rational use ab - 2011

8/2/2019 Rational Use AB - 2011

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Rational Use ofAntibiotics

Dr Ruzilawati Abu BakarJabatan Farmakologi

ext 6128

4th Year Medical Posting

2011/2012



Outline of the lecture

1)Indications for antibacterial therapy – definitive, empiric & prophylaxis

2) Selection of antibacterial agents

3) Methods of administration of antibacterialagents

4) Antibiotics Resistance5) Classification of antibacterial agents



Indications for antibacterial therapy:

1. Definitive therapy•This is for proven bacterial infections

•Attempts should be made to confirm the bacterialinfection by means of staining ofsecretions/fluids/exudates, culture & sensitivity,serological tests & other tests

•Based on the reports, a narrow spectrum, least toxic,easy to administer & cheap drug should be prescribed.

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2. Empirical therapy

• Empirical antibacterial therapy should be restrictedto critical cases, when time is inadequate foridentification & isolation of the bacteria & reasonablystrong doubt of bacterial infection exists:

- septicemic shock/sepsis syndrome- immunocompromised patients with severe systemic infection

- hectic temperature

- neutropenic patient (reduction in neutrophils)

In such situations, drugs that cover the most probable infective agent/s should be used.

Empiric antibiotic is antibiotic therapy that is begunbefore a specific pathogen is identified



3. Prophylactic therapy

• Certain clinical situations require the use of antibiotics

for the prevention rather than the treatment ofinfections.

• In all these situations, only narrow spectrum & specificdrugs are used

• The duration of prophylaxis is dictated by theduration of the risk of infection.

• eg.

1. Prevention for persons from non-malarious areas whovisit areas endemic for malaria.

2. Treatment prior to certain surgical procedures toprevent infections



Bacteria vs Host

Bacteria Host

Pathogen Vs non pathogen

Virulence

Host defence

antibiotic

Disease

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Selection of

antibacterial agents



Factors should be considered beforeprescribing antibacterial agent

1. Site of infection

2.Type of infection

3.Severity of infection

4.Isolate & its sensitivity

5.Source of infection6.Patient factors

7.Drug-related factors



Koda-Kimble M.A.et al, AppliedTherapeutics , TheClinical Use ofDrugs (LippincottWilliams & Wilkin,9th ed.), 2009

1. Site of infection



1. Site of infectionInfection above the diaphragm:

•URTI eg pharyngitis, tonsilitis, sinusitis, otitis,epiglottitis etc.

- commonly caused by organism like Strep. pyogenes ,S. pneumoniae , Fusobacteria , Peptostreptococci (rarely Mycoplasma , H. influenzae )

- Can be treated with drugs like penicillinsmacrolides

cephalosporins



1. Site of infection…con’t

Lower respiratory tract infections:

Eg. Bronchitis, pneumonitis, pneumonia, lung abscessetc

-generally caused by the organisms Strep. pyogenes,S. pneumoniae , Fusobacteria , Peptostreptococci,Staph aureus (rarely Mycoplasma , H. influenzae ,Moraxella, Klebsiella) etc.

- can be treated penicillins, cephalosporins,macrolides & tetracylines



1. Site of infection …. con’t

Infection below the diaphragm:

•Eg UTI, intra-abdominal sepsis, pelvic infections etc ---these are caused by the organisms like E. coli, Klebsiella,Proteus, Pseudomonas, Bacteroides etc.

• Quinolones, aminoglycosides, 3rd generationcephalosporins & metronidazole alone or in combination are useful in these infections.

Rule of the thumbInfections above the diaphragm Cocci & Gram +ve organisms

Infections below the diaphragm Bacilli & Gram -ve organisms



1. Site of infection …. con’t

• There are certain sites where the infection tends to be difficult fortreatment :

- meningitis (impenetrable BBB),

- chronic prostatitis (non-fenestrated capillaris),

- intra-ocular infections (non-fenestrated capillaries),

- abscesses (thick wall, acidic pH, hydrolizing enzymes etc.),- cardiac & intravascular vegetations (poor reach & penetration),

- osteomyelitis (avascular sequestrum) etc

In such cases:-Higher & more frequent doseLonger duration of therapyCombinationsLipophilic drugs

may have to be used



2. Type of infection

Infections can be localised/extensive; mild/severe;

superficial/deep-seated; acute/sub acute/chronic &extracellular/intracellular.

For extensive, severe, deep-seated, chronic &intracellular infections –

• Higher & more frequent dose

• Longer duration of therapy

• Combinations

• Lipophilic drugs

may have to be used



3. Severity of infections• Bacteremia / sepsis syndrome / septic shock;

• abscess in lung / brain/ liver/ pelvis/ intra-abdominal;

• meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperalsepsis;

• Severe soft tissue infections / gangrene & hospital acquired infections

For severe infectionsonly IV route- to ensure adequate blood levels.

only bactericidal drugs- to ensure faster clearance of the infection.

dose should be higher & more frequent.- If the site is unknown, attempt should be made to cover all possibleorganisms, including drug resistant Staphylococcus, Pseudomonas, &anaerobes.

- A combinations of Penicillins / 3rd generation cephalosporins,aminoglycosides & metronidazole may be used.



4. Isolate & sensitivity

• Ideal management of any significant bacterial

infection requires culture & sensitivity (C&S) study ofthe specimen.

