ANTIMICROBIAL THERAPY

PORTIONS DETAILS
 Antibiotics: chemotherapy @ the use of drugs to treat a disease.
 Selective toxicity: a drug that kills harmful microbes w/o damaging host.
OVERVIEW  Antibiotic @ antimicrobial antibiotic: chemical produced by a microorganism that kills or inhibit the growth of
another microorganism.
 Antimicrobial agent: chemical that kills or inhibits the growth of microorganism.
 Antibiotics r classified based on:
1. Chemical structure.
2. Their activity:
 Bacteriostatic/bactericidal.
 Spectrum.
 Mechanism of action.
 Types of antibiotics:
1. Bacteriostatic: arrests e growth & replication of bacteria at serum levels achievable in e patients, thus limiting e
CLASSIFICATION spread of e infection while e immune system attacks e pathogens.
2. Bactericidal: kills bacteria at drug serum levels achievable in e patients.
 In general : cell wall active agents are cidal while protein synthesis inhibitor are static (aminoglycosides)
 Static and cidal agents – equally effective in immunocompetent host for most infection.
 Cidal agent – when host defence mechanism is impared, serious condition (endocarditis, meningitis, neutropenic
cancer patients).
 Combined use – not recommended – statics cell cannot grow, cidal cannot kill actively multiplication cells.
Bactericidal Bacteriostatic
 Microorganisms’ strategies in infection:
Aminoglycosides Tetracyclines
1. Bacteria: have their own enzymes in cell wall formation,
Beta-lactams Sulphonamides
proteinQuinolones
synthesis, DNA replication, RNA synthesis, & synthesis E more similar E pathogen and
Trimethoprim
of essential metabolites. host enzymes, E more side effects
Vancomycin Rifampin Chloramphenicol
2. Virus: use their host enzymes inside host cells.
Isoniazid Macrolides the antimicrobials will have.
MECHANISM OF 3. FungiPyrazinamide
& protozoa: have their own eukaryotic enzymes. Clindamycin
ACTION  Counter attack by antimicrobial agents:
Metronidazole Ethambutol
1. Inhibition of cell wall. Nitrofurantoins
2. Inhibition of protein synthesis.
3. Inhibition of nucleic acid replication and transcription.
4. Inhibition of synthesis essential metabolites.
5. Injury to plasma membrane.
1. Narrow-spectrum antibiotic:
 Acting onlt on a single or limited group of microorganisms.
 E.g.: isoniazid for mycobacterial infection.
2. Extended-spectrm antibiotic:
 Effective against gram-positive & gram-negative bacteria.
ANTIBIOTIC
 E.g.: ampicillin.
SPECTRA 3. Broad-spectrum antibiotic:
 Affect a wide-variety of microbial species.
 Administration can drastically alter e nature of e normal flora & precipitate a superinfection of an organism such
as Candida albicans.
 E.g.: tetracycline & chloramphenicol.
 I.e. a relative or complete lack of effect of  Factors promote:
antimicrobial against a previously susceptible microbe 1. Exposure to sub-optimal levels of antimicrobial.
increase MIC. 2. Exposure to microbes carrying resistance genes.
 Mechanism of antibiotic resistance  MRSA – methicillin- resistant Staphylococcus aureus:
1. Enzymatic destruction of drugs. 1. Most frequent nosocomial (hospital acquired)
2. Prevention of penetration of drugs. pathogen.
3. Alteration of drug’s target site. 2. Resistant to several other antibiotics.
4. Rapid ejection of the drug.  Proposal to combat antimicrobial resistance:
RESISTANCE 5. Decreased drug accumulation in e target cells. 1. Speed of development of new antibiotics.
6. Enzymes inactivation. 2. Track resistance data nationwide.
 Inappropriate antimicrobial use: 3. Restrict antimicrobial use.
1. Prescription not taken correctly. 4. Direct observes dosing (TB).
2. Antibiotics for viral infection. 5. Use narrower spectrum antibiotics.
3. Antibiotics sold without medical supervision. 6. Use antimicrobial cocktails.
4. Spread of resistant microbes in hospital due to lack  Consequences of antimicrobial resistance:
of hygiene. 1. Infections resistant available antibiotics.
2. Increase cost of treatment.
USAGE OF ANTIBIOTICS
EMPIRIC: therapy is  Empirical therapy (usually up to 72 hours):
chosen based on info.  Diagnosis of infection made based on S/S, lab, & etc: likely pathogens suspected but specific pathogen not yet
available, if not, choose known.
a broad spectrum  Antibiotic selectivity is based on:
antibiotic. 1. Likely pathogens: can be diagnosed using gram stain, detection of microbial Ags, DNA, or RNA, &
detection of host inflammatory reaction.
2. Local susceptibility trends towards antibiotic can be detected using:
a. MIC & MBC:
 Only MIC is routinely measured for most infections.
  MBC useful for infections where bactericidal therapy is required for eradication.
 Results to be correlated with known drugs concentration in the body compartments.
b. Β-lactamase assays – for identifying susceptible/ resistance species.
3. Patient-specific factors: allergies, organ dysfunction, immune system, adverse reaction, age, pregnancy, &
lactation.
4. E drug properties at e sites of infection: drug’s lipid solubility (> lipid soluble, > easily absorbed),
molecular weight (> lighter, > easily penetrate), & protein binding (↑ serum protein binding, ↓ penetration).
5. Safety of e agent: chose drugs with less toxicity.
6. E cost of therapy: > cheaper e better.
 Pearls:
1. Get cultures on the front end.
2. Start appropriate antibiotics ASAP.
 Microbiologic or serologic diagnosis with susceptibilities r known or presumed.
 E.g.: syphilis which is susceptible to penicillin.
 Antibiotic therapy:
 Antibiotics combinations
 Best to treat with single agent as far possible
 Unnecessary combination lead to :
1. Increased toxicity.
2. Increased cost.
3. Sometimes reduced efficacy.
 Indication for combined use:
 Broad spectrum empiric therapy.
DEFINITIVE
 Polymicrobial ifx (intraabdominal abscess).
 Decreae emergence of resistant strains (TB).
 To decrease dose related toxicity: e.g. Amphotericin B+ flucytosine for cryptococcal meningitis allows
lower dosing of AMB (reduced nephrotoxicity).
 To obtain enhanced killing effect: combination cell wall active agents with aminoglycosides.
 How long to treat:
 Not well defined.
 Ussulaly less than 14 days.
 Longer for endocarditis, osteomyelitis, prostatitis (varies by bugs & drugs).
 Endometritis ; until a febrile 24-18 hours.
 Prolonged therapy  increased risk resistance, adverse effects and cost.
1. Surgical prophylaxis
 Purposes:
a. To prevent surgical wound infection.
b. Contaminated wounds.
c. Operations lasting more than 2 hours.
d. Placement of presthetic devices.
e. To prevent endocarditis during dental / surgical procedures in susceptible cases – valve defects.
f. Treatment prior to certain surgical procedures such as bowel surgery & joint replacement to prevent
infection.
 Precautions:
a. The antibiotic should be active against common surgical wound pathogens.
PROPHYLAXIS b. Unnecessary broad spectrum antibiotics avoided.
c. Greater than the MIC concentrations must be present at time of incision.
d. Shortest possible course – ideally single dose – of least toxic antibiotic should be used.
e. Parenteral administration 60 min before incision.
f. Cefazolin is preferred for most of the common surgical procedures.
g. Vancomycin for MRSA.
2. Medical prophylaxis:
a. Temporary exposure to virulent procedures.
b. Patients with predisposing medical diagnosis immunocompromised host.
c. Prophylaxis against recurrent infection such as UTI.
d. Prevention of TB or meningitis in individuals who is in close contact with infected patients.
e. Treatment of e mother wit zidovudine to protect e fetus in e case of an HIV-infected, pregnant woman.
RATIONAL  Based on e drug’s pharmacodynamics & pharmacokinetics.
DOSING  3 properties of rational dosing:
1. Concentration-dependent killing:
 I.e. e rate of bacterial killing is increases as e concentration of antibiotic increases.
 Rapid killing of e infecting pathogens by this drug is favored by giving a once-a-day bolus infusion (which
gives rise to high peak level).
 E.g.: aminoglycosides & fluoroquinolones.
2. Time-dependent killing: killing is best predicted by e % of time that blood concentrations of a drug remains
above e MIC. E.g.: penicillin.
3. Post-antibiotic effect (PAE):
 I.e. a persistent suppression of microbial growth that occurs after levels of antibiotic have fallen below e
MIC.
 Also defined as e length of time it takes (after e transfer) for e culture to achieve log phase growth.
 Antimicrobial drugs with long PAE require only one dose per day.
 Dosing adjustment is needed in:
1. Renal dysfunction:
 Preferred drugs:
a. Aminoglycosides (traditionally Q8h)
- Must adjust to get through < 2.
 - Consider once daily dosing.
b. Vancomycin: adjust to get through 5-10.
 Dosing adjustment needed for:
- Cephalosporins.
- Clarithromycin.
- Fluconazole.
- Penicillins (except dicloxacillin, nafcillin).
- Quinolones.
- TMP-SMZ.
 Contraindicated drugs:
- Nalidixic acid.
- Nitrofurantoin.
- Sulphonamides.
- Tetracyclines (except doxycycline).

