You are on page 1of 150

Rational Use of Antibiotics

Dr Ruzilawati Abu Bakar Jabatan 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 antibacterial agents 4) Antibiotics Resistance

5) Classification of antibacterial agents

Indications for antibacterial therapy:
1. Definitive therapy
•This is for proven bacterial infections •Attempts should be made to confirm the bacterial infection by means of staining of secretions/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.

when time is inadequate for identification & isolation of the bacteria & reasonably strong doubt of bacterial infection exists: . Empirical therapy • Empirical antibacterial therapy should be restricted to critical cases.neutropenic patient (reduction in neutrophils) In such situations.hectic temperature . Empiric antibiotic is antibiotic therapy that is begun before a specific pathogen is identified . drugs that cover the most probable infective agent/s should be used.2.septicemic shock/sepsis syndrome .immunocompromised patients with severe systemic infection .

eg. Prevention for persons from non-malarious areas who visit areas endemic for malaria.3. Treatment prior to certain surgical procedures to prevent infections . only narrow spectrum & specific drugs are used • • The duration of prophylaxis is dictated by the duration of the risk of infection. Prophylactic therapy • Certain clinical situations require the use of antibiotics for the prevention rather than the treatment of infections. 2. 1. • In all these situations.

Bacteria vs Host Bacteria Pathogen Vs non pathogen Virulence Host Host defence antibiotic Disease .

Selection of antibacterial agents .

Severity of infection 4. Isolate & its sensitivity 5.Factors should be considered before prescribing antibacterial agent 1. Site of infection 2. Drug-related factors . Patient factors 7. Source of infection 6. Type of infection 3.

Applied Therapeutics . Site of infection Koda-Kimble M. et al. The Clinical Use of Drugs (Lippincott Williams & Wilkin.). 9th ed.1.A. 2009 .

Can be treated with drugs like penicillins macrolides cephalosporins . pneumoniae. sinusitis.commonly caused by organism like Strep.1. epiglottitis etc. pyogenes. tonsilitis. Site of infection Infection above the diaphragm: •URTI eg pharyngitis. H. S. otitis. influenzae) . Fusobacteria. Peptostreptococci (rarely Mycoplasma. .

Bronchitis. Peptostreptococci. pyogenes. Fusobacteria. pneumonitis. lung abscess etc -generally caused by the organisms Strep. Staph aureus (rarely Mycoplasma. pneumoniae. Klebsiella) etc. H. cephalosporins. Site of infection…con’t Lower respiratory tract infections: Eg. pneumonia.1. Moraxella.can be treated penicillins. S. macrolides & tetracylines . influenzae. .

aminoglycosides. Pseudomonas. con’t Infection below the diaphragm: •Eg UTI. Rule of the thumb Infections above the diaphragm Infections below the diaphragm Cocci & Gram +ve organisms Bacilli & Gram -ve organisms .1. Klebsiella. 3rd generation cephalosporins & metronidazole alone or in combination are useful in these infections. Site of infection …. Proteus. intra-abdominal sepsis. coli. pelvic infections etc --these are caused by the organisms like E. Bacteroides etc. • Quinolones.

.1.chronic prostatitis (non-fenestrated capillaris). . .). hydrolizing enzymes etc. Site of infection ….cardiac & intravascular vegetations (poor reach & penetration).osteomyelitis (avascular sequestrum) etc In such cases:Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs may have to be used . . acidic pH. .abscesses (thick wall.intra-ocular infections (non-fenestrated capillaries). con’t • There are certain sites where the infection tends to be difficult for treatment : .meningitis (impenetrable BBB).

deep-seated. For extensive. severe. superficial/deep-seated. Type of infection Infections can be localised/extensive. mild/severe.2. acute/sub acute/chronic & extracellular/intracellular. chronic & intracellular infections – • • • • Higher & more frequent dose Longer duration of therapy Combinations Lipophilic drugs may have to be used .

Severity of infections • abscess in lung / brain/ liver/ pelvis/ intra-abdominal. • meningitis/ endocarditis/ pneumonias / pyelonephritis / puerperal sepsis. dose should be higher & more frequent. only bactericidal drugs . 3. & anaerobes.to ensure faster clearance of the infection. .A combinations of Penicillins / 3rd generation cephalosporins. . Pseudomonas. • Severe soft tissue infections / gangrene & hospital acquired infections For severe infections only IV route . attempt should be made to cover all possible organisms. aminoglycosides & metronidazole may be used.to ensure adequate blood levels. .If the site is unknown. including drug resistant Staphylococcus.• Bacteremia / sepsis syndrome / septic shock.

