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Principles of Antibacterial Agent Selection

Dr Utkarsh ShahDepartment of Pharmacology,Medical College Baroda

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General principles of antibacterial therapy

• Clinical diagnosis- From clinical features, lab investigations and

culture and sensitivity report

• Decision to use antibiotic (actually needed or not).

• Removal of barrier, if any.

• Select the best drug

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Factors affecting antibacterial selection

Selection of antibacteri

al agent

Causative organism

Antibacterial agent

Patient

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ORGANIS

M

• Prevalence

• Sensitivity

• Selection of antibacterial

• Resistance

ANTIBACTERIA

L AGE

NT

• Selective toxicity

• Type of activity

• Spectrum

• CDK, TDK, PAE

• Route of administration

• Drug partitioning

• ADR

• Cost

PATIENT

• Age

• Renal & Hepatic function

• Pregnancy

• Lactation

• Immunity

• Penetration barrier

• Drug allergy

• Food

• Poor perfusion

• Microsomal enzymes

• Other drugs

• Presence of pus & secretion, foreign body

• Haematoma

Outline

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Factors related to Organism• Prevalence of organism- varies from place to place

• Sensitivity pattern- varies from place to place- may be different in vivo and in vitro

- culture and sensitivity guide to choose an antibacterial agent.

- Because of in vitro activity that may not be same as in vivo in some cases - in certain situation if it is not serious, it is better to rely on clinical response.

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Minimum Inhibitory Concentration (MIC)- lowest concentration of antibacterial which

prevents growth of microorganism.

Minimum Bactericidal Concentration (MBC)

- concentration of antibacterial which kills 99.9% of the bacteria.

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Dilution Tests• Antibiotics in serially diluted concentrations on solid agar

or in broth medium that contains a culture of test organism

• MIC can be calculated.

• Result: lowest concentration of antibacterial that prevents visible growth after 18-24 hours of incubation-MIC

• Automated systems measure optical density of broth culture of clinical isolate in presence of drug is determined.

• If OD exceeds threshold-growth occurred.• If OD below threshold-MIC

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Disk diffusion method• Qualitative assessment

• Performed by applying filter paper disks impregnated with specific amount of antibacterial onto an agar surface, over which culture of microorganism has been streaked.

• Result: after 18-24 hours of incubation, size of clear zone of inhibition is measured.

• Standardized values for zone sizes for each bacterial species and antibiotic permit classification as resistant or susceptible.

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Epsilometer Test (E-Test)• Variant of disk diffusion

test

• A rectangular strip impregnated with changing concentration of antibacterial, is placed on agar plat inoculated with organism.

• Result: clear elliptical zone which bisects the strip at MIC

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• Selection of Antibacterial agentCases where diagnosis decides choice of drug- causative organism is single and its sensitivity pattern

is well known.- e.g. typhoid, syphilis, diphtheria, tetanus, plague,

cholera etc.

Cases where causative organism can be guessed- Based on c/f and local experience of organism and its

sensitivity- e.g. otitis media, tonsillitis, boils, urethritis etc.

Cases where causative organism can not be guessed- culture and sensitivity is preferred.- e.g. meningitis, pneumonia, empyema, UTI, wound

infection etc.

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Bacteriological examination not available- empirical therapy with broad spectrum

antibacterial to cover all possible organisms.

- further treatment is modified according to response.

Bacteriological examination available but treatment can not be delayed

- in serious infections like meningitis, septicemias

- sample for bacteriological examination is collected and empirical therapy started which is changed according to sample result.

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Bacteriological examination available and treatment can be delayed

- as in chronic UTI

- wait for culture and sensitivity and start definitive therapy

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• Resistance

• Natural resistance- organism lacks the metabolic process or target

site which is affected by particular antibacterial.

- e.g. gram negative bacilli- penicillin G anaerobic bacteria- aminoglycoside

• Acquired resistance- development of resistance by an organism which

was sensitive earlier.

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Mechanism of ResistanceMutation

- Genetic alteration.

- replicate and transmit properties to daughter cells.

- vertical transfer of resistance.

- Occur by insertion, deletion or substitution of one or more nucleotide within the genome.

.

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DNA transfer (infectious resistance)

- resistance acquired due to DNA transfer from one organism to other.

- resistance properties are encoded in extrachromosomal genetic elements (plasmid).

- plasmids enter cell by conjugation, transduction and transformation.