2. Hepatic dysfunction:
 Adjustment needed for
- Ceftriaxone, Nafcillin.
- Clindamycin, Metronidazole.
- Macrolides, Tetracyclines.
- Rifampin, Isoniazid.
 Serum concentration monitoring for antibiotics: For most antibiotics e relationship between dose & therapeutic
outcome is well established, thus, routine monitoring is unnecessary.
ANTIBIOTIC  Monitoring is justified when:
1. Substantial interpatient variability in serum concentration
MONITORING 2. Difference between therapeutic and toxic concentration is small
3. Clinical efficacy or toxicity of the drugs is delayed or difficult to measure
 Thus, monitoring required for aminoglycosides – through concentration is more important for limiting toxicity.
1. Drugs cleared by CYP 450):
 E.g.: Statin, cyclosporine, benzodiazepined, theophyling, anticonvulsion and oral hypoglycemic.
 Level increased by (metabolism inhibited by):
a. Macrolides (erythromycin).
DRUG b. Azoles – fluco and itra.
INTERACTION c. Ciprofloxacin.
 Level decreased by (metabolism induced by): rifampin and rifabutin.
2. Oral concentratives: decreased with rifampin & nafcilin +/- others.
3. Multivalent cations (Ca,Mg,Iron) +/- TF: decreased absorption of fluoroquinolones and tetracyclines.
4. Muscle relaxants: potentiated by aminoglycosides and possibly tetracyclines.
1. Hypersensitivity: HS reactions towards antimicrobial drugs or their metabolic products such as penicillin.
2. Direct toxicity: high serum level of certain antibiotic may cause toxicity by directly affecting cellular processes in e
COMPLICATIONS
host such as aminoglycoside.
OF ANTIBIOTIC 3. Super infection: drug therapy can lead to alterations of e normal microbial flora of e URT, GIT, & UGT, permitting e
overgrowth of opportunistic organism especially fungi or resistant bacteria which is difficult to treat.
 CELL WALL & MEMBRANE ACTIVE ANTIBIOTICS
PORTION DETAILS
 E antibiotics interfere with e synthesis of e bacterial cell wall which is built up with peptidoglycan layers.
OVERVIEW  E inhibitors of cell wall inhibitors r bactericidal & require actively proliferating microorganisms.
1. Beta-lactams 2. Others
 Penicillins.  Vancomycin.
CELL WALL  Cephalosporins.  Teicoplanin.
INHIBITORS  Monobactums.  Bacitracin.
 Carbepenems.  Cycloserin.
 Beta- lactamase inhibitors.
PENICILLINS
 Members of this drug differ from one another in e R substituent attached to 6-aminopenicillanic acid residue. This
side chain is important because it determines:
1. E antimicrobial spectrum.
STRUCTURE 2. E stability to stomach acid.
3. E susceptibility to β-lactamase.
 Hydrolysis of beta lactam ring by beta-lactamase yields penicilloic acid which inactive.
 Share 4 sided ring (β-lactam ring).
Extended spectrum Penicillinase – resistant
Penicillins Antistaphylococcal penicillins
penicillins penicillins
Anti Staph. – Cloxacillin,
Ampicillin
Oxacillin, nafcillin
Methicillin Amoxicillin
Carbapenems: very broad
Penicillin G (IV) Cloxacillin Ticarcillin –
spectrum
Penicllin V (oral) Oxacillin antipseudomonal
CLASSIFICATION Monobactam: Gram
Nafcillin Piperacillin –
negative
antiklebsiella

