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Rational Use ofAntibiotics
Dr Ruzilawati Abu BakarJabatan Farmakologi
ext 6128
4th Year Medical Posting
2011/2012
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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
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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
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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
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Bacteria vs Host
Bacteria Host
Pathogen Vs non pathogen
Virulence
Host defence
antibiotic
Disease
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Selection of
antibacterial agents
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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
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Koda-Kimble M.A.et al, AppliedTherapeutics , TheClinical Use ofDrugs (LippincottWilliams & Wilkin,9th ed.), 2009
1. Site of infection
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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
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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
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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
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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
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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
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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.
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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
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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)
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• 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.
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• 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
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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
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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
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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
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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.
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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.
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Methods of
administration ofantibacterial agents
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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.
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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.
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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.
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Route of administration…….con’t
•However, some drugs are not availablefor parental use (eg. Most macrolides,sulpha drugs, tetracyclines)
• Antibacterials are also used topically
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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.
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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.
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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
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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
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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
’
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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
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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
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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
A. Patient undergoing cancer chemotherapy
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A. Patient undergoing cancer chemotherapy
- 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
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Clinical failure of
antimicrobialtherapy
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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 ( )
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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
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Antibiotic Resistance
―P i illi E ‖
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―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
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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
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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
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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
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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
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(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
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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
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• 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
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(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
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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.
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-lactamases
Enzymes produced by bacteria whichdestroy -lactam antibiotics
Many different types Penicillinases, cephalosporinases,
carbapenemases
Most are plasmid mediated
Overcoming lactam Resistance
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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
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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
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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
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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
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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
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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
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Measuring AntimicrobialSensitivity
Disk Diffusion
E- test(antimicrobialgradient method)
Serial dilution
Measuring Antimicrobial
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MIC increase in
the case ofresistance
(Minimal inhibitory concentration)
- important in diagnosticlaboratories to confirm resistanceof microorganisms to anantimicrobial agent
Measuring AntimicrobialSensitivity
Consequences of Antimicrobial
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Consequences of AntimicrobialResistance
Infectionsresistant to
availableantibiotics
Increased costof treatment
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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
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• 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
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Classification of
antibacterial agents
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Chemical structure
Mechanism of action
Spectrum of activity
Broad, extended, narrow
Types of actions i i i i
Classification of antibacterial agents
Chemical structure
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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
Spectrum of activity
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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 )
Spectrum of activity
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Spectrum of activity
Summary of antibiotic’s spectrum
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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
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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
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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
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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
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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
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Bacterial cell wall antibioticsinhibit
transpeptidasesenzymes that
form thesecrosslinkages
Glycopeptidesbind D-alanineand preventcrosslinkage
A schematic of peptidoglycan’s structure The NAM and NAG
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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
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Penicillins - classifications
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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
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Penicillins - pharmacokinetics
Given parenterally – well distributed
Crosses inflamed biological barrier
Mainly excreted via kidney Inhibited by probenecid
Penicillins - indication
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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
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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
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Cephalosporins
1. 1st generation cephalosporins
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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
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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
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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
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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
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- 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
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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
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1) Aminoglycosides
2) Tetracyclines
3) Chloramphenicol
4) Macrolides5) Fusidic Acid
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Aminoglycosides
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Aminoglycosides
Bactericidal From various Streptomyces species
Streptomycin
Neomycin Amikacin
Gentamicin
Tobramycin Netilmicin
Aminoglycosides – physical
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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
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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
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Use against Gram –ve infection Usually combined with -lactam
antibiotic Better coverage Synergistic effect
No activity against anaerobe
Aminoglycoside: clinical use
Aminoglycosides -
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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
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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
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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
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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
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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
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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
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Amikacin
Semi synthetic aminoglycoside More resistant than genta towards
inactivating enzymes
Active against MDR M. tuberculosis Usually use as second line antibiotic
Spectinomycin
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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
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Macrolides
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Macrolides
azithromycin erythromycin clarithromycin
Macrolides
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Macrolides
MOA
Bind reversibly to
the 50S subunit Inhibit elongation
of the protein
• Streptomycin obtained from Streptomyces erythreus
• Clarithromycin & azithromycin are semisynthetic
Erythromycin- spectrum
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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
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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
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Erythromycin uses
Corynebacterialinfection Diphteria
Clamydial infection Community acquired
pneumonia
Pertussis
Syphilis Penicillin allergy
Erythromycin- ADR
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Erythromycin ADR
GIT Nausea, vomiting,diarrhoea
Liver toxicity Cholestatic jaundice
Drug interaction Inhibit cytochrome P450
Clarithromycin
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Clarithromycin
Improved acid stability Better absorption
Longer t1/2 BD dosing
Metabolised by liver
More active against Mycobacterium avian complex
More expensive
Azithromycin
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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
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Tetracyclines
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Tetracyclines
Tetracyclines - MOA
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Tetracyclines MOA
Bind reversibly tothe 30S subunit
Misalignment of
anticodons of thecharged tRNAs withthe codons of themRNA.