• If the situation permits, antibacterials can bestarted only after the sensitivity report is available.

• Narrow spectrum, least toxic, easy to administer &

cheapest of the effective drugs should be chosen.

If the patient is responding to the drug that hasalready been started, it should not be changed even if

the in vitro report says otherwise



5. Source of infection

Community-acquired infections areless likely to be resistant

whereas

Hospital-acquired infections arelikely to be resistant & more difficultto treat (eg. Pseudomonas, MRSAetc)



• In the elderly, achlorhydria may affect absorption ofanticbacterial agents; drug elimination is slower, requiringdose adjustments & ototoxicity of aminoglycosides may be

increased.

Patient factors…….con’t

Children

Elderly

- Tetracycline are contraindicated < 8 years because they discolour the teeth- < 18 years ALL fluoroquinolones arecontraindicated because they cause

arthropathy by damaging the growingcartilage.



• In patients with likelihood ofcompromised immune status, likeextremes of age, HIV infection,diabetes mellitus, neutropenia,splenectomy, using corticosteroidsor immunosuppresants, patients

with cancers/blood dyscrasias,ONLY bactericidal drugs should beused.

Patient factors…….con’t

Patients with compromised immune status



Patient factors…….in pregnancyContraindicated in all trimesters Contraindicated in the last trimesters

Safe in pregnancy Contraindicated in lactatingmothers

• tetracylines

• quinolones

• streptomycin

• clarithromycin

• sulpha drug• nitrofurantoin

• chloramphenicol

•penicillins

•cephalosporins

•erythromycin

•isoniazid

•ethambutol

• sulpha drug

• tetracylines

•nitrofurantoin

• quinolones

•metronidazole

Drugs with limited data on safety like aminoglycoside, azithromycin,clindamycin, vancomycin, metronidazole, trimethoprim, rifampicin &pyrazinamide should be used with caution when benefits overweigh the risks



Patient factors…….in patientswith renal failure

Absolutely contraindicatedRelatively contraindicated

Relatively safe

It is better to avoid combinationsof cephalosporins & aminoglycosides in these patients because bothclasses can cause nephrotoxicity

• tetracycline

•Penicillins

•Macrolides

•Vancomycin

•Metronidazole

•Isoniazid

•Ethambutol

•Rifampicin

•Aminoglycoside

•Cephalosporins

•Fluoroquinolones

•Sulpha drug



Patient factors…….in patientswith hepatic failure

No drugs are absolutely contraindicated.

Relatively contraindicated Safe

•Chloramphenicol•Erythromycin estolate

•Fluoroquinolones

•Pyrazinamide

•Rifampicin

•Isoniazid

•Metronidazole

•Penicillins

•Cephalosporins

•Ethambutol

•Aminoglycosides



7. Drug factors

1. Hypersensitivity:If the patient has prior history of hypersensitivity theantibacterial agent should be avoided. It is thereforeimportant to elicit this history in all patients (common

with penicillin)

2. Adverse reactions:Certain ADRs warrant discontinuation of therapy & thedoctor should adequately educate the patients on theseadverse effects.

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7. Drug factors

3. Cost:

It should always be remembered that just because as

particular drug is expensive, it need not be superiorthan the cheaper ones.

Eg. Cheaper drug like doxycycline or co-trimoxazoleare as effective as the costlier clarithromycin or

cephalosporins in the management of lower RTI.



7. Drug factors…….con’t

4. Interactions:Interactions with food & other concomitant drugs should beconsidered before instituting antibacterial therapy so as tomaximize efficacy & minimize toxicity.

a) Interactions include enhanced nephrotoxicity or ototoxicity

when aminoglycosides are given with loop diuretics, vancomycin orcisplatin.

b) Rifampicin, a strong inducer of hepatic drug-metabolizingenzymes, decreases the effects of digoxin, ketoconazole, oralcontraceptives, propranolol, quinidine & warfarin.

c) Erythromycin inhibits the hepatic metabolism of a number ofdrugs, including phenytoin, terfenadine, theophylline & warfarin.



Methods of

administration ofantibacterial agents



Methods of administration of antimicrobials

Route of administration

The route of administration depends on the site, type &severity of the infection & the availability of a suitabledrug

- Oral route is the most preferred, easy & cheap,but may not be reliable in all circumstances, esp. inpatients with severe infections, non-compliant patients,in the presence of vomiting etc.

Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral

administration.



Methods of administration of antimicrobials

- IM route should generally be restrictedfor the administration of procaine & benzathine

penicillin.

The absorption is not very reliable & it is

painful & dislike by the patients.



Route of administration…….con’t

- IV route is the best for the management ofsevere & deep-seated infections since it ensures

adequate serum drug levels.

Procaine penicillin & benzathine penicillin should

never be given IV.



Route of administration…….con’t

•However, some drugs are not availablefor parental use (eg. Most macrolides,sulpha drugs, tetracyclines)

• Antibacterials are also used topically



Dosage

- Dosage depends on patient’s age, weight, associatedconditions like pregnancy, renal & hepatic failure &site, type & severity of infection.

- Generally the dose should be higher in cases ofsevere, deep-seated infections & lower in cases ofrenal-failure.

- Unnecessary overdosage only adds to the cost &adverse effects.