Effective against Resistant to B- lactamase.

gram +ve Effective against penicillinase- Better against gram Against staphylococcus &
organism, gram producing stapylococcus. and –ve organism gram –ve bacteria.
–ve cocci streptococci.
 Inhibit bacteria cell wall synthesis:
Bind with penicillin binding protein → inhibit transpeptidation reaction → halts Peptidoglycan synthesis →
exposure of osmotically < stable membrane → cell lysis actively → growing bacterial is killed.
 Other mechanisms:
1. Penicillin-binding protein:
MECHANISM OF
 Penicillin inactivates PBPs on e bacterial cell membrane which act as bacterial enzymes of cell wall
ACTION
synthesis & e maintenance of e bacterial morphological features.
 Results: prevent cell wall synthesis & change or lyse susceptible bacteria.
2. Inhibition of transpeptidase: penicillin inhibits transpeptidase-catalyzed reaction (cross-linkage b/w
peptidoglycan chain which is essential for cell wall integrity).
3. Production of autolysin: presence of penicillin causes autolysin to destroy existing bacterial cell wall.
1. Routes of absorption (depends on e stability of e drug to gastric acid & e severity of infection):
a. Oral absorption available.
b. Penicillin G – parenterally (crystalline sodium pen G).
c. Penicillin V – oral (poor bioavailability).
d. Procaine penicillin & benzathine penicillin (IM) – for delayed absorption and prolonged duration (depot).
2. Preparation: Unitage - I unit penicillin G – o.6mcg.
PHARMACOKINETIC
3. Absorption: most r incompletely absorbed after oral administration. Absorption is decreased by food in e stomach
(gastric emptying time is lengthened & drugs r destroyed by acid).
4. Distribution: tissue & placental cross distribution r good, but does not penetrate BBB (except during meningitis d/t
inflammation).
5. Excretion: by kidney tubular secretion, but can be inhibited by Probenecid. Can also be secreted into breast milk,
saliva, & bile.
1. Natural resistance: occurs in organisms which lack a peptidoglycan cell wall or have cell wall which is
impermeable to e drug.
2. Acquired resistance: d/t plasmid transferring resistance genes:
a. β-lactamase activity: hydrolyzes e cyclic amide bond of e β-lactam ring which results in loss of bactericidal
activity. Gram +ve bacteria secrete it extracellularly while gram –ve bacteria have e enzyme in e periplasmic
RESISTANCE
space.
b. Decreased permeability to e drug: d/t decrease penetration of e antibiotic to attach to PBPs & e presence of
efflux pump.
c. Altered PBPs: modified PBPs have a lower affinity to β-lactam antibiotic, reducing its concentration &
bacterial inhibition.
ADVERSE EFFECTS  Generally safe, but can also yield serious effects:
1. Hypersensitivity:
a. Anaphylactic shock (rare).
b. Serum sickness like (joint swelling, urticaria, fever).
c. Skin rashes.
2. Hematologic toxicity: decreased agglutination leads to hemolytic anemia & eosinophilia d/t penicillin G &
antipseudomonal penicillin.
3. Interstitial nephritis: all penicillin particularly methicillin.
4. Neurotoxicity: can cause seizures if injected intrathecally or in high dose.
 5. Ampicillin: diarrhea, pseudomembranous colitis,2 nd ifx, candidiasis.
CEPHALOSPORINS
 Similar to penicillin but more stable to bacterial β-lactamase & with a broader spectrum of activity.
 Has aminocephalosporanic acid nucleus which is similar to penicilanic acid.
 Classified into 4 groups (generations):
1. First generation: 3. Third generation:
 Cefadroxil, cefazolin, cephalexin, cephalothin, & cephradine.  Cefoperazone, cefotaxime, ceftriaxone, & moxalactum.
 Good against gram +ve , modest against gram –ve bacteria.  Further increased in gram –ve bacteria spectrum.
2. Second generation: 4. Fourth generation:
 Cefaclor, cefuroxime, cefoxitin, & cefotetan.  Cefepime.
 Increased activity against gram –ve bacteria.  Increased activity as compared to 3rd generation.
 Pharmacokinetics:
1. Administration: all must be administered IV 0r IM d/t poor oral absorption.
2. Distribution: all distribute very well into body fluid & cross placenta. However, only 3rd generation can cross BBB.
3. Fate: elimination occurs through tubular secretion or glomerular filtration, & cefoperazone & ceftriaxone r excreted through bile & feces.
 Clinical uses:
1. 1st – broad spectrum, not specific to an ifx, cefazolin is DOC for surgical prophylaxis
2. 2nd – active vs beta lactamase producing H.influenza, cefoxitin,cefotetan effective against anaerobes (diverticulitis,peritonitis)
3. 3rd – serious ifx resistant to most drugs, ceftriaxone,cefotaxime effective against resistant pneumococci
4. 4th – cefemine resistant to hydrolysis by chromosomal beta-lactamase (enterobacter),penetrated well into CSF, good activity vs penicillin
resistant streptococci, useful in treatment enterobacter.
 Adverse effects:
1. Allergic as penicillin: d/t cross sensitivity with penicillin (5-10%), thus, is not used if e history of penicillin anaphylaxis is present.
2. A disulfram-like effect: happens when cephalosporin is ingested with alcohol. Cephalosporin blocks alcohol oxidation & leads to
accumulation of aldehyde which causes toxicity.
3. Bleeding.
MONOBACTAMS
 Drugs – aztreonam:  Not active against gram +ve or anaerobes.
 Monocyclic beta-lactam ring.  Penicillin sensitive subjects can tolerate aztreonam.
 Resistant to beta-lactamases.  No major toxicity but can cause phlebitis, skin rash, & abnormal LFT.
 Active against gram negative rods & Enterobacteriaceae.  Administered by IV or IM & excreted in urine.
 Low immunogenic potential & little cross-reactivity.
CARBAPENEMS
 Drugs – imipenem:  Good also against +ve organism, anaerobes.
 Structurally related to penicillin.  Penetrates all tissue and CSF.
 Resistant to most beta-lactamases.  Excreted by gromerular filtration.
 Good activity against gram negative rods.  Adverse effects, nausea, vomiting, diarrhea, & rashes.
 Used in UTI.  Cross sensitivity with penicillins.
β-LACTAMASE INHIBITORS
Bind to & inactivate β-lactamase, thus
protecting e antibiotic from e enzymes.

