Dr. V.K. GUPTA

Division of Medicine

Principles and therapeutics of antimicrobialsPrinciples and therapeutics of antimicrobials

Antibiotic :Is naturally produced substance or produced synthetically or semi synthetically that inhibits the growth or kills a microorganism.

Antimicrobial agent : has a broader definition than antibiotic. It includes any substance produced naturally, synthetically or semi synthetically that kills or inhibits the growth of micro organisms, while ideally causing minimal or no damage to the host.

Antibiotic

Sources of Antibiotics

• Natural - Mainly fungal sources Benzylpenicillin and Gentamicin are natural antibiotics

• Semi-synthetic - Chemically-altered natural compound Ampicillin and Amikacin are semi-synthetic antibiotics

• Synthetic - Chemically designed in the lab Moxifloxacin and Norfloxacin are synthetic antibiotics

• There is an inverse relationship between toxicity and effectiveness as you move from natural to synthetic antibiotics

Role of Antibiotics

To inhibit multiplication

Antibiotics have a bacteriostatic effect

Minimal Inhibitory Concentration = MIC

MIC = lowest concentration of antibiotic that inhibits growth

(Riviere 2009)

Role of Antibiotics

• To destroy the bacterial population

• Minimal Bactericidal Concentration = MBC

• MBC = lowest concentration of antibiotic that kills bacteria

• Antibiotics have a bactericidal effect (Riviere

2009)

Mechanisms of Action Antibiotics operate by inhibiting crucial life

sustaining processes in the organism: the synthesis of cell wall material,DNA, RNA, ribosome's and proteins.

Target

The target of the antibiotic should be selective to minimize toxicity for host but all antibiotics are toxic to some degree

(Riviere 2009)

Ideal Antibiotics

Selective target – target unique Narrow spectrum – does not kill normal flora

High therapeutic index – ratio of toxic level to therapeutic level

Few adverse reactions – toxicity, allergy

Various routes of administration – IV, IM, oral Good absorption from site of injection

Good distribution to site of infection Emergence of resistance is slow ( Goodman & Gilman's 2006)

(A) Based on spectrum of activity Narrow spectrum Active against either gram-negative or gram-

positive bacteria e.g. penicillin, streptomycin, erythromycin

Broad-spectrum Active against both gram-positive and gram-

negative bacteria e.g. tetracycline & chloramphenicol (Riviere 2009)

Classification of antibiotics

(B)Based on effects of AB

(a)Bacteriostatics inhibit bacterial growth.

The body requires an effective innate and acquired immune system in the case of bacteriostatic antibiotics.

For immuno-compromised patients bacteriostatic antibiotics usually not effective.

Antimetabolites and inhibitors of protein synthesis (except aminoglycoside antibiotics) are usually bacteriostatic

(Riviere 2009)

(b) Bactericidal

Antibiotic kills bacteria.

Inhibitors of cell wall synthesis and agents affecting cell membrane permeability are bactericidal

(Riviere 2009)

(C) Based on mode of action

A. Antibacterial agents that inhibit the cell wall synthesis

B. Antibacterial agents that alter the function of the cytoplasmic membrane

C. Antibacterial agents that inhibit the protein synthesis

D. Antibacterials that inhibit the nucleic acid synthesis ( Goodman & Gilman's 2006)

1. Cause misreading of mRNA code and affect permeability e.g. streptomycin & gentamicin

2. Inhibit DNA gyrase e.g. fluoroquinolones

3. Interfere with DNA function e.g. Rifampin4. Interfere with DNA synthesis e.g. acyclovir

(D) Uses of antibiotics

Antibacterial A. Gram positive bacteria Penicillin, Erythromycin

B. Gram negative bacteria Streptomycin, Gentamicin

C. Broad spectrum Chloramphenicol, Tetracycline,fluroquinalones

D. Antitubercular Streptomycin, rifampicin kanamycin capriomycin

(Riviere 2009)

Prophylactic – prior to surgical procedure best time half an hr prior to surgery e.g. Penicillin

Use a growth promoter – use in adult ruminantsmonencin & salinomycin

Antifungal -systemic antifungal agent amphotericin-B -topical antifungal agent Griseofulvin,

(Riviere 2009)

Antiviral antibiotics- inhibit viral mRNA polymerase and interfere viral protein and maturation e.g. Rifampin

interfere viral protein synthesis e.g. Mytomycin, Puromycin

Antineoplastic – prevent RNA transcription and

protein synthesis e.g. actinomycin-D inhibition of RNA & DNA synthesis e.g.

Doxorubincin, Daunorubicin

( Riviere 2009)

Uses of antibiotics (contd.)

• Potentiation of inhibitory neurotransmitters in nematodes and ectoparasite e.g. Ivermectin,doramectin.