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Altered expression of proteins in drug resistant organismModification of target site- loss of affinity to target site

- altered PBP- penicillin resistance

- plasmid mediated synthesis of dihydrofolate reductase- low affinity to trimethoprim.

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Decreased drug accumulation- ↓permeability of antibacterial into organism- seen with tetracycline and aminoglycoside.

- active efflux pump which pump out the antibacterial.

- seen with tetracycline, floroquinolones.

Enzymatic inactivation- resistant microbes secrete an enzyme which

inactivates the drug

- β- lactamase, chloramphenicol acetyl transferase and adenylate / acetylase / phosphorylase against aminoglycoside.

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Altered targets

Decreased accumulation Enzymatic inactivation↓ permeability ↑ efflux

β- lactams β- lactams β- lactamsVancomycinSulfonamide SulfonamideTrimethoprimFlouroquinolones

Flouroquinolones

Flouroquinolones

Aminoglycoside Aminoglycoside Aminoglycoside

Tetracycline Tetracycline Tetracycline TetracyclineChloramphenicol

Chloramphenicol

Macrolide Macrolide MacrolideClindamycin

Mechanism of resistance for antibacterial agent

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Factors related to antibacterial agent

•Selective toxicity to organism- maximized by finding and exploiting differences

between normal human cells and pathogenic cells.

- human cells do not possess a structure analogue to bacterial cell wall; thus β- lactams are effective against streptococci but little toxicity to humans.

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•Type of activity- With normal host defense – response equally well

to bacteriostatic and bactericidal.

- Bacteriostatic drug arrest the growth and replication of bacteria → limit spread of infection.

- Body’s immune mechanism attacks, immobilizes and eliminates the pathogen.

- If the drug is removed before the immune system has scavenged the organism, enough viable organisms remain to begin a second cycle of infection.

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- By contrast, addition of bactericidal agent, kills bacteria.

•Spectrum- narrow spectrum- acting on a single or limited group of microorganisms e.g. Cloxacillin

- Extended spectrum- effective against both gram +ve and gram –ve e.g. ampicillin

- Broad spectrum- covers wide variety of microorganism e.g. tetracycline

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• Selection of dose and dosing scheduleMIC- response of organism to fixed dose of

antibacterials differs according to susceptibility.

- vancomycin resistance is said when MIC ˃ 2 mg/L.

- In one study, when patients with MRSA infection were treated with vancomycin

→61% success rate with MIC of 0.5 mg/L→28% success rate with MIC of 1.0 mg/L→11% success rate with MIC of 2.0 mg/L

- Thus, outcome were poorer with increasing MIC.

- so, it is important to index drug exposure to MIC.

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Optimal dose- Dose itself is a poor measure of drug exposure,

given between-patient and within-patient pharmacokinetic variability. Rather, actual drug concentration achieved at site of infection is important.

- non-protein-bound antimicrobial exposures associated with 80-90% of Emax are termed “optimal“ concentrations.

- The optimal dose of the antibiotic for a patient is the dose that achieves IC80 to IC90 exposures at the site of infection.

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Dosing scheduleD

rug

conc

entr

atio

n(m

g/L)

0 3 6 9 12 15 18 21 24

0 3 6 9 12 15 18 21 24

Time in hours

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• As same cumulative dose has been given for dosing interval of 24 hours and 8 hours, so

- AUC0-24=AUC0-8+AUC8-16+AUC16-24

- MIC is 0.5mg/L (same for both).

- So, AUC/MIC will be same for both.

- Cmax is decreased by a third in thrice daily dosing compared to once daily dosing.

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- So, Cmax / MIC ratio decrease when drug administered more frequently.

- T˃MIC- fraction of dosing interval for which the drug concentration remains above the MIC

- Which is increased with more frequent dosing.

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• Concentration dependant killing ( CDK )- Inhibitory effect depends on the ratio of peak

concentration to the MIC (Cmax/MIC).

- More effective at higher concentration.

- Seen with aminoglycoside, flouroquinolones and metronidazole.

- Giving combined doses on more intermittent basis (once a day) will maximize the drug action.

- Aminoglycosides are more effective and have less toxicity in single daily dose in comparison to thrice daily dose.

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• Time dependant killing ( TDK )- Kill best when concentration persists above MIC

for longer duration (T˃MIC).

- Increasing drug concentration 4-6 times the MIC does not increase microbial kill.

- Seen with β- lactams and vancomycin.

- Drug optimized for T˃MIC should be dosed more frequently or their t1/2 should be prolonged by other drug.

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• Cumulative dose- does not show CDK or TDK.