 Drug - clavulanic acids, sulbactam, & tazobactum:

 Resemble beta-lactam molecule.
 Very weak antibacterial action.
 Combined with penicillin to restore activity against beta-lactamse producing bacteria.
 Available as fixed dose combinations only.
OTHER CELL WALL INHIBITORS
1. Vancomycin: 2. Teicoplanin:
 Tricyclic glycopeptides which inhibit synthesis of bacterial cell wall  Similar to vancomycin in action
phospholipids & peptidoglycan polymerazition which result in weaken cell wall  Can be given IM or IV.
& damaged cell membrane. 3. Polypeptide antibiotics:
 Important last line versus antibiotic resistant S. aureus (MRSA & MRSE) or in  Bacitracin – topical application, versus gram
patients with serious allergy to β-lactam. +ve bacteria.
 Can be given orally or IV & r widely distributed in body. 4. Isoniazid (INH) and Ethambutol:
 Adverse effects: fever, chills, phlebitis, ototoxicity, & nephrotoxicity.  Antibiotics vs Mycobacteria – interfere with
 Cleared by glomerular filteration which can accumulate in renal insufficiency. mycolic acid synthesis or incorporation.
 Resistance d/t plasmid-mediated changes in ↓ binding & permeability.
 INHIBITORS OF PROTEINS SYNTHESIS
PORTION DETAILS
TETRACYCLINES
 Consist of 4 fused rings with a system of conjugated double bonds. Substitutions on these rings lead to drug
DRUGS variation.
 Tetracycline, Chlortetracycline, Oxytetracycline, Demeclocycline, Doxycycline, & Minocycline.
 Enter the bacterial cell by passive and active transport → Bind irreversibly to 30S subunit of bacterial ribosome
MECHANISM OF
→ Blocking access of e amino acyl-tRNA to e mRNA-ribosome → Inhibit protein synthesis – Affects
ACTION
multiplication.

A bacteriostatic antibiotic.

ANTIBACTERIAL  Attack a broad spectrum of bacteria:

SPECTRUM 1. Gram +ve & gram –ve bacteria.
2. Anaerobes, rickettsiae, chlymadiae, & mycoplasma.
 Activity of all tetracyclines is similar.
 Some strains may be resistant to others & may be susceptible to Doxycycline and Minocycline.
 Resistance is a common problem.
 Mechanisms which lead to an inability of e organism to accumulate e drug:
1. Impaired influx of e drug.
2. Increased efflux (most common) of e drug via Mg2+ dependent efflux pump mediated by plasmid-encoded
RESISTANCE
resistance protein, TetA.
3. Interference with binding to ribosomes through e production of bacterial proteins.
4. Enzymatic inactivation of e drug.
 Many species are resistant to older tetracyclines, once resistant to one tetracycline is resistant to all.
1. Administration:
a. Oral: 6 hrly for most tetracycline.
b. Once or twice daily for Doxycycline and Minocyclin.
c. Doxycycline is preferred for oral once daily, not affected by food.
d. Parenteral: IV preparations available for severe cases.
2. Absorption:
 Variable absorption from intestine
a. Chlortetracycline: 30 %.
b. Others: 60-70%.
c. Doxycycline (parenterally prefered) and Minocyclin: 95-100 %.
 Absorption impaired by dairy food & divalent cations: d/t formation of nonabsorbable chelates of e
tetracycline with Ca2+ ions.
PHARMACOKINETIC 3. Distribution:
 Protein binding – 40-80%
 Widely distributed to tissues & fluids (except CSF). For minocycline, it can enter brain w/o inflammation &
also appears in tears & saliva.
 Can cross e placenta barrier & accumulate in fetal bones & dentition.
 Concentrate in e liver, kidney, spleen, & skin & also bind to tissue undergoing calcification or tumor that
has high Ca2+content.
4. Fate:
 In liver: concentrated, metabolized, & conjugated to form soluble glucuronides.
 E parent drug & its metabolites r secreted into bile.
 Most r reabsorbed in e intestine via enterohepatic circulation & enter urine by glomerular filtration.
 Obstruction in liver & kidney can increase e half-life.
1. Drug of choice for Mycoplasma pneumoniae, & chlamydiae.
2. Used for anti H.pylori in gastric ulcer.
3. Various gram +ve and gram –ve infections.
 E.g.: acne, bronchitis, & community acquired pneumonia.
CLINICAL USE
 Use has decreased due to resistance.
4. Sometimes used for amoebiasis (in combination).
5. Contraindications: should not be used in renally impaired patient, azotemia, & pregnant & breast feeding
women.
 Most adverse effects are due to direct toxicity or alteration of normal flora.
1. GIT – nausea, vomiting, & diarrhea d/t alteration of flora & superinfection (Candida & Clostridium).
2. Bony structures and teeth: tetracyclines bind with calcium causes staining, hypoplasia, & deformity of e
bones.
3. Renal damage can occur with outdated tetracyclines.
ADVERSE EFFECTS
4. Fatal hepatotoxicity: occurs in pregnant women receiving high dose of tetracyclines.
5. Phototoxicity: severe surnburn occurs in patients receiving tetracycline exposed to UV light & e sun.
6. Vestibular problem: dizziness, nausea, & vomiting occur when minocycline concentrates in e endolymph of
e ear.
7. Pseudotumor cerebri: benign intracranial hypertension characterized by headache & blurred vision.
MACROLIDES - ERYTHROMYCIN
OVERVIEW  Consist of a macrocyclic lactone structure to which one or > deoxy sugars r attached.
MECHANISM OF  E macrolides bind irreversibly to a site on e 50S subunit of e bacterial ribosome → inhibit e translocation &
ACTION transpeptidation steps of protein synthesis → affect multiplication.
 1. Mainly against gram +ve organisms: pneumococci, streptococci, & helicobacter.
ANTIBACTERIAL 2. Some gram –ve organisms: Neisseria & Bordetella pertusis.
SPECTRUM 3. Bacteriostatic at usual doses.
4. Bactericidal at higher doses.
 Resistance develops in susceptible organisms (mostly staphylococci) d/t:
1. E inability for e organism to take up e drug d/t reduced influx & increased efflux (via efflux pump).
RESISTANCE
2. E presence of plasmid-associated erythromycin esterases which modifies e binding site.
3. E decrease affinity of e 50S ribosomal subunit for e antibiotic.
1. Administration:
 Administered in e form of enteric-coated tablets or esterified form d/t susceptibility to gastric acid.
 Food interferes in e absorption of erythromycin.
 Administration: mainly oral for every 6 hours.
2. Distribution:
 Widely distributed to all tissue fluids including prostatic fluid & macrophages except in e brain and CSF.
PHARMACOKINETIC  Can cross placenta & concentrate in e liver, neutrophils, macrophages, & fibroblasts.
 Greater tissue penetration in inflammation.
3. Fate: r extensively metabolized & r known to inhibit e oxidation of other drugs.
4. Excretion:
 Concentrated & excreted in an active form in e bile.
 Partial reabsorption occurs via enterohepatic circulation.
 Inactive metabolites r excreted into urine.
1. Drug of choice for diphtheria & chlamydial infections, community acquired pneumonia, pneumococci,
mycoplasma, & legionella.
CLINICAL USE
2. Substitute in penicillin sensitive subjects for gram +ve infections.
3. Resistance has limited its use for many common infections like pharyngitis, skin and soft tissue infections.
1. Epigastric distress: anorexia, nausea, vomiting, & diarrhea.
2. GIT intolerance due to direct effect on gut motility.
3. Liver: acute cholestatic hepatitis (especially estolate).
ADVERSE EFFECTS
4. Allergic reactions: fever, rash, & eosinophilia.
5. Interactions: Inhibits Cytochrome P450 which leads to increase in concentration of many drugs.
6. Contraindications: patients with hepatic & renal dysfunctions should be given e drug with care cautions.
MACROLIDES – OTHER DRUGS
1. Clarithromycin: 2. Azithromycin:
 Semisynthetic derivative of erythromycin.  Similar to erythromycin.
 More acid stable & better absorption.  Differs mainly in pharmacokinetic properties.
 Spectrum almost identical to erythromycin.  Penetrates most tissues (except brain): slowly
 More effective against Mycobacterium avium complex. released from there – elimination half life of 3 days.
 Cross resistance with erythromycin.  Hence once daily dosing is possible.
 Longer half life hence twice daily dosing.  Rapidly absorbed and well tolerated orally.
 Drug interactions similar to erythromycin.  Does not inhibit Cy P450 hence free of drug interactions.
 Lower incidence of GIT side effects.
CHLORAMPHENICOL
1. Overview:
 Restricted only to life-threatening infection for which no alternatives exist.
 Crystalline, stable compounds which r poorly soluble in water.
 Succinate is highly soluble – used for IV.
2. Mechanism of action: it binds to e bacterial 50S subunit & inhibit protein synthesis at e peptidyl transferase reaction.
3. Antimicrobial spectrum:
 Broad spectrum bacteriostatic antibiotic.
 Effective against aerobic & anaerobic gram +ve as well as gram –ve organisms & rickettsiae.
 Not effective against Pseudomonas aeruginosa & chlamydiae.
4. Resistance:
 Low level resistance develops by mutant selection.
 Clinical resistance due to chloramphenicol acetyl transferase which inactivates the drug & also d/t inability of e drug to penetrate e organism.
5. Pharmacokinetics:
 Rapidly and completely absorbed from GIT. 7. Adverse effects:
a. GIT: occasional nausea, vomiting, & diarrhea.
 IV chloramphenicol succinate hydrolysed to free
b. Bone marrow: dose related reversible suppression of RBCs.
chloramphenicol.
c. Aplastic anaemia: idiosyncratic, unrelated to dose, tends to be
 Widely distributed to all tissues including brain & CSF.
irreversible & fatal but, relatively rare & serious (1 in 40000).
 Inactivated by glucuronide conjugation in liver. d. In New Born: Gray baby syndrome - insufficient conjugation.
 Eliminated mainly in urine. e. Interactions: inhibits hepatic microsomal metabolism of many
 Small amount excreted through bile and faeces. drugs.
6. Clinical use:
a. Used rarely now d/t potential serious toxicity, resistance, & better alternatives.
b. May be used for serious rickettsial infections (eg. typhus), bacterial meningitis resistant to penicillins or in penicillin sensitive subjects,
topical use in eye (d/t good penetration).
7. Adverse effects:
CLINDAMYCIN
 Effective against Streptococci, Staphylococci, & Pneumococci.  Administration :
 Also effective against anaerobes (Gram +ve & -ve organisms). 1. Oral – 8 hourly.
 MOA : similar to erythromycin. 2. IV – 8 hourly.
 Cross resistance with erythromycin.  Prophylaxis of endocarditis in valvular heart disease.
 Penetrates most tissues except brain and CSF.  Adverse effects: GIT disturbance, liver dysfunction, &
 Uses: anaerobic & mixed infections. neutropaenia.