Frequency of administration

• The drug should be administered 4-5x the plasmahalf-life to maintain adequate therapeuticconcentrations in the serum throughout the day.

• Frequency can be:-

- increased in cases of severe, deep seated &sequestrated infections

- reduced in cases of renal & hepatic failure.



Duration

• Duration of therapy depends on the site

1) Tonsilitis – 10 days

2) Bronchitis – 5-7 days

3) UTI – single shot to 21 days4) Lung abscess- 2-4 weeks

5) Tuberculosis – 6-24 months

• Longer courses of therapy are usually required for infections dueto fungi or mycobacteria

• Endocarditis & osteomyelitis require longer duration of treatment

om nat ons



om nat ons1) For synergistic effect:

eg: combination of 2 bacteriostatic drugs such as

trimethoprim + sulfamethoxazole =

Co-Trimoxazole (bacterim®)

Therapeutic advantage of sulphonamide+ trimethoprim

1) Synergistic effects

2) Bactericidal activity

3) Decrease resistance4) Bigger spectrum of activity

5) Reduced toxicity

http://en.wikipedia.org/wiki/File:THFsynthesispathway.png



2) Treatment of infections with multipleorganisms:

Mixed infections in lung abcess, peritonitis, soiled

wounds etc naturally require multiple antibioticsfor complete clearance of the infection – penicillins (for Gram +ve & certain anaerobes) &aminoglycosides (for Gram –ve); metronidazole for

bacteroides.

penicillins + aminoglycosides + metronidazole

Combinations…….con’t

’



3) To prevent resistance: Use of combination is a well known method ofpreventing drug resistance. The classic example is theantiTB therapy,

Eg isoniazid + ethambutol + rifampicin

4) To overcome resistance: Combination of specific drugs can be useful inovercoming that resistant infections, egPenicillins + -lactamase inhibitors

(Co-amoxiclav/augmentin)

Combinations…….con’t



The following combinations are irrational, not usefulor even harmful:

1) Bactericidal with bacteriostatic

eg. Penicillins (bactericidal) with tetracyclines ( bacteriostatic)

Bactericidal a/b (kill bacteria) – tend to be used in combinationwith one another

Bateriostatic a/b (prevent bacteria’s reproduction) – tend tobe used on its own

2) Combinations of drugs with similar toxicity

eg. Chloramphenicol & sulpha drug

3) Combining drugs for non-existing ―mixed infections‖

eg. Tablets of ciprofloxacin + metronidazole/tinidazole



Which one of the following patients is least likely torequire antimicrobial treatment tailored to theindividual’s condition?

A. Patient undergoing cancer chemotherapy

B. Patient with kidney disease

C.Elderly patient

D.Patient with hypertension

E. Patient with liver disease





- Anticancer drugs often suppress immune function 7 these patients require additional

antibiotics to eradicate infections

B. Patient with kidney disease

- Impaired renal function may lead to accumulation of toxic levels of antimicrobial drugs

C. Elderly patient

- Renal & hepatic function are often decreased among the elderly

D. Patient with hypertension- Elevated BP would not be expected to markedly influence the type of antimicrobial

treatment employed.

E. Patient with liver disease

- Impaired liver function may lead to the accumulation of toxic levels of antimicrobial drugs



Clinical failure of

antimicrobialtherapy



Failure of an antibiotic regimen (1)

1) Drug factors• incorrect choice,

• poor tissue penetration

• inadequate dose• pH – low pH reduces effectiveness of

aminoglycosides, erythromycin, clindamycin

Inadequate clinical or microbiological response toantimicrobial therapy can result from multiplecauses, including;

l ( )



Failure of an antibiotic regimen (2)

2) Host factors

• poor host defense,

• age

• renal & liver function• pre-existing dysfunction

of other organs

3) Pathogen factors

resistance

superinfection

A tibi ti R sist



Antibiotic Resistance

―P i illi E ‖



―Penicillin Era‖

1942-1950 available without a prescriptionPublic demand followed by production of throatsprays, cough lozenges, mouthwashes, soaps and otherproducts containing penicillin

Alexander Fleming Warned that excessive use could result in

antimicrobial resistance ―the microbes are educated to resist penicillin and

a host of penicillin-fast organisms is bred out

which can be passed to other individuals and from them to others until they reach someone who gets a pneumonia or septicemia which penicillin cannot save .‖ The New York Times 1945

Fleming’s words proved to be correct....

Th P bl f A tibi ti



The Problem of AntibioticResistance

Penicillin resistance first identified in 1940’s

Since then, antibiotic resistance hasdeveloped faster than new drugs

Estimated cost of infections: $4-5 million per year

Antibiotic resistance previously concentratedin hospitals, especially ICUs

MRSA recently estimated to kill 18,000Americans yearly



History

APPEARANCE

DRUG INTRODUCTION OF RESISTANCE

Penicillin 1943 1946

Streptomycin 1945 1959

Tetracycline 1948 1953

Erythromycin 1952 1988

Vancomycin 1956 1988

Methicillin 1960 1961

Ampicillin 1961 1973

Cephalosporins 1964 late 1960’s



Antibiotic Resistance

Relative or complete lack ofeffect of antimicrobial againsta previously susceptiblemicrobe

• Bacteria are said to beresistant to an antibiotic if themaximal level of that antibiotic

that can be tolerated by thehost does not stop theirgrowth.