4. it should not be changed even if the in vitro report says otherwise . antibacterials can be started only after the sensitivity report is available. least toxic. • If the situation permits. • Narrow spectrum. easy to administer & cheapest of the effective drugs should be chosen. Isolate & sensitivity • Ideal management of any significant bacterial infection requires culture & sensitivity (C&S) study of the specimen. If the patient is responding to the drug that has already been started.

Pseudomonas.5. Source of infection Community-acquired infections are less likely to be resistant whereas Hospital-acquired infections are likely to be resistant & more difficult to treat (eg. MRSA etc) .

immune status . Patient factors • Factors should be considered in choosing the antibacterial agent: . hepatic failure.associated conditions like renal failure.pregnancy & lactation . epilepsy etc.Age of the patient .6. chloramphenicol (can cause grey baby) & sulpha drugs (can cause kernicterus) are contraindicated . • In infants.

drug elimination is slower.< 18 years ALL fluoroquinolones are contraindicated because they cause arthropathy by damaging the growing cartilage. Elderly • In the elderly. . achlorhydria may affect absorption of anticbacterial agents.Tetracycline are contraindicated < 8 years because they discolour the teeth .Patient factors…….con’t Children . requiring dose adjustments & ototoxicity of aminoglycosides may be increased.

neutropenia. using corticosteroids or immunosuppresants. like extremes of age.Patient factors……. HIV infection. patients with cancers/blood dyscrasias.con’t Patients with compromised immune status • In patients with likelihood of compromised immune status. diabetes mellitus. ONLY bactericidal drugs should be used. splenectomy. .

metronidazole. trimethoprim. clindamycin.in pregnancy Contraindicated in all trimesters • tetracylines • quinolones Contraindicated in the last trimesters • sulpha drug • nitrofurantoin • streptomycin • clarithromycin Safe in pregnancy •penicillins •cephalosporins •erythromycin •isoniazid •ethambutol • chloramphenicol Contraindicated in lactating mothers • sulpha drug • tetracylines •nitrofurantoin • quinolones •metronidazole Drugs with limited data on safety like aminoglycoside. rifampicin & pyrazinamide should be used with caution when benefits overweigh the risks . azithromycin. vancomycin.Patient factors…….

in patients with renal failure Absolutely contraindicated Relatively contraindicated •Aminoglycoside •Cephalosporins •Fluoroquinolones Relatively safe •Penicillins •Sulpha drug • tetracycline •Macrolides •Vancomycin •Metronidazole •Isoniazid •Ethambutol •Rifampicin It is better to avoid combinations of cephalosporins & aminoglycosides in these patients because both classes can cause nephrotoxicity .Patient factors…….

in patients with hepatic failure No drugs are absolutely contraindicated.Patient factors……. Relatively contraindicated •Chloramphenicol •Erythromycin estolate •Fluoroquinolones •Pyrazinamide •Rifampicin Safe •Penicillins •Cephalosporins •Ethambutol •Aminoglycosides •Isoniazid •Metronidazole .

It is therefore important to elicit this history in all patients (common with penicillin) 2.7. Adverse reactions: Certain ADRs warrant discontinuation of therapy & the doctor should adequately educate the patients on these adverse effects. Hypersensitivity: If the patient has prior history of hypersensitivity the antibacterial agent should be avoided. . Drug factors 1.

Eg. Cost: It should always be remembered that just because as particular drug is expensive. . Cheaper drug like doxycycline or co-trimoxazole are as effective as the costlier clarithromycin or cephalosporins in the management of lower RTI. it need not be superior than the cheaper ones. Drug factors 3.7.

vancomycin or cisplatin. a strong inducer of hepatic drug-metabolizing enzymes. terfenadine.7. c) Erythromycin inhibits the hepatic metabolism of a number of drugs.con’t 4. b) Rifampicin. theophylline & warfarin. including phenytoin. Interactions: Interactions with food & other concomitant drugs should be considered before instituting antibacterial therapy so as to maximize efficacy & minimize toxicity. a) Interactions include enhanced nephrotoxicity or ototoxicity when aminoglycosides are given with loop diuretics. ketoconazole. . quinidine & warfarin. oral contraceptives. Drug factors……. propranolol. decreases the effects of digoxin.

Methods of administration of antibacterial agents .

Oral route is the most preferred. type & severity of the infection & the availability of a suitable drug . Certain drugs like the aminoglycosides & most 3rd generations cephalosporins are not available for oral administration. in patients with severe infections. esp. easy & cheap.Methods of administration of antimicrobials Route of administration The route of administration depends on the site. non-compliant patients. . in the presence of vomiting etc. but may not be reliable in all circumstances.