• Milbemycin-D & Milbemycin oxime active against

HWP(Heart worm parasites) in dog • Moxidectin active against nematodes and ectoparasite in

cattle

( Riviere 2009)

Uses Anticoccidial inhibit coccidial protein synthesis e.g. Oxytetracycline (curative) and chlortetracycline

(prophylactic) Use as preventive e.g. Monencin

Antianaplasmic Tetracycline

Antitheilerial Oxytetracycline & rolitetracycline ( Riviere 2009)

Advantages Easily available, cheap and least toxic Easily distributed in body tissues and fluids

least untoward reaction If used properly drugs resistant does not developed  

Antibiotics have saved countless lives Broad-spectrum antibiotics which work equally well on

bacteria and fungus

Each antibiotic is effective only for some types of disease

Right antibiotic cures the disease in the shortest span of time

DisadvantagesToxicity Pain, abscess formation on I/M injection Thrombophlebitis on I/V injection Tetracycline, erythromycin & chloramphenicol Ototoxic & nephrotoxic Aminoglycoside Hepatotoxic & nephrotoxic Tetracycline Bone marrow depression and aplastic anemia Chloramphenicol (Adams 2001)

Disadvantages

Allergic reaction -hypersensitivity reaction Penicillins, aminoglycosides & cephalosporin Superinfection - Tetracycline, Chloramphenicol

Microbial resistance- Staphylococcus to penicillin Enterococci to streptomycin

Vitamin deficiencies- vitamin-B & vitamin-K Production of residues in animal products ( Adams 2001)

Disadvantages of combination

Increase chance of toxicity

Increase intensity of toxicity of a drug by another drug

Increase in nephrotoxicity (gentamycin + cephaloridine)

Chance of Superinfection increase

Increase cost of therapy ( Adams 2001)

Do’s and don’t antibiotics Newborn can not metabolized and excreted because

lack of metabolizing enzyme e.g. Chloramphenicol & tetracycline

Young animal accumulate in developing teeth and bone e.g. tetracycline

Old animal poor renal function slow excretion e.g. aminoglycoside

Pregnancy penicillin and erythromycin can safely given

avoid all antibiotic in first trimester period of organogenesis

× tetracycline, aminoglycoside

Milking animal Iprinomectin nil milk withholding period

(radostits 2000)

× Chloramphenicol & ivermectin

Renal dysfunction× tetracycline, aminoglycoside, amphotericin-B

Hepatic dysfunctionDon’t- erythromycin, chloramphenicol, & rifampin

Drug allergy Erythromycin is alternative to penicillin allergy × Penicillin, aminoglycoside, erythromycin & trimethoprim

Presence of blood, pus, CSFpenicillin × aminoglycoside

Food animal follow withdrawal time × chloramphenicol

Penicillin, aminoglycoside,& chloramphenicolDo’s- parenterally × Don’t- orally

Meningitis Do’s- chloramphenicol, cefotaxime & rifampin × Don’t- aminoglycoside

Pleural& peritoneal membrane Do’s- chlortetracycline× Don’t- penicillin

Toxicity prefer penicillin, cephalosporin's & erythromycin× Aminoglycoside, tetracycline chloramphenicol,

vancomycin

Follow directions Dos- full course of antibiotics× Don’t - stop antibiotics too early Spectrum narrow spectrum drugs × Broad spectrum drugs Combination bacteriostatics + bacteriostatics or bactericidal +

bactericidal × bacteriostatics + bactericidal

Mechanism by which small doses of an antimicrobial can lead to Mechanism by which small doses of an antimicrobial can lead to propagation/selection of resistant strains of bacteriapropagation/selection of resistant strains of bacteria

1. ß-LACTAM ANTIBIOTICS

Kidneys/bladder/genitourinary tract → exceed MIC (Rock, 2007; Bill, 2006)

CNS infections (Vaden , 2001)

PENICILLINS

• Penicillin G (natural); ampicillin, amoxycillin (aminopenicillins; broad-spectrum ); cloxacillin (penicillinase-resistant; narrow-spectrum), carbenicillin, ticarcillin (extended-spectrum)

• Procaine penicillin G (1 day) and benzathine penicillin G (7 days): not IV → affect cardiac conduction system

(Vaden , 2001)

• Aminopenicillins: empty stomach (Bill, 2006)

Eye/brain/prostate/intracellular bacteria (Bill, 2006; Vaden, 2001)

Resistant: Pseudomonas, Staphylococci; cross-resistance

Cloxacillin: staphylococcal infections (Bill, 2006)

Add clavulanic acid and sulbactam → potentiated compound Kidneys/liver/lung (Rock, 2007)

• Hypersensitivity reactions most common ADR → record; mild skin rash to life-threatening anaphylactic shock; injectable > oral; emergency treatment (epinephrine + corticosteroids); cross-reactivity