AMINOGLYCOSIDES
PORTIONS DETAILS
 Streptomycin, gentamicin, amikacin, neomycin kanamycin, tobramycin, netilmicin, & sisomicin.
 Water soluble, stable in solution, & more active in alkaline pH.
OVERVIEW  Structure: 2 animo sugars joined by a glycosidic linkage to a central hexose (aminocyclitol) nucleus.
 E polycationic nature precludes their easy passage across tissue membrane.
 Aminoglycosides fuse into organism through porin channels or oxygen-dependent system → bind to 30S ribosomal
subunit prior to ribosome formation → interfere with assembly of e functional ribosomal apparatus → cause 30S
MECHANISM OF
subunit of e completed ribosome to misread e genetic code → interrupt e process of polysome disaggregation &
ACTION assembly → polysome becomes depleted → inhibit protein synthesis → affect multiplication.
 Effect is enhanced by cell wall active drugs such as penicillin & vancomycin.
 Empirical treatment of infection d/t aerobic gram –ve bacilli including Pseudomonas aeruginosa.
ANTIBACTERIA
 All r bactericidal protein synthesis inhibitors.
L SPECTRUM  Lower efficacy against gram +ve bacteria.
 Resistance can be caused by:
1. Decreased uptake of drugs when oxygen-dependant transport system & porin channels r absent.
RESISTANCE 2. An altered 30S ribosomal subunit aminoglycoside-binding site has a decreased affinity for e drugs.
3. Plasmid-associated synthesis of enzymes that modify & inactivate e drugs.
1. Administration:
 Prevent adequate absorption after oral administration. Thus, parenteral administration (IM or IV) is used
because it is well absorbed from IM site.
 E bactericidal effect is concentration & time dependent, thus, e greater e concentration of e drug, e greater e rate
at which e organisms die.
 Post-antibiotic effect: leads to once-daily dosing to reduce toxicity & cost. However, in pregnancy, neonatal
infection, & bacterial endocarditis, it is administered for every 8 hours.
2. Distribution:
 Level achieved in most tissues r low & penetration into most body fluid is variable d/t highly poor compound:
a. Do not enter cells readily.
b. Do not enter CNS or eye.
PHARMACO- c. Most tissues do not get high concentrations.
KINETICS d. Low levels in secretions (30 % in bile).
 High concentrations in renal cortex.
 Higher CSF levels in presence of meningitis.
 All cross e placental barrier & may accumulate in fetal plasma & amniotic fluid.
 Serum half life is 2-3 hours & may increase many fold in renal impairment. Serum level estimation is necessary
to avoid serious toxicity (trough concentrations more relevant).
 Usual dosing – twice or thrice daily.
3. Fate:
 Metabolism does not occur in e host because all r rapidly excreted into e urine by glomerular filtration.
 Excretion directly proportional to creatinine clearance.
 Dosage adjustment required in renal impairment.
1. E organisms:
a. Mainly against gram –ve enteric bacteria.
b. Combined with β-lactam antibiotic to increase efficacy and to extend over e gram +ve bacteria.
c. Choice of agents depends on susceptibility of isolated organism.
CLINICAL USE 2. Clinical preparation:
 Concentration dependent killing effect.
 Post antibiotic effect for several hours.
 Concentration & time dependent toxicity: trough concentrations > 2 mcg/mL.
 Single daily dosing effective with possibly lower toxicity is recommended in selected conditions.
 Narrow margin of safety which if exceeded causes:
1. Ototoxicity d/t accumulation of antibiotic in e endolymph & perilymph of e inner ear. Toxicity correlates with no. of
destroyed hair cells in e organ of Corti. Results in:
a. Auditory – tinnitus & hearing loss.
b. Vestibular – vertigo, ataxia, & loss of balance.
ADVERSE 2. Nephrotoxicity d/t retention of e aminoglycosides by e proximal tubular cells which disrupts calcium-mediated
EFFECTS transport. Leads to:
a. Directly toxic to renal tubules.
b. Reduced creatinine clearance.
3. In high doses: neuromuscular blockade d/t a decrease in e release of acetylcholine from prejunctional nerve endings
& e sensitivity of e postsynaptic site.
4. Allergic reactions: contact dermatitis in topically applied neomycin.