- So more the total concentration to MIC ratio (AUC/MIC), more drug effect is seen.

- Seen with daptomycin.

• Post antibiotic effect- Persistent suppression of bacterial growth after

brief exposure of an antibacterial.

- Inhibition of bacterial growth when its concentration is below MIC.

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- reflects time required for bacteria to return to normal growth.

- due to disruption in bacterial ribosomal or DNA gyrase function whose resumption requires time.

- seen with aminoglycosides, flouroquinolones, tetracycline, chloramphenicol and rifampicin.

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• Route of administration- Aminoglycosides, penicillin G, carbenicillin, many

cephalosporins have to be given by parental route only.

- For less severe infection-oral route

- For serious infection- parental route is preferable.

• Drug partitioning into cell- Some bacteria such as chlamydia and mycoplasma

are intracellular pathogens which will be killed by those antibacterial which can enter into cell. e.g. macrolide and flouroquinolones.

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•Side effects and toxicity- More likely in tissues that interact with drug.- e.g. aminoglycoside effect on kidney and ear.

- Some adverse reactions are unrelated to either allergy or overdose known as idiosyncratic.

- e.g. chloramphenicol induced aplastic anaemia

•Cost- Least expensive drug should be preferred.

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Factors related to Patient•Age- affects kinetics of antibacterials and produces

age related effects.

- renal & hepatic elimination processes are poorly developed in newborn

- sulfonamide→ kernicterus in neonate- chloramphenicol → grey baby syndrome in

newborn- aminoglycoside → 8th nerve toxicity in elderly- tetracycline → yellowish discoloration of teeth

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•Renal function- cautious use and modification of the dose of an

antibacterial which is excreted by kidney becomes necessary when renal function is defective.

- serum creatinine level used as index of renal function.

- monitoring of serum level of antibacterial should be done.

- elderly patients have decreased number of functioning nephron→ vulnerable to drug accumulation.

- e.g. penicillin, sulfonamide, aminoglycoside

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•Hepatic function- drug which is eliminated by liver should be

avoided in patient with poor hepatic function.

- e.g. erythromycin estolate, pyrazinamide, tetracyclines.

•Pregnancy- all antibacterials should be avoided.

- penicillins, many cephalosporins and erythromycin are safe.

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-Tetracycline → yellow atrophy of liver, pancreatitis & kidney damage to mother

- Brown discoloration of teeth & bone in offspring.

-Aminoglycoside → foetal ear damage

-Flouroquinolones → foetal tendon damage

-Metronidazole/Sulfonamide/Chloramphenicol →contraindicated in earlier trimester.

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•Lactation- Drug administered to a lactating mother may

enter the nursing infant via breast milk.

- even though the concentration of antibacterial in milk is usually low, the total dose to the infant may be enough to cause problems.

• Immunity- normal immunity→ bacteriostatic antibacterial

- impaired immunity → bactericidal antibacterial (higher doses and longer treatment)

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- neutropenic patients → pyogenic infection

- HIV, leukemia, severe debilitated immobile patient, burn, generalized metastasis → opportunistic infection with intracellular pathogen

•Penetration barrier

- to be effective, each antibacterial has to get to where pathogen is, to penetrate into the infected compartment

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- for levofloxacin skin/plasma peak concentration ratio is 1.4, epithelial lining fluid to plasma ratio is 2.8 and urine to plasma ratio is 67.

- failure rate of therapy was 0% with UTI, 16% for skin & soft tissue infection.

- poorer the penetration into anatomical compartment →more chances of failure.

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- hydrophobic molecule → concentrated in bi-lipid cell membrane bi-layer.

- hydrophilic molecule → concentrated in blood, cytosol and other aqueous compartment.

- membrane transporter such as P-glycoprotein → actively export drug from cellular or tissue compartment back into blood.

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Blood brain barrier- polar drug are impermeable

- most antibacterial not permeable- inflammation facilitates penetration (not all

antibacterial) e.g. ampicillinEye- for endophthalmitis antibacterial must reach

occular cavity

- generally poor penetration so, therapy is direct instillation into occular cavity

- chloramphenicol, amphotericin B have sufficient penetration.

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Prostate

43•Drug allergy- H/o previous exposure to an antibacterial which

caused allergic reaction should be obtained.

- Same should be avoided, alternative antibacterial.

- Seen with β- lactams, sulfonamide, flouroquinolones and nitrofurantoin.

•Food- ↓absorption of ampicillin, azithromycin

- Drug should be taken 1-2 hours before or after food.