Methods of administration of antimicrobials

- IM route should generally be restricted for 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 of severe & 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 available for parental use (eg. Most macrolides, sulpha drugs, tetracyclines) • Antibacterials are also used topically

type & severity of infection. weight.Generally the dose should be higher in cases of severe.Dosage depends on patient’s age. renal & hepatic failure & site. associated conditions like pregnancy. deep-seated infections & lower in cases of renal-failure.Unnecessary overdosage only adds to the cost & adverse effects.Dosage . . . .

increased in cases of severe.Frequency of administration • The drug should be administered 4-5x the plasma half-life to maintain adequate therapeutic concentrations in the serum throughout the day. deep seated & sequestrated infections . .reduced in cases of renal & hepatic failure. • Frequency can be:.

2-4 weeks 5) Tuberculosis – 6-24 months • Longer courses of therapy are usually required for infections due to fungi or mycobacteria • Endocarditis & osteomyelitis require longer duration of treatment .Duration • Duration of therapy depends on the site 1) Tonsilitis – 10 days 2) Bronchitis – 5-7 days 3) UTI – single shot to 21 days 4) Lung abscess.

Combinations 1) 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 resistance 4) Bigger spectrum of activity 5) Reduced toxicity .

peritonitis.Combinations……. metronidazole for bacteroides. penicillins + aminoglycosides + metronidazole .con’t 2) Treatment of infections with multiple organisms: Mixed infections in lung abcess. soiled wounds etc naturally require multiple antibiotics for complete clearance of the infection – penicillins (for Gram +ve & certain anaerobes) & aminoglycosides (for Gram –ve).

The classic example is the antiTB therapy. 3) To prevent resistance: Eg isoniazid + ethambutol + rifampicin 4) To overcome resistance: Combination of specific drugs can be useful in overcoming that resistant infections.Combinations…….con’t Use of combination is a well known method of preventing drug resistance. eg Penicillins + -lactamase inhibitors (Co-amoxiclav/augmentin) .

Penicillins (bactericidal) with tetracyclines ( bacteriostatic) Bactericidal a/b (kill bacteria) – tend to be used in combination with one another Bateriostatic a/b (prevent bacteria’s reproduction) – tend to be used on its own 2) Combinations of drugs with similar toxicity eg. Chloramphenicol & sulpha drug 3) Combining drugs for non-existing ―mixed infections‖ eg. not useful or even harmful: 1) Bactericidal with bacteriostatic eg. Tablets of ciprofloxacin + metronidazole/tinidazole .The following combinations are irrational.

Patient with kidney disease C.Which one of the following patients is least likely to require antimicrobial treatment tailored to the individual’s condition? A. Patient with liver disease . Patient undergoing cancer chemotherapy B. Elderly patient D. Patient with hypertension E.

Patient with liver disease . Patient with hypertension .Impaired liver function may lead to the accumulation of toxic levels of antimicrobial drugs . Patient with kidney disease .A. Elderly patient .Anticancer drugs often suppress immune function 7 these patients require additional antibiotics to eradicate infections B.Renal & hepatic function are often decreased among the elderly D. Patient undergoing cancer chemotherapy . E.Elevated BP would not be expected to markedly influence the type of antimicrobial treatment employed.Impaired renal function may lead to accumulation of toxic levels of antimicrobial drugs C.

Clinical failure of antimicrobial therapy .

poor tissue penetration inadequate dose • pH – low pH reduces effectiveness of aminoglycosides. including.Failure of an antibiotic regimen (1) Inadequate clinical or microbiological response to antimicrobial therapy can result from multiple causes. 1) Drug factors • • • incorrect choice. erythromycin. clindamycin .

age renal & liver function • pre-existing dysfunction of other organs 3) Pathogen factors  resistance  superinfection .Failure of an antibiotic regimen (2) 2) Host factors • • • poor host defense.

Antibiotic Resistance .

‖ The New York Times 1945  Fleming’s words proved to be correct.. mouthwashes. cough lozenges.―Penicillin Era‖  1942-1950 available without a prescription Public demand followed by production of throat sprays.. soaps and other products 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.. .

antibiotic resistance has developed faster than new drugs Estimated cost of infections: $4-5 million per year Antibiotic resistance previously concentrated in hospitals. especially ICUs MRSA recently estimated to kill 18.The Problem of Antibiotic Resistance      Penicillin resistance first identified in 1940’s Since then.000 Americans yearly .

History DRUG Penicillin Streptomycin INTRODUCTION 1943 1945 APPEARANCE OF RESISTANCE 1946 1959 Tetracycline Erythromycin Vancomycin Methicillin Ampicillin Cephalosporins 1948 1952 1956 1960 1961 1964 1953 1988 1988 1961 1973 late 1960’s .

Antibiotic Resistance  Relative or complete lack of effect of antimicrobial against a previously susceptible microbe • Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not stop their growth. .