AMINOGLYCOSIDE
 AMINOGLYCOSIDES – E VARIOUS DRUGS
 From streptomyces griceus.
 resistance has dev – utility of single agent limited
 2nd line drug in TB.
Streptomycin
 Penicillin + streptomycin  enterococcal infection.
 IM administered.
 Vestibular toxicity n ototoxicity – dependent of dose, age, & duration.
 From micromonospora pupurea.
 Versus both +ve n –ve organisms (pseudomonas, enterobacteriacae, klebsiella, &
proteus).
 Synergism with vancomycin & β-lactam antibiotics.
 Resistance: streptococci & enterococci r resistant d/t a poor penetration, thus is used in
combination with penicillin & vancomycin.
 Staphylococcus rapidly resistance by selection.
 Susceptible –ve organism developing resistance.
Gentamicin  Aminoglycoside modifying enzymes.
 These may retain susceptibility to amikacin.
 Clinical use in severe gram –ve infection, which may be resistant to other drugs such as
pseudomonas, proteus, klebsiella, & enterobactericea.
 Used in combination: not effective alone except UTI.
 IV, IM, & TDS once daily.
 Level monitoring for prolonged use.
 Topical use in creams/ointments/eye.
 AE: nephrotoxicity (>3 days) and ototoxicity (mainly vestibular
 Semisynthetic derivative of kanamycin.
 Resistant to many enzymes that inactivate gentamicin & tobramycin.
 Can be used for org that resistant to above agents.
Amikacin  Strain MDR: TB susceptible.
 IM: 12 hourly.
 Toxicity: ototoxicity & nephrotoxicity.
 Level monitored.
 Similar spectrum as gentamicin.
 Slightly active against pseudomonas.
Tobramycin
 Pharmacokinetics and toxicity same as gentamicin.
 IM n IV.
 Spectrum: gram –ve and +ve bacteria.
 Some mycobacteria.
Neomycin and  Poor absorb from GIT.
kanamycin  Too toxic for parenteral use.
 Topical: cream, ointments, & solution.
 Oral: for local action for bowel sterilization n hepatic coma.
 Structurally related to aminoglycosides.
Spectinomycin  Versus +ve and –ve bacteria.
 In gonorrhea: drugs resistanct or in penicillin sensitive patient.

JOM SOLAT SUBUH.

Dari Imam al-Bukhari dan Muslim dari Jarir bin Abdullah r.a. meriwayatkan: “Kami sedang duduk
bersama Rasulullah, ketika melihat bulan purnama. Baginda berkata, ‘Sungguh kalian akan melihat Rabb
kalian sebagaimana kalian melihat
bulan yang tak terhalang dalam melihatNya’, Merakalah yang menjaga dua solat, iaitu solat SUBUH dan
ASAR. Apabila kalian mampu, janganlah kalian menyerah dalam melakukan solatsebelum terbit matahari
dan solat sebelum terbenam matahari. Maka lakukanlah.”

(HR Bukhari dan Muslim).