(Rock, 2007; Bill, 2006)

• Hydrolysis → degradation (main) (Vaden , 2001)

• Clavulanate packaged individually in foil → absorbs moisture

(Bill, 2006)

CEPHALOSPORINS

• 4 generations: ↑ → ↓G+; ↑ G- (Bill, 2006)

• Cephadroxil, cephalexin, cefpodoxime (PO), cefotaxime & ceftazidime

• Stable in solutions for short time, unless frozen

• False + reaction: glucosuria and proteinuria (Vaden , 2001)

• Reactions: much less (Bill, 2006)

2. AMINOGLYCOSIDES

• Neomycin (topical), amikacin (broadest spectrum) & gentamicin

(Riviere, 2001)

• ↓ cross-resistance (Bill, 2006)

• Usually administered parenterally (Riviere, 2001)

• t1/2 : 2-5 h; post antibiotic effect (PAE) (Bill, 2006)

Eye/brain/prostate/respiratory tract (Strausbaugh, 1983)

Cellular debris (pus) → flush thoroughly (Bill, 2006)

Anaerobic bacteria/conditions (Riviere, 2001)

Denuded skin/surgical sites → renal failure (Mealey, 1994)

DOC for serious G- infections (Riviere, 2001)

+ penicillin (Bill, 2006)

• ↑ toxicity potential; accumulate within kidneys (PCT) and inner ear by pinocytosis (active) → nephrotoxicity and ototoxicity (auditory: dogs; vestibular toxicity: cats) (Bill, 2006; Bennett, 1982)

• Monitoring renal function: urine sediment (casts or increased protein are early signs) & urine SG (not for cats)

(Bill, 2006; Grauer,1995)

• Hydrophilic → steep gradient for diffusion; OD → much safer (Freeman, 1997)

3. FLUOROQUINOLONES

• Enrofloxacin, difloxacin, orbifloxacin and marbofloxacin • Broad-spectrum; aerobic bacteria (Papich, 2007)

• Well absorbed PO; not affected by food; reduced (90%) with ulcer treatment medication (Bill, 2006; Nix, 1989)

First-choice antibiotics (WHO, 1997)

Streptococcal infections (Bill, 2006)

Infections: prostate/skin/soft tissue/wounds/bone/ear/ respiratory & urinary tract (DeManuelle, 1999; Paradis, 1990)

↑ intracellular concentrations → ↑ concentrations in infected tissue e.g., pyoderma (WHO, 1997; Garaffo, 1991)

Pregnancy (Papich, 2001)

• Very safe drugs; but affect developing joint cartilage → not in young

• Cats: retinal degeneration → enrofloxacin dose reduced to 5 mg/kg OD • ↑ seizure activity → avoid in epileptics (Papich, 2007; Bill, 2006)

4. TETRACYCLINES

• TC, OTC (hydrophilic) and minocycline/ doxycycline (lipophilic)

• Irritating: give PO or IV; slow IV or dilute (Riviere, 2001)

• PO preferred: chelation decreases absorption (Bill, 2006; Aronson, 1980)

• Distribution ~ lipid solubility (Riviere, 2001)

• TC/OTC → not metabolised; enterohepatic circulation; doxycycline largely excreted into the intestine

(Bill, 2006; Kunin, 1961)

• OTC: light-sensitive drug (Rock, 2007)

Doxycycline/minocycline → eye/CNS/prostate/ intracellular bacteria/↓ renal function (Bill, 2006; Shaw, 1986)

• Yellow, mottled tooth discoloration; slow bone development (first few weeks) (Bill, 2006; Moffit, 1974)

• Dogs: irritation of GIT; cats less tolerant; ® doxycycline + food (Rock, 2007)

• Expired TC/OTC → nephrotoxic compound → Fanconi’s syndrome

(Bill, 2006)

5. SULPHONAMIDES/SULPHA DRUGS

• Sulphasalazine, sulphadiazine, sulphadimethoxine & sulphamethoxazole

• Many bacteria resistant (Bill, 2006)

• Potentiated sulphonamides → + TMP→ ↓ MIC of both drugs → ↓ SE, ↑ efficacy, bactericidal → OD/ BID (Rock, 2007; Bill, 2006)

Necrotic tissue (Rock, 2007)

Topical use: except silver sulphadiazine & mafenide (Spoo, 2001)

Serosal/synovial/ocular/CS fluid/prostate/respiratory & urinary tract

(Rock, 2007; Bill, 2006)

Sulfasalazine → IBD → 70% in LI → sulfapyridine (sulphonamide) + 5-aminosalycilic acid (local anti-inflammatory effect) (Rock, 2007)

• Dogs: decreased tear production (KCS, or “dry eye”) (Bill, 2006; Collins, 1986)