What Factors Promote Antimicrobial



What causes the rapid occurrence of widespreadresistance?

(1) Incomplete treatment:

- people fail to finish the full course of their medication

- 25% of previously-treated tuberculosis patientsrelapsed with drug resistant strains; most had failed tocomplete their initial course

What Factors Promote AntimicrobialResistance?

What Factors Promote Antimicrobial



(2) Mis-prescription:

- patients demand antibioticsfor cold

- widespread inappropriate use:up to 50% of prescriptions indeveloping countries are for viral

infections that cannot respond

What Factors Promote AntimicrobialResistance?

(3) Exposure to microbes carrying

resistance genes

I i t A tibi ti U



Inappropriate Antibiotic Use

Prescription not taken correctly Antibiotics for viral infections Antibiotics sold without medical supervision Spread of resistant microbes in hospitals due

to lack of hygiene Lack of quality control in manufacture or outdated

antimicrobial Use of broad-spectrum agents when a narrow-

spectrum drug would suffice (eg, use of third-generation cephalosporins for community-

acquired pneumonia)

Mechanisms of Antibiotic



• The four main mechanisms by which microorganismsexhibit resistance to antibiotics are:

(1) Drug inactivation or modification:

e.g. enzymatic deactivation of Penicillin G in somepenicillin-resistant bacteria through the productionof β-lactamases.

(2) Alteration of target site: e.g. alteration of PBP—the binding target site ofpenicillins—in MRSA and other penicillin-resistantbacteria – resulting in decreased binding of the

antibiotic to its target.

Mechanisms of AntibioticResistance (1)

Mechanisms of Antibiotic



(3) Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do notrequire para-aminobenzoic acid (PABA), an importantprecursor for the synthesis of folic acid and nucleic

acids in bacteria inhibited by sulfonamides. Instead,they turn to utilizing preformed folic acid.

(4) Reduced drug accumulation: by decreasing drug permeability

and/or

increasing active efflux (pumping out) of the drugsacross the cell surface.

Mechanisms of AntibioticResistance (2)

R i t l t E



Resistance: -lactamase Enzymes

•Bacteria produce-lactamase enzymes to hydrolyze the

-lactamring before drugs can reach inner membrane where PG synthesis

occurs

•A cell may produce 100,000 - lactamase enzymes, each of whichcan destroy 1,000 penicillins per second 100 million molecules of

drug destroyed per second

• β-Lactamantibiotics act byinhibiting thesynthesis of thepeptidoglycan

layer of bacterialcell walls.



-lactamases

Enzymes produced by bacteria whichdestroy -lactam antibiotics

Many different types Penicillinases, cephalosporinases,

carbapenemases

Most are plasmid mediated

Overcoming lactam Resistance



Overcoming -lactam Resistance

slow to

hydrolyze

As a response to bacterial resistance to -lactam drugs, there aredrugs, such as Augmentin, which are designed to disable the -lactamase enzyme.

Augmentin is made of amoxicillin, a -lactam antibiotic, andclavulanic acid, a -lactamase inhibitor.

The clavulanic acid is designed to overwhelm all -lactamaseenzymes, bind irreversibly to them, and effectively serve as an

antagonist so that the amoxicillin is not affected by the -lactamase enzymes.

Overcoming lactam Resistance



Amoxicillin (-lactam antibiotic)

+ clavulanic acid (a -lactamase inhibitor)

= Co-amoxiclav (Augmentin®)

Ampicillin (-lactam antibiotic)+ sulbactam (a -lactamase inhibitor)

= Unasyn®

Overcoming -lactam Resistance

Resistance in Simpler Terms



Resistance in Simpler Terms…

BA

By-pass Alteredtarget

Efflux

Impermeability

Inactivation

(alteration of metabolic pathway)

(reduced drug accumulation)

(reduced drug accumulation)

Genetic alterations in drug



Genetic alterations in drugresistance

Acquired antibiotic resistance requires thetemporary or permanent gain or alterationof bacterial genetic information.

Resistance develops due to the ability ofDNA:-

1. To undergo spontaneous mutation

2. To move from one organism to another(DNA/gene transfer)

Spontaneous mutation of DNA



Spontaneous mutation of DNA

Stable and heritable genetic change

Not induced by antimicrobial agents

Resistance variant will proliferate

Eg. The emergence of rifampicin-resistant M.tuberculosiswhen rifampicin is used as a single antibiotic

DNA/Gene transfer of drug



DNA/Gene transfer of drugresistant

transduction

conjugation

transformation

DNA Most resistance genes are plasmid mediated

Plasmid may enter cells by processes such as conjugation,transduction (phage mediated) & transformation

Measuring Antimicrobial



Measuring AntimicrobialSensitivity

Disk Diffusion

E- test(antimicrobialgradient method)

Serial dilution

Measuring Antimicrobial



MIC increase in

the case ofresistance

(Minimal inhibitory concentration)

- important in diagnosticlaboratories to confirm resistanceof microorganisms to anantimicrobial agent

Measuring AntimicrobialSensitivity

Consequences of Antimicrobial



Consequences of AntimicrobialResistance

Infectionsresistant to

availableantibiotics

Increased costof treatment



Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use

Narrow spectrum Combination in longterm use (TB) Direct observed dosing (TB) Appropriate dose and duration Use more narrow spectrum antibiotics Use antimicrobial cocktails

Prevention of resistance



• A pregnant woman was hospitalized andchatheterized with a catheter. She developed aurinary tract infection caused by Pseudomonasaeruginosa and was treated with gentamicin. Whichof the following adverse effects was arisk to the fetuswhen the woman was on gentamicin?