 INHIBITORS OF NUCLEIC ACID SYNTHESIS
DETAILS PORTIONS DETAILS
Sulphonamides ANTIFOLATES Trimethoprims
 Susceptible organisms cannot use exogenous folic acid, hence synthesize it from PABA (p-aminobenzoic acid) which is catalyzed by
dihydropteroate syntethase (inhibited by sulphonamide) & Dihydrofolate reductase inhibited by trimethoprim).
 Inhibition of these enzymes will inhibit nucleic acid synthesis & prevent bacterial replication.
 A bacteriostatic drug.
 E drugs: sulphadiazine, sulphamethoxazole, sulphadoxine, &
 Inhibitor of bacterial dihydrofolate
sulphacetamide.
OVERVIEW reductase.
 Structural similarity with PABA.
 Much more soluble at alkaline than acid pH.
 Because of structural similarity, e sulphonamide competes with  Inhibit e formation of folate active form
PABA for dihydropteroate syntethase & inhibits folic acid MECHANISM OF leading to a decreased availability of e
formation & its cofactor forms. ACTION tetrahydrofolate coenzyme required for
nucleic acid synthesis.
1. Gram +ve and gram –ve bacteria, Chlamydia, trachomatis, & some
 Similar to that of sulphamethoxazole but
protozoa.
ANTIMICROBIAL with 25x higher in potency.
2. Enteric bacteria like E coli, klebsiella, salmonella, shigella, &
SPECTRUM  May be used alone in UTI & bacterial
enterobacteriacae.
prostatitis.
3. Toxoplasmosis & chloroquine-resistant malaria.
 Natural resistance: organism that do not synthesize their own folic 1. Resistance in gram –ve bacteria d/t e
acid. presence of an altered dihydrofolate
 Acquired resistance: plasmid transfer of random mutation d/t: reductase that has a lower affinity for e
RESISTANCE
1. Altered dihydropteroate synthetase. drug.
2. Decreased cellular permeability to sulfa drugs. 2. Overproduction of e enzyme which
3. Enhanced production of PABA. decrease drug permeability.
1. Administration:
 Oral: most r well absorbed in e small intestine.
 IV: for patients who r unable to take it orally.
 Similar to that of sulphonamides.
 Topical: in burn patients.
 Because it is a weak base, higher
2. Distribution: Widely distributed to tissues including CNS, CSF,
concentrations of e drug r achieved in
placenta, & foetus & bind to serum albumin. PHARMACO-
acidic prostatic & vaginal fluid.
3. Fate: KINETIC
 Penetrate CSF.
 R acetylated in e liver, but can be crystallized in e kidney,
 Undergo some O-demethylation.
forming crystalluria.
 Most r excreted unchanged via e kidney.
 Unchanged drug and metabolites excreted in urine & breast
milk.
 Tend to precipitate in acidic medium.
1. Seldom used alone now.
2. Oral: Sulphamethoxazole combined with trimethoprim for
treatment of susceptible infections & Sulfadoxine + pyrimethamine
 May be used alone in UTI & bacterial
for malaria. CLINICAL USE
prostatitis & vaginitis.
3. Topical: sodium sulphacetamide ophthalmic solution for bacterial
conjunctivitis & trachoma.
4. Silver suphadiazine for prevention of infection in burn wounds.
1. Allergic reactions: Fever, skin rash, exfoliative dermatitis, 1. Folic acid deficiency:
photosensitivity, urticaria, & steven-Johnson syndrome.  Magaloblastic anemia.
2. Stomatitis, conjunctivitis, & arthritis.  Leucopenia.
3. Urinary tract: crystalluria, haematuria, & obstruction. However, ADVERSE EFFECTS
 Granulocytopenia.
alkalinizing the urine prevents it.  May be reversed by e administration of
4. Blood: haemolytic & aplastic anaemia (in G6PD), & granulopaenia. folinic acid.
Trimethoprim sulphamethoxazole combination
1. Overview: 3. Administration:
 sulphamethoxazole – T1/2 = 10 -12 hours.  Oral: one double strength tablet 12 hourly.
 Trimethoprim – T1/2 = 11 hours.  IV: available.
 Both easily absorbed form the gut & widely distributed. 4. Adverse effect: S + T - megaloblastic anemia,
 Combination: sequential block of bacterial folate synthesis. leucopenia,granulocytopenia.
 Combination: bactericidal, alone bacteriostatic.
 Combined in ratio 5:1 – optimal effect.
 Resistance can develop to one or both agents.
2. Clinical uses:
 Wide variety of ifx depend on susceptibility
 Active versus S. aureus (MRSA), pneumococcus, hemophilus & klebsiella.
 Used for systemic salmonella infection, shigellosis, UTI, & prostatitis.
 E.coli and pneumococi: resistant.
DNA GYRASE INHIBITORS - QUINOLONES
OVERVIEW  Flourinated analogues of nalidixic acid.
 Active against many gram +ve and gram –ve bacteria.
 Nalidixic acid itself also effective but useful only for lower UTI – does not achieve effective systemic concentration.
 Fluorinated derivatives have better antibacterial effects.
  Achieve bactericidal levels in blood and tissues.
 Enter e cell by passive diffusion through porin channel → bind to DNA gyrase & topoisomearse IV to from a ternary
complex → inhibit resealing step → cleavage of DNA → cell death.
MECHANISM OF  Mechanisms of action:
ACTION 1. Inhibit bacterial tropoisomerase II (DNA Gyrase)
2. Inhibit tropoisomerase IV
a. Prevents relaxation of supercoiled DNA.
b. Prevents  normal
Prevents separation&ofreplication.
transcription replicated DNA.
 1st Group :
 Norfloxacin.
 Least active among quinolones against both gram –ve & gram +ve bacteria.
 2nd Group :
 Ciprofloxacin, ofloxacin, & pefloxacin.
 Excellent gram –ve and moderate gram +ve bacteria.
ANTIMICROBIAL
 MRSA tend to be resistant.
SPECTRUM
 3rd Group :
 gatifloxacin, moxifloxacin, & gemifloxacin.
 Improved activity against gram +ve bacteria.
 4th generation:
 Trovafloxacin.
 Active against many anaerobic & gram +ve bacteria.
1. Altered target: mutation in DNA gyrase & topoisomerase IV leads to decrease affinity for e drugs.
2. Decreased accumulation in intracellular compartment d/t:
RESISTANCE
a. A decreased in e no. of porin channels.
b. E presence of an energy-dependent efflux-system in e cell membrane.
1. Absorption:
 Only 35 to 70% of orally administered norfloxacin is absorbed.
 Most have e IV preparation.
 Absorption is interfered with e ingestion of sucralfate, antacids containing aluminum or magnesium, or dietary
supplements containing iron or zinc as well as calcium & other diavalent ions.
PHARMACOKINATIC 2. Fate:
 10 – 40% bind to plasma protaeins.
 All r distributed well into all tissues & body fluids.
 Level r high in bone, urine, kidney, & prostathic tissue, & concentration in e lung exceeds those in serum.
 Accumulates in macrophages & PMNs.
 Excreted by renal routes.
1. Ciprofloxacin:
 E most effective against gram –ve organisms & systemic infections caused by MRSA, enterococci, &
pneumococci.
 Treating infection caused by Enterobacteriaceae & E. coli.
 DOC for prophylaxis & treatment of anthrax.
 Treatment for paeusomonal infection associated with cystic fibrosis.
2. Fluoroquinolones: active against M. tuberculosis, M. avium complex, mycoplasma, & chlamydiae.
3. Norfloxacin: effective against gram –ve & +ve organisms in treatin complicated & uncomplicated UTIs &
CLINICAL USE prostatitis.
4. Levofloxacin:
 Treatment of prostatitis d/t E. coli & of STD except syphilis.
 Alternative therapy in patient with gonorrhea.
 Treatment of skin & LRTI.
 Excellent activity against respiratory infection d/t S. pneumonia.
5. Trovafloxacin & moxifloxacin:
 Enhanced activity against gram +ve organism & anaerobes.
 Poor activity against P. aeruginosa.
1. Generally well tolerated.
2. Most common: Nausea, vomiting, & diarrhea.
3. CNS problems: delusions siezures (especially with NSAIDs or theophylline), headache, & dizziness.
4. Phototoxicity: drug should be discontinued with e 1st sign of phototoxicity.
ADVERSE EFFECTS 5. Hapatotoxicity: trovafloxacin use is restricted to infections that r life-threatening d/t severe hapatotoxicity. It also
cannot be used in longer than 14 days.
6. Connective tissue problems: fluoroquinolones should be avoided in pregnancy & nursing mothers, & in children
under 18 years old, because of articular cartilage erosion.
7. Not recommended for pre-pubertal children because it can cause cartilage damage arthropathies & joint swelling.
1. Inhibits DNA dependent RNA polymerase of mycobacteria and other organisms.
2. Suppression of RNA synthesis.
RIPAMFICIN 3. Has activity against gram +ve as well as many gram -ve bacteria.
4. Major use is in therapy of tuberculosis.