Failure of proteinsynthesis
Tetracyclines
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Tetracyclines
Introduced in 1948 (chlortetracycline) Bacteriostatic
Coverage
Gram +ve & -ve Atypical bacteria
Rickettsiae
Chlamydia
mycoplasma Protozoa
Amoebas
Tetracyclines – P’kinetics
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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
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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
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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
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Chloramphenicol
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Chloramphenicol
Binds to 50 S ribosomalsubunit
Mainly bacteriostatic
Bactericidal H. influenza
N. meningitidis
Broad spectrum (includingrickettsiae)
Chloramphenicol – P’kinetics
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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
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r mp n u
Staph brain abscess Typhus
As an alternative in meningitis
Conjunctivitis – eye preparation
Chloramphenicol - ADR
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mp D
Blood dyscrasias Idiosyncratic aplastic anemia
Gray baby syndrome Neonates if doses not adjusted
ANTIMETABOLITES
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1) Trimethoprim
2) Sulfonamides
Sulphonamide - MOA
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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
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Bacteriostatic Active against
Both Gram +ve & -ve
E. coli, Klebsiella, Salmonella Clamydia
Some protozoa –
Pneumocystis carinii Not active against rickettsiae
Sulfonamides -Pharmacokinetics
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Pharmacokinetics
Preparation available Topical
Oral
Well absorbed from gut Distributed widely including CSF
Metabolized in liver
Excreted via kidney
Sulfonamides - uses
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Topical Sulfacetamide ophthalmic solution
Conjunctivitis
Trachoma Silver sulfadiazine (SSD)
burns
Systemic Use in combination
Sulfonamides - ADR
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Fever Skin rash
Exfoliative
dermatitis Steven Johnson
syndrome
Crystalluria
Sulfonamides - combination
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Sulfadiazine + pyrimethamine Pyrimethamine inhibit protozoan
DHFR Synergistic
Penetrates CSF 1st line for acute toxoplasmosis
Sulfadoxin + pyrimethamine (Fansidar)
Long acting Prophylaxis & treatment for
malaria
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Trimethoprim + sulfamethoxazole(TMP + SFX = co-trimoxazole)
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(TMP + SFX = co-trimoxazole)
TMP Inhibit DHFR
Synergistic whencombined with SFX
Combination isbactericidal
co-trimoxazole – p’kinetics
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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
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Infection caused by Shigella Salmonela
UTI Treatment prophylaxis
Community acquired pneumonia PCP pneumonia (P. jiroveci )
Treatment prophylaxis
Co-trimoxazole - ADR
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Sulfonamides ADR Megaloblastic anaemia
Leukopenia
Granulocytopenia
Inhibit DNA gyrase
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Quinolones
Essential structure of all quinoloneantibiotics
Metronidazole
- Fluoroquinolones
Interfere with DNA function
Fluoroquinolones
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q
Synthetic fluorinated analogs ofnalidixic acid
Inhibit bacterial DNA synthesis
Inhibit DNA gyrase & topoisomerase Examples
Ciprofloxacin
Norfloxacin Perfloxacin
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Required fornormal
transcriptionand
replication
Inhibition of topoisomerase IV
prevents separationof replicated DNA
Fluoroquinolones
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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
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Usually used in multidrug resistantinfection
UTI
Bacterial AGE Gonorrhea
Eradication of meningococci from
carriers
Fluoroquinolones - ADR
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Usually well tolerated GIT upset
Allergic reaction
May damage growing cartilage (rat)
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Metronidazole - anaerobes- It is used mainly in the treatment of infections caused
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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
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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
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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
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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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