• A. Skeletal deformity• B. Hearing loss

• C. Teratogenesis

• D. Blindness

• E. Mental retardation



Classification of

antibacterial agents



Chemical structure

Mechanism of action

Spectrum of activity

Broad, extended, narrow

Types of actions i i i i

Classification of antibacterial agents

Chemical structure



Chemical structure

Sulfonamides sulfadiazines

Diaminopyrimidines Trimethoprim

Quinolones Nalidixic acid, ciprofloxacin

b-lactam antibiotics Penicillins, cephalosporins,

carbapenems, monobactams

Tetracyclines Tetracycline, doxycycline

Nitrobenzene derivatives Chloramphenicol

Aminoglycosides Gentamicin

Macrolides Erythromycin

Nitrofuran derivatives Nitrofurantoin

Glycopeptide

Vancomycin Nitroimidazoles

Metronidazoles




Terms Definitions

Narrow-spectrumantibiotics

Antibiotics acting only on a single or alimited group of microorganisms

Eg.- isoniazid active only againstmycobacteria

Extended-spectrumantibioticsAntibiotics that are effective against gram+ve organisms & also against a significantno. of gram -ve organisms.

Eg.- ampicillin – acts against gram +veorganisms (Listeria monocytogenes) & somegram -ve organisms (E. coli ).

Broad-spectrumantibiotics

Antibiotics affect a wide variety ofmicrobial species

Eg.- tetracycline active against chlamydia,mycoplasma, actinomyces, anaerobicorganisms, gram –ve rods (E. coli )





Summary of antibiotic’s spectrum



y p

Narrow Spectrum

• Aztreonam

• Benzylpenicillin

• Cloxacillin• Phenoxymethyl-penicillin

• Cephalexin

Broad Spectrum•Amoxycillin

•Aminoglycoside

•Ciprofloxacin

•Chloramphenicol

•Imipenam

•Tetracycline

•Vancomycin

•Carbenicillin

•3rd generation cephalosporins

B d l b



Bactericidal vs. bacteriostatic

Bactericidalagents

outright kill

bacteria.

Bacteriostatic agentsinhibit growth but

don’t kill. They rely onbody defenses toclear the infection.

Penicillins

Cephalosporins Macrolides

Tetracyclines

M h f



Mechanism of action

Inhibit cell wall synthesis Penicillins, cephalosporins, vancomycin

Inhibit protein synthesis Macrolides, tetracyclines, CMC

Inhibit DNA gyrase Quinolones

Interfere with DNA function

Rifampicin, metronidazole Antimetabolites

Sulfonamides, Trimethoprim

Cell Wall Inhibitors



1. Beta-lactam antibiotics1) Penicillin derivatives

2)Cephalosporins

3)Monobactams

4)Carbapenems

1) Penicillin 2) Cephalosporins

-lactam ring in red

Cell Wall Inhibitors

2. Glycopeptides1) Vancomycin

3. Beta-lactamase inhibitors1) Clavulanic acid

2) Sulbactam

C ll ll i hibi

http://upload.wikimedia.org/wikipedia/commons/d/d8/Beta-lactam_antibiotics_example_1.svg



Cell wall inhibitors

1. -lactam antibiotics Penicillins

Cephalosporins

Carbapenems Monobactams

2. Glycopeptide Vancomycin

Teicoplanin

Penicillin core structure."R" is variable group.

B i l ll ll-lactam

antibiotics

http://en.wikipedia.org/wiki/File:Penicillin-core.png



Bacterial cell wall antibioticsinhibit

transpeptidasesenzymes that

form thesecrosslinkages

Glycopeptidesbind D-alanineand preventcrosslinkage

A schematic of peptidoglycan’s structure The NAM and NAG



A schematic of peptidoglycan s structure. The NAM and NAGsugars are shown as green and blue spheres respectively. Thetetrapeptides linked to NAM are cross-linked by a pentaglycinepeptide, shown as red lines linking the D-glutamine (L) to the D-alanine (A).

-lactamantibiotics

inhibittranspeptidasesenzymes thatform these

crosslinkages

Glycopeptidesbind D-alanineand preventcrosslinkage

Penicillins - structure



Penicillins - classifications



Penicillin G like drugs Penicillin G (Benzylpenicillin) Penicillin V Procaine penicillin G Benzathine penicillin G

Penicillinase- resistant penicillins (anti staph)