• Dog develops new CS → suspect ADR’s (notorious: 82%); Dobermanns predisposed; dermal reactions (drug eruptions); hypersensitivity: type III (Rock, 2007; Noli, 1995)

• Cats: PO: salivation

• Sulfasalazine: cautious in cats & aspirin hypersensitive animals

• Crystalluria (dehydration or acidic urine) → concern in small animals (Bill, 2006)

Sulfonamide crystals are typically yellow in color

6. LINCOSAMIDES

• Lincomycin and clindamycin (↑ used)• ® G+ infections when penicillin resistance/intolerance (Rock, 2007)

Clindamycin: anaerobic bacteria (Bill, 2006; Noli, 1999)

7. MACROLIDES

• Erythromycin, azithromycin, clarithromycin & tylosin (Papich, 2007)

• Spectrum ~ penicillin → substitutes (Bill, 2006)

• PO: preferred; food affects absorption (Kirst, 1989)

CSF (Wilson, 1984)

Acidic environment (Sabath, 1968)

Respiratory tract (Papich, 2001)

Well distributed (prostate) (Bill, 2006)

• Inhibits cytochrome P-450; erythromycin ~ motilin (Papich, 2001; Lester, 1998)

• Vomiting/regurgitation → most common adverse effects

(Bill, 2006; Kunkle, 1995)

8. CHLORAMPHENICOL

• Broad spectrum (Papich, 2001; IARC, 1990)

Lactating animals (Papich, 2001)

Serious CNS infections (Rahal, 1979)

Well distributed (eye/CNS/prostate) → new agents (Bill, 2006; Hird, 1986)

• SE: myelosuppression (cats) → ↓ dose than dogs → ↓ liver metabolism + ↓ elimination; neonates (Bill, 2006)

• Inhibits cytochrome P-450; ↑ half lives e.g., pentobarbital

(Adams, 1970) • Myelosuppression → avoid repeated contact or inhalation (Bill, 2006; Yunis, 1988)

9. METRONIDAZOLE

• Bactericidal

• Anaerobic conditions (Bill, 2006)

• Neurologic side effects (Longhofer, 1988)

REQUISITES FOR RATIONAL ANTIBACTERIAL THERAPY

1) Lesion management and supportive care (Davis,1985)

2) Following the “five rights” of drug administration:

a) Right drug

b) Right dose

c) Right patient

d) Right routee) Right time (Galbraith, 1999)

3) Monitoring of patient

4) Client education

5) Monitoring response to therapy (Rock, 2007)

a. RIGHT DRUG

• Necessary conditions: In vitro susceptibility: by CST/AST (Rock, 2007)

In vivo susceptibility Host tolerance (Bill, 2006)

• Other considerations: Cost, client compliance, ease of administration & convenient dosage interval

(Bill, 2006) Risks/ interactions: avoid compounding (never mix cationic & anionic drugs)

(Papich, 2007; Mir, 1998)

Impact of the disease process on drug pharmacokinetics (e.g., aminoglycosides) and pharmacodynamics (e.g., sulfonamides)

(Novotny 1993; Wilcke 1986)

• Check name (Rock, 2007)

b. RIGHT DOSE

• Optimum concentrations at site of infection (Bill, 2006)

• Formula:

• Under doing (larger dogs) → more serious• Over dosing (cats) (Barragry, 1994)

No diuretics (Mir, 1998)

Check strength (Rock, 2007)

c. RIGHT PATIENT

• Neonatal & pediatric patients:Tetracyclines, sulfonamides, and fluoroquinolones (Novotny, 1993)

↓ hepatic biotransformation → avoid chloramphenicol (Short, 1984)

↑ Vd → ↑ dose (Novotny, 1993)

• Pregnancy: Basic drugs concentrate in fetal plasma (Novotny, 2001)

• Geriatric patients: Water-soluble drugs: ↓ Vd ↓ elimination (Ritschel, 1987)

• Liver failure: ß-lactams

Lincosamides, macrolides, sulfonamides, and chloramphenicol (Bunch, 1995; Tams, 1984)

• Renal failure: Aminoglycosides → same dose; ↑ interval (Bill, 2006; Polzin, 2000)

Sulphonamides (prevent crystalluria) (Spoo, 2001)

d. RIGHT ROUTE

• PO: Giving a drink of water before administration

Enteric-coated formulations/capsules : do not break (Rock, 2007)

Empty stomach (Scherer, 1992)

Vomiting

Suspensions : SC or IM • Severe dehydration: ↓ SC absorption (Novotny, 2001)

e. RIGHT TIME

• Frequency: t1/2 = 2-3 h: time & concentration dependent (Bill, 2004)

• Time dependent drugs: 100% contact time → compromised IS; ≥ 50% contact time → working IS (Aucoin, 2002)

• Duration (Novotny, 2001)

T h a n k y o u … …