What Factors Promote Antimicrobial Resistance? What causes the rapid occurrence of widespread resistance? (1) Incomplete treatment: . most had failed to complete their initial course .people fail to finish the full course of their medication .25% of previously-treated tuberculosis patients relapsed with drug resistant strains.

widespread inappropriate use: up to 50% of prescriptions in developing countries are for viral infections that cannot respond (3) Exposure to microbes carrying resistance genes .patients demand antibiotics for cold .What Factors Promote Antimicrobial Resistance? (2) Mis-prescription: .

use of third-generation cephalosporins for communityacquired pneumonia) .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 narrowspectrum drug would suffice  (eg.

(2) Alteration of target site: e.Mechanisms of Antibiotic Resistance (1) • The four main mechanisms by which microorganisms exhibit resistance to antibiotics are: (1) Drug inactivation or modification: e. alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria – resulting in decreased binding of the antibiotic to its target.g. .g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.

Instead.Mechanisms of Antibiotic Resistance (2) (3) Alteration of metabolic pathway: e. (4) Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA). .g. an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. they turn to utilizing preformed folic acid.

Resistance: -lactamase Enzymes
• β-Lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

•Bacteria produce -lactamase enzymes to hydrolyze the -lactam ring before drugs can reach inner membrane where PG synthesis occurs •A cell may produce 100,000 - lactamase enzymes, each of which can destroy 1,000 penicillins per second 100 million molecules of drug destroyed per second

-lactamases

Enzymes produced by bacteria which destroy -lactam antibiotics Many different types

Penicillinases, cephalosporinases, carbapenemases

Most are plasmid mediated

Overcoming -lactam Resistance
slow to hydrolyze

As a response to bacterial resistance to -lactam drugs, there are drugs, such as Augmentin, which are designed to disable the lactamase enzyme.
Augmentin is made of amoxicillin, a -lactam antibiotic, and clavulanic acid, a -lactamase inhibitor. The clavulanic acid is designed to overwhelm all -lactamase enzymes, 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® .

Resistance in Simpler Terms… (reduced drug accumulation) Inactivation Impermeability (reduced drug accumulation) Efflux A By-pass B Altered target (alteration of metabolic pathway) .

2.Genetic alterations in drug resistance  Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information. Resistance develops due to the ability of DNA:To undergo spontaneous mutation To move from one organism to another (DNA/gene transfer) .  1.

tuberculosis when rifampicin is used as a single antibiotic . The emergence of rifampicin-resistant M.Spontaneous mutation of DNA     Stable and heritable genetic change Not induced by antimicrobial agents Resistance variant will proliferate Eg.

transduction (phage mediated) & transformation .DNA/Gene transfer of drug resistant conjugation transformation transduction   DNA Most resistance genes are plasmid mediated Plasmid may enter cells by processes such as conjugation.

Measuring Antimicrobial Sensitivity  Disk  E- Diffusion (antimicrobial gradient method) test  Serial dilution .

Measuring Antimicrobial Sensitivity  MIC increase in the case of resistance (Minimal inhibitory concentration) .important in diagnostic laboratories to confirm resistance of microorganisms to an antimicrobial agent .

Consequences of Antimicrobial Resistance  Infections resistant to available antibiotics cost of treatment  Increased .

.

Prevention of resistance Speed development of new antibiotics  Track resistance data nationwide  Restrict antimicrobial use  Narrow spectrum Combination in long term use (TB)  Direct observed dosing (TB)  Appropriate dose and duration  Use more narrow spectrum antibiotics  Use antimicrobial cocktails  .

Mental retardation • • • • • . Hearing loss C. She developed a urinary tract infection caused by Pseudomonas aeruginosa and was treated with gentamicin. Teratogenesis D. Blindness E.• A pregnant woman was hospitalized and chatheterized with a catheter. Which of the following adverse effects was arisk to the fetus when the woman was on gentamicin? A. Skeletal deformity B.

Classification of antibacterial agents .

Classification of antibacterial agents    Chemical structure Mechanism of action Spectrum of activity  Broad. extended. narrow Types of actions  Bactericidal. bacteriostatic  .

ciprofloxacin b-lactam antibiotics  Penicillins. cephalosporins. doxycycline       Nitrobenzene derivatives  Chloramphenicol Aminoglycosides  Gentamicin Macrolides  Erythromycin Nitrofuran derivatives  Nitrofurantoin Glycopeptide  Vancomycin Nitroimidazoles  Metronidazoles . carbapenems.Chemical structure      Sulfonamides  sulfadiazines Diaminopyrimidines  Trimethoprim Quinolones  Nalidixic acid. monobactams Tetracyclines  Tetracycline.

tetracycline active against chlamydia.isoniazid active only against mycobacteria Extended-spectrum antibiotics Antibiotics that are effective against gram +ve organisms & also against a significant no.ampicillin – acts against gram +ve organisms (Listeria monocytogenes) & some gram -