Cloxacillin Flucloxacillin Methicillin

Extended spectrum penicillin Ampicillin-like drugs

Ampicillin Amoxicillin Broad-spectrum (antipseudomonal) penicillins

Carbenicillin Piperacillin

P i illi h ki ti

http://e/antibiotics/beta%20lactam.htm






















Penicillins - pharmacokinetics

Given parenterally – well distributed

Crosses inflamed biological barrier

Mainly excreted via kidney Inhibited by probenecid

Penicillins - indication



Penicillins - indication Penicillin G

Gram +ve infectionStreptococciMeningococci Pneumococci Clostridium

Syphilis

Penicillinase-resistant penicillins Staph infection

ImpetigoAbcess

Extended spectrum penicillin Gram +ve & Gram –ve

Pneumonia, otitis media

P i illi d ti



Penicillins – adverse reaction

Relatively non-toxicAllergic reaction

Anaphylaxis- will occur in approximately in

0.01% patients

A rash on the back of aperson with anaphylaxis

C h l i

http://en.wikipedia.org/wiki/File:BackRed.JPG



Cephalosporins

1. 1st generation cephalosporins



g p p

2. 2nd generation cephalosporins-best for Gram +ve & -ve-Extended Gram –ve coverage- eg. Cefuroxime, Cefaclor

- best for Gram +ve- eg. Cephalexin, Cephazoline

3. 3rd generation cephalosporins -best for Gram –ve-antipseudomonas- eg. Ceftazidime, Ceftriaxone, Cefotaxime,

Cefoperazone

4. 4th generation cephalosporins -Good coverage for both Gram +ve & -ve

- antipseudomonal activity

-Eg. Cefipime

C h l i d ti



Cephalosporins – adverse reactions

Fairly safeAllergic reaction

Cross reaction with penicillinSuperinfection

(an infection following a previous infection, esp. when caused bymicroorganisms that have become resistant to the antibiotics

used earlier)

Carbapenem



Carbapenem Examples

Imipenem

Meropenem

Wide spectrum

Resistant against -lactamase Good activity against both Gram +ve & -ve

Active against pseudomonas

Use in resistant organisms Hospital acquired infection

M n b t m



Monobactam

ExampleAztreonam

Resistant against -lactamase

Antipseudomonal activity Inactive against Gram +ve

GIT side effects – diarrhea, nausea &

vomiting IV – poorly absorbed when given via oral

route.

l t m s inhibit s



- lactamase inhibitors

Resemble -lactam molecules No antibacterial activity Inhibits bacterial -lactamase Use in combination with penicillins

Ampicillin–sulbactam Piperacillin-tazobactam

Amoxycillin-clavulanate (clavulanic acid)

Glycopeptides



Glycopeptides

Vancomycin, teicoplanin Active against Gm +ve esp staph

Not active against Gm –ve

Use in MRSA infection

Nephrotoxicity, red man syndrome

PROTEIN SYNTHESIS INHIBITOR



1) Aminoglycosides

2) Tetracyclines

3) Chloramphenicol

4) Macrolides5) Fusidic Acid

http://en.wikipedia.org/wiki/File:Average_prokaryote_cell-_en.svg



Aminoglycosides



Aminoglycosides

Bactericidal From various Streptomyces species

Streptomycin

Neomycin Amikacin

Gentamicin

Tobramycin Netilmicin

Aminoglycosides – physical



g y p yproperties

Water soluble (polar)Poorly absorbed from gut

Given parenterallyLess able to cross biological

barrier

More active at alkaline pH

Aminoglycosides MOA



Aminoglycosides - MOA

Irreversible inhibitor ofprotein synthesis

Passive diffusion via porinchannels of outer

membrane

Actively transport intocytoplasm

Bind to 30S subunitribosome

Interfere with synthesis

of protein

Aminoglycoside: clinical use



Use against Gram –ve infection Usually combined with -lactam

antibiotic Better coverage Synergistic effect

No activity against anaerobe

Aminoglycoside: clinical use

Aminoglycosides -



pharmacokinetic

Polar substance Given i.m. or i.v.

Poorly penetrate CSF or eye 20% blood level in inflamed meninges

May be given intrathecal

t1/2 = 2-3 hours

Excreted unchanged by the kidneys

Adjust dosage with renal impairment Can be calculated based on creatinine clearance

Aminoglycosides: PK PD



Aminoglycosides: PK-PD

Concentration dependent killing Rate of killing depend on concentration

Post antibiotic effect

Antibacterial activity persist after thelevel reduce to below MIC

Can be given single daily dose Same efficacy Reduce risk of toxicity convenience

Aminoglycosides: toxicity



g y y Ototoxic

Auditory damage Vestibular damage

Nephrotoxic Potentiated by other

nephrotoxic drugs

Need to measurelevel (TDM)

Peak and trough High dose

Block neuromuscular junction

Streptomycin



Mainly use in the treatment of TB Combine with other anti TB

Resistance easily developed withoutcombination

Side effect Fever, rashes Impair vestibular function

Contraindicated in pregnancy

Deafness in newborn

Gentamicin



Gentamicin

Active both in Gram +ve & -ve Staphylococci

Resistance rapidly developed

Pseudomonas, klebsiella No activity against streptococci and

enterococci

But can enhance the effect of -lactam orvancomycin

Gentamicin – clinical uses



Gentamicin – clinical uses

Combine with cell wall inhibitor in severeinfection

With penicillin G in Strep viridans

endocarditis Should not be used alone for pneumonia

Poor penetration

Requires TDM If use more than 5 days Renal impairment

Amikacin



Amikacin

Semi synthetic aminoglycoside More resistant than genta towards

inactivating enzymes

Active against MDR M. tuberculosis Usually use as second line antibiotic

Spectinomycin



Spectinomycin

Structure related to aminoglycoside butlack of amino sugars

Given i.m.

