucoronic acid or
reduction to aryl amines
• Excretion: urine 90%. Bile or faeces(active
drug 10%)
• Dosage: 50- 100mg/kg/24hrs; 25mg/kg/24hrs
in those < 1 wk old
• Resistance : mediated thru <transfer of R –
factor
 Uses
• Serious Rickettsia infxn like typhus
• Rocky mountain spotted fever in children
• Penicillin resistant bacteria meningitis
• Opthalmic chlamydia infection
 Adverse effects
• Irritating effect: nausea, vommitting, diarrhea,
pain at injection site
• Superinfection: oral/vaginal candidiasis
• Bone marrow suppression : dose related
(reversible); aplastic anaemia occurs in
1/24,000-40,000. which tends to be
irreversible
• New born toxicity: newborns lacks effective
glucoronic acid conjugation mechanism for
degradation/detoxification of
chloramphenicol. Dosages > 50mg/kg/24hrs
lead to accumulation --- grey baby syndrome (
vommitting flacidity, hypothermia, grey
colour, shock& collapse)
• Innhibits hepatic microsome PI(protese
inhibitors,tolbutemide, chlorpropamide,
cyclophosphamide & warfarin, phenobarbital,
phenytoin, rifampicin enhance
• Hypersensitivity: rashes, fever, atrophic
glossitis, angiedema
• Resistance is due to CPL acetyl-transferase, a
plasmid activated enzyme that inactivates it.
 Sulfonamides
• Limited use because of emergence of
resistance; use as antimalaria in combination
with trimethoprim
Classification
• Oral absorbable
• Short acting (4- 8hrs) e.g sulfasoxazole,
sulfamethoxazole used for UTI
• Intermediate acting(10-17hrs) e.g sulfadiazine,
acute toxoplasmosis , sulfamethazone
• Long acting(7-9 days ) e,g
sulfadoxine/pyrimethamine(fansidar)
• Oral non absorbable e.g
phthalylsulfathiazole(thalazole) also called
sulfathalidine
sulfasalazine--- used in ulcerative colitis, enteritis,
inflammatory bowel dx
• Topical agents : Na sulfacetamide( eye ointment)
Mafenamide acetate(sulfamylum) for tx of burns
Silver sulfadiazine (dermazine; tx of burns)
 MOA
• Structural analogs of PABA; They inhibit
dihychopteroate synthase and folate production
• They are absorbed from stomach/small intestine,
body fluids(cns, csf), placenta and fetus. Blood
level peaks 2-6hrs after oral. A portion of
absorbed drug is acetylated or glucoronidated in
liver. Sulfonamides and inactive metabolites
excreted into urine by glomerular filteration
• Lipid soluble: most of them are well absorbed
from small intestine
Adverse effects:
• Common : nausea vommitting epigastric pain
• Rashes, bleeding, steven johnson syndrome(1
% of pts)
• Exfoliative dermatitis
• Pruritus
• Drug fever, dizziness and malaise
• Urinary: crystalluria, haematuria, intrarenal
damage
• Kerniterus : when given last 2 wks of preg.
Displaces bilirubin from albumin
• Heamopetic disturbances: hemolytic anaemia
in G-6-PD, granulocytopenia, aplastic anaemia
• Resistance : via plasmid mediated impairment
to drugs
 Uses
• Sulfadoxine/pyrimethamine: falciparum
malaria
• Sulfadiazine/pyrimethamine: toxoplasmosis
for 4-6wks
• Topical tx
 Aminoglycosides
Basic molecules: amino acids linked in glycosidic
bond to a central hexose. Aminohexose can be
1,2 or more
• Streptomycin
• Gentamycin
• Topramycin
• Paromycin
• Neomycin
• Sisomycin
• Netilmycin
• Amikacin
• Spectinomycin
 Mechanisms of action
• At the ribosomal level, inhibits proteosynthesis
(30sribosome), consequently the RNA are
unnable to bind hence proteosynthesis stops
• Induce misreading of m RNA template and with
this incorrect amino acids are incorporated into
the growing polypeptide chain and consequently
the synthesis of non functional or toxic or
nonsense proteins produce
• Aminoglycosides break up polyzones into no
functional monozomes and action lethal to
cell
 PK
• Aminoglycosides not well absorbed. Given
parenterally in systemic infection
• Distribute well into various body fluids except
CNS, bone, tissues, in the bronchial
secretions,fatty,connective tissues and
acqueous humour
• Excreted almost unchanged in the urine. Thus
useful in UTI
 Uses
• Treatment of enterobactericae
• Agerobic gram –ve meningitis. Injected
intrathecal
• Tx of tb e.g streptomycin,kanamycin
Combination with other antibiotics in the ff
infections
• Antipseudomonal penicillin e.g carbemicillin,
piperacillin
• Empirical tx in febrile illness in combination with
other broad spectrum antibiotic
• Tx of serious staph infections e,g with
cloxacillin
• Bowel prep e.g neomycin
• Topical application for burns
 Mode/mechanism of resistance to
aminoglycosides
• < cell membrane permeability
• Ribosomal mutation : causes alteration on the
site of aminoglycoside attachment to
ribosome and results in innability of the drug
to bind to ribosome
• Enzyme produced by plasmid or R- factor
found on the cell memb. May inactivate
aminoglycosides by process of adenylation –
acetylation or phosphorylation
 Properties of individual members
• Streptomycin : reserved for tx of TB
• Gentamycin: useful in tx of UTI, combined
with b-lactam
• Tobramycin : uti,rti
• Kanamycin: most broad spectrum of all; gram
+ve , +ve as well as in milliary tband some
spirochaetes like leptospira species. It is
however very toxic
• Neltimicin : semisynthetic derivative of
sisomicin, less ototoxic & nephrotoxic than
gentamycin indicated in systemic infection of
the biliary tract., osteomylitis, peadiatric
infections and pseudomonas infection
• Amikacin : semi- synthetic & derived from
kanamycin, least toxic of all aminoglycosides
and most resistant to enzyme inactivation
 Amikacin
• Amikacin is indicated in severe infections
caused by problematic orgs
• Amikacin has a special role in hospitals, where
gentamycin and tobramycin resistant
organisms are prevalent
• Adverse effect: ototoxicity, nephrotoxicity
• Potentiated by furosemide and mannitol