- Ca+2, Mg+2, Al+3, milk- ↓absorption of tetracycline & flouroquinolones.

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•Poor perfusion- ↓circulation to an anatomic area, as in lower

limbs of the diabetic → reduces amount of antibacterial that reaches the extremities.

•Cytochrome P450- heterogeneity in human population for hepatic

microsomal cytochrome P450.

- possession of an unfavorable phenotype → risk for drug toxicity.

- slow acetylators of isoniazid → peripheral neuropathy at standard dose of isoniazid.

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•Other drugs- if patient already on other drugs, precautions

should be taken to prevent drug interaction.- e.g. enzyme inducer/inhibitor, theophylline with

erythromycin etc.

•Presence of pus & secretion- ↓entry of aminoglycosides- ↓efficacy of sulfonamide & aminoglycosides- in abscess, vascularity is low as pus causes

tension in cavity leading to collapse of blood vessel → antibacterial can not reach.

- drainage of abscess → ↓infective material & organism

↓anaerobic environment

↑diffusion of antibacterial

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•Presence of necrotic material or foreign body

- bacteria adhering foreign body such as catheters, implants and prosthesis, are difficult to eradicate.

- bacteria secrete polysaccharide which act as a bridge which kept them adhered to foreign body known as biofilm.

- such bacteria are difficult to reach and less vulnerable to antibacterial.

•pH- lowering of pH→↑activity of tetracycline,

nitrofurantoin- increasing pH →↑activity of aminoglycoside &

macrolide

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•Haematoma- foster bacterial growth.- tetracycline, penicillin, cephalosporin→ get

bound to degraded Hb of haematoma.

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Combined use of antibacterials• To prevent emergence of resistance- Valid for chronic infections needing prolonged therapy- e.g. TB, leprosy, HIV , H.pylori, malaria.

• To reduce severity of incidence of adverse effects- Possible only if combination is synergistic so that the

dose can be reduced.

- In c/o drug with low safety margin- For strep. faecalis in SABE → Streptomycin +

penicillin G

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• To broaden the spectrum of action Treatment of mixed infection

- e.g. colorectal surgery, brain abcess, diabetic foot , gynaecological infection are often mixed infection.

- For colorectal surgery → likely pathogen are E.coli, streptococci, clostridia & bacteriods. So ampicillin+ gentamicin + metronidazole or cefotaxime+ metronidazole.

- Gynaecological surgery → likely pathogen are coliforms, streptococci & bacteriods. So, cefotaxime + metronidazole is suitable.

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Initial treatment of severe infection- for empirical therapy, drugs covering both gram

+ve and gram –ve both and for anaerobes in certain cases.

- e.g. penicillin + streptomycin cephalosporin + aminoglycoside with or without metronidazole.

Topically- Antibacterials which are not used systemically, are

poorly absorbed from local site also. - Such antibacterials which cover gram +ve and

gram –ve are combined for topical use.- e.g. bacitracin + neomycin + polymyxin B

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• To achieve synergism- Manifests in terms of decrease in the MIC of one

antimicrobial in the presence of another, or the MIC of both may be reduced.

- If MIC of each antibacterials is reduced to 25% or less → synergistic.

- 25- 50% → additive.

- ˃ 50% → antagonism.

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Two bacteriostatic drug

- Often additive, rarely synergistic

- e.g. combination of tetracycline, chloramphenicol, erythromycin etc.

- Sulfonamide + trimethoprim → supraadditive.

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Two bactericidal drugs- Frequently additive & sometime synergistic if

the organism is sensitive to both.

- e.g. penicillin + aminoglycoside or vancomycin + aminoglycoside for enterococcal SABE.

- Carbenicillin/ ticarcillin + gentamicin for pseudomonas infection.

- Here , combination causes faster cure and reduces the chances of relapse.

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Combination of bactericidal with bacteriostatic

- Synergistic or antagonistic

- If organism is highly sensitive to cidal drug → response to combination is equal to the static drug given alone (antagonism).

- For pneumococcal meningitis → penicillin + tetracycline.

- For group A streptococci → penicillin + erythromycin.

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- If organism has low sensitivity to cidal drug

- Synergism seen

- For actinomycosis → penicillin + sulfonamide

- For brucellosis → streptomycin + tetracycline

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Types & goals of antibacterial therapy

Antibacterial therapy- disease progression timeline

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Prophylaxis- Treat the patients who are not yet infected or have

not developed disease yet.