Only use as an alternative to penicillin ingonorrhoea therapy Penicillin sensitivity

Resistant gonococcal Rarely nephrotoxic



Macrolides



Macrolides

azithromycin erythromycin clarithromycin

Macrolides



Macrolides

MOA

Bind reversibly to

the 50S subunit Inhibit elongation

of the protein

• Streptomycin obtained from Streptomyces erythreus

• Clarithromycin & azithromycin are semisynthetic

Erythromycin- spectrum



Erythromycin spectrum

Gram +ve Pneumococci, streptococci, staph

Atypical organism

Mycoplasma, clamydia Mycobacteria

M. kansasii

Gram –ve Neiserria sp, B pertussis,

Corynebacteria

Treponema pallidum (syphilis)

Erythromycin - pharmacokinetics

http://en.wikipedia.org/wiki/File:Treponema_pallidum.jpg



Erythromycin pharmacokinetics

Destroyed by stomach acid Enteric coated tablet

Food interferes absorption

t1/2 = 1.5 hours Well distributed except CSF

Excreted in biles

Erythromycin- uses



Erythromycin uses

Corynebacterialinfection Diphteria

Clamydial infection Community acquired

pneumonia

Pertussis

Syphilis Penicillin allergy

Erythromycin- ADR



Erythromycin ADR

GIT Nausea, vomiting,diarrhoea

Liver toxicity Cholestatic jaundice

Drug interaction Inhibit cytochrome P450

Clarithromycin



Clarithromycin

Improved acid stability Better absorption

Longer t1/2 BD dosing

Metabolised by liver

More active against Mycobacterium avian complex

More expensive

Azithromycin



Azithromycin

More active against M avian complex

Toxoplasma gondii

Penetrates well into tissues Concentration > 10 – 100 times serum

Tissue t1/2 = 2-4 days Single daily dose Short courses



Tetracyclines



Tetracyclines

Tetracyclines - MOA

http://project.bio.iastate.edu/Courses/MIPM302/302new/9_1chemother.html



Tetracyclines MOA

Bind reversibly tothe 30S subunit

Misalignment of

anticodons of thecharged tRNAs withthe codons of themRNA.

Failure of proteinsynthesis

Tetracyclines



Tetracyclines

Introduced in 1948 (chlortetracycline) Bacteriostatic

Coverage

Gram +ve & -ve Atypical bacteria

Rickettsiae

Chlamydia

mycoplasma Protozoa

Amoebas

Tetracyclines – P’kinetics



GI absorption

tetracycline (60-80%), doxycycline (95%), minocycline (100%)

Impaired by food (esp with Mg2+,Ca2+)

Ditributed widely except intoCSF

Crosses placenta Excreted both thru bile and

urine T 1/2

Short acting (6 hrs) Tetracycline

Intermediate (12 hrs) demeclocycline

Long (18 hrs)

doxycycline, minocycline

Tetracyclines - uses



Tetracyclines uses

Drug of choice in atypical bacteria infection Ricketsiae

Used in combination to treat gastric or

duodenal ulcer To eradicate H. Pylori

Cholera

Acne

Lyme disease (Borelia burgdorferi )

Tetracyclines - ADR



Tetracyclines ADR

GIT Nausea, vomiting,

diarrhoea

Damage growingbone & teeth Due to Ca2+ chelating

property

Yellow discolouration Contraindicated in

children < 8 years old

Hepatic injury Increased during

pregnancy

Nephrotoxicity

Photosensitization Severe sunburn ;

doxy/demeclocycline



Chloramphenicol



Chloramphenicol

Binds to 50 S ribosomalsubunit

Mainly bacteriostatic

Bactericidal H. influenza

N. meningitidis

Broad spectrum (includingrickettsiae)

Chloramphenicol – P’kinetics



hloramphen col k net cs

IV (prodrug) or orally Complete oral absorption

Excretion depends on conversion in liver

to glucuronide, then secretion in kidney Slow excretion in liver impairment

Chloramphenicol - uses



r mp n u

Staph brain abscess Typhus

As an alternative in meningitis

Conjunctivitis – eye preparation

Chloramphenicol - ADR



mp D

Blood dyscrasias Idiosyncratic aplastic anemia

Gray baby syndrome Neonates if doses not adjusted

ANTIMETABOLITES



1) Trimethoprim

2) Sulfonamides

Sulphonamide - MOA



p

Bacteria cannottransport folate intocells

Tetrahydrofolate is aDNA precursor

p-aminobenzoic acid(PABA) is a precursorfor folate synthesis

Sulfonamides arestructurally similar to

PABA Inhibits synthesis ofdihydropteroatesythase (DHPS)

DHPS & DHFR absent inmammalian cells

Sulfonamides - effect



Bacteriostatic Active against

Both Gram +ve & -ve

E. coli, Klebsiella, Salmonella Clamydia

Some protozoa –

Pneumocystis carinii Not active against rickettsiae

Sulfonamides -Pharmacokinetics



Pharmacokinetics

Preparation available Topical

Oral

Well absorbed from gut Distributed widely including CSF

Metabolized in liver

Excreted via kidney

Sulfonamides - uses



Topical Sulfacetamide ophthalmic solution

Conjunctivitis

Trachoma Silver sulfadiazine (SSD)

burns

Systemic Use in combination

Sulfonamides - ADR



Fever Skin rash

Exfoliative

dermatitis Steven Johnson

syndrome

Crystalluria

Sulfonamides - combination



Sulfadiazine + pyrimethamine Pyrimethamine inhibit protozoan

DHFR Synergistic

Penetrates CSF 1st line for acute toxoplasmosis

Sulfadoxin + pyrimethamine (Fansidar)

Long acting Prophylaxis & treatment for

malaria



Trimethoprim + sulfamethoxazole(TMP + SFX = co-trimoxazole)



(TMP + SFX = co-trimoxazole)

TMP Inhibit DHFR

Synergistic whencombined with SFX

Combination isbactericidal

co-trimoxazole – p’kinetics



p

TMP:SFX = 1:5 Available in IV and oral

Oral Well absorbed T1/2 = 10 hrs (both)

Penetrates well into CSF, prostate

Excreted in urine Usually given BD dose

co-trimoxazole - uses



Infection caused by Shigella Salmonela

UTI Treatment prophylaxis

Community acquired pneumonia PCP pneumonia (P. jiroveci )

Treatment prophylaxis

Co-trimoxazole - ADR



Sulfonamides ADR Megaloblastic anaemia

Leukopenia

Granulocytopenia

Inhibit DNA gyrase

http://en.wikipedia.org/wiki/File:Chinolone.png



Quinolones

Essential structure of all quinoloneantibiotics

Metronidazole

- Fluoroquinolones

Interfere with DNA function

Fluoroquinolones

http://en.wikipedia.org/wiki/File:Chinolone.png



q

Synthetic fluorinated analogs ofnalidixic acid

Inhibit bacterial DNA synthesis

Inhibit DNA gyrase & topoisomerase Examples

Ciprofloxacin

Norfloxacin Perfloxacin



Required fornormal

transcriptionand

replication

Inhibition of topoisomerase IV

prevents separationof replicated DNA

Fluoroquinolones



Spectrum depend on drugs Earlier fluoroquinolones (ciprofloxacin)

Mainly cover Gram –ve

Later drug (gatifloxacin) Better coverage for Gram +ve

Also useful in

Atypical pneumonia TB, M. avian

Fluoroquinolones - uses



Usually used in multidrug resistantinfection

UTI

Bacterial AGE Gonorrhea

Eradication of meningococci from

carriers

Fluoroquinolones - ADR



Usually well tolerated GIT upset

Allergic reaction

May damage growing cartilage (rat)



Metronidazole - anaerobes- It is used mainly in the treatment of infections caused



yby susceptible organisms, particularly anaerobic bacteria

and protozoa.

- It is used to treat ameobic dysentry, giardiasis,gangrene, pseudomonas coitis & various abdominalinfections, lung abscess & dental sepsis.

Mechanism of actions- The nitro group of metronidazole is able to serve as anelectron acceptor, forming reduced cytotoxic compoundsthat bind to proteins and DNA, resulting in cell death.

Metronidazole - anaerobes



Side Effects

PK

It is well absorbed after oral or rectaladministration

•Nausea & vomiting

•Peripheral neuropathy

•Convulsions, headaches•Hepatitis

Pathogen Drug (s) of first choice Alternative Drug (s)

Gram +ve cocciPneumococcus Penicillin G, Ampicillin Erythromycin, Cephalosporin



Streptococcus (common) Penicillin G Erythromycin, Cephalosporin

Staphylococcus

(penicillase-producing)

Augmentin ® , Unasyn ® , Cloxacillin,Methicillin, Nafcillin, Timentin ®

Cephalosporin

Staphylococcus

(methicillin resistance)

Vancomycin TMZ-SMZ

Enterococcus Penicillin G plus gentamicin Vancomycin plus gentamicin

Gram -ve cocciGonococcus Cetrriaxone Penicillin G, Ampicillin, Spectinomycin

Meningococcus Penicillin G, Ampicillin Cefotaxime, Cefuroxime,Chloramphenicol

Gram -ve rodsE.coli , Proteus, Klebsiella Aminoglycosides, 3rd generation

cephalosporinTMZ-SMZ, Fluoroquinolone,extended spectrum penicillin

Shigella Fluoroquinolone TMZ-SMZ, Ampicillin

Enterobacter, Citrobacter,

Serratia

Imipenam, Fluoroquinolone TMZ-SMZ, extended spectrum

penicillin

Hemophilus spp Cefuroxime or 3rd generationcephalosporin

TMZ-SMZ, Ampicillin,

Chloramphenicol

Pseudomonas aeruginosa Aminoglycosides plus extendedspectrum penicillin

Ceftazidime, Aztreonam, Imipenam

Bacteroides fragillis Metronidazole, Clindamycin Imipenam, Chloramphenicol,Ampicillin/sulbactam

A patient with degenerative joint disease is toundergo insertion of a hip prosthesis. To avoidcomplication due to postoperative infection the



complication due to postoperative infection, thesurgeon will pretreat this patient with anantibiotic. This hospital has a significant problemwith MRSA. Which of the following antibioticsshould the surgeon select?

• A. Ampicillin

• B. Imipenem/cilastatin

• C. Gentamicin/piperacillin

• D. Vancomycin• E. Cefazolin



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rational use ab - 2011

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