- Goal is to prevent infection.

- Principle is targeted therapy.

• Immunocompromised patients

- In HIV infection for opportunistic infection- For post transplantation patients.

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• Surgical prophylaxis- To prevent superficial, deep and organ infection.

- Begin 60 minutes before surgical incision & should be discontinued within 24 hours of end of surgery.

- Selected on the basis of likely pathogen at the site of surgery & susceptibility to drug.

59Category Criteria Possibili

ty of infection

Clean •Elective, closed procedure•No viscera or tract entered.•No inflammation at site•No break in technique.

2% or less

Clean contaminated

•Emergency cases which are clean , elective•Controlled opening of viscera but minimal spillage or minor break in technique.

10% or less

Contaminated •Acute nonpurulent inflammation•Major spillage or major break in technique•Penetrating injury ˂ 4 hours old.•Grafted wound

20%

Dirty •Abcess or purulence•Preoperative perforation of viscera or tract•Penetrating injury ˃ 4 hours old

40%Classification of surgical wounds based on

National Research Council Criteria

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- Not required for clean surgery except in patient at special risk.

- Incidence of post operative infection is higher when surgery lasted for 2 hours or more, prosthesis insertion, diabetes, steroid recipients, Immunocompromised, malnourished, infants, elderly.

- Post operative antibacterials are indicated in contaminated surgery up to 5 days.

- Relatively high dose is given as surgical prophylaxis.

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Oral ( single dose 60 minutes before surgery )1. Amoxycillin 2 g2.Cephalexin 2 g3.Cefadroxyl 2 g4.Clindamycin 600 mg ( penicillin allergic )5.Azithromycin 500 mg ( penicillin allergic )6.Clarithromycin 500mg ( penicillin allergic )Parenteral ( single injection just before surgery)1.Ampicillin 2g IM/IV2.Cefazolin 1g IV3.Vancomycin 1g( MRSA/ Penicillin allergic)4.Clindamycin 600 mg IV ( Penicillin allergic)5.Cefuroxime 1.5 g IV + Metronidazole 0.5 g IV ( for gut/ biliary surgery)

Antimicrobial for surgical prophylaxis

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• For dirty contaminated wound

- Cefazolin + Vancomycin- Clindamycin + Gentamicin- Vancomycin + Gentamicin + Metronidazole- Amoxycillin + clavulanic acid.

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• Post exposure prophylaxis

- To prevent acquisition of specific microorganism to which they are exposed.

- Rifampin → meningococcal meningitis- Macrolide → pertusis.- Combination of ART → HIV.

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Pre- emptive therapy- Early targeted therapy in high risk patients who

are already been infected but have not developed symptoms.

- For short & defined duration.

- Ganicyclovir for Cytomegalovirus after hematopoietic or stem cell transplants & after solid organ transplantation.

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Empirical therapy- Diagnosis may be masked if therapy is started and

appropriate cultures are not obtained.

- If cost of waiting for few days is low → wait for microbiology data & no empirical therapy.

- If the risks for waiting is high (immuno-compromised, neutropenic) → empirical therapy is started.

- Mostly broad spectrum antibacterials are selected.

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Definitive therapy• When pathogen has been isolated and

susceptibility results are available → therapy is streamlined to narrow targeted antibacterial.

- Monotherapy is preferred.

- Duration of therapy should be as short as possible.

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Post treatment suppressive therapy• After initial control of disease with definitive

therapy, therapy is continued at a lower dose.

- Because infection is not completely eradicated & immunological or anatomical defect that lead to original infection is still present.

- Goal is secondary prophylaxis.

- In c/o HIV, malaria, post transplant patients.

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References• Goodman & Gilman’s The Pharmacological Basis

of THERAPUTICS ,12th edition, page 1365-1381.

• Essentials of MEDICAL PHARMACOLOGY, KD Tripathi, 7th edition, page 688-703.

• Principles of Pharmacology, HL Sharma & KK Sharma, 2nd edition, page 697-698.

• Lippincott’s Illustrated Reviews: Pharmacology, 2nd edition, page 279-287.

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• Modern Pharmacology with Clinical Application, Charles R. Craig & Robert E. Stitzel, page 543-549.

• Clinical Pharmacology, D R Laurence, P N Bennell, 7th edition ,page 151-156.

• A complete Textbook of Medical Pharmacology, S K Srivastava, 1st edition, page 781-789

• Quintessence of Medical Pharmacology, Sujit Chaudhuri, 1st edition, page 435-438.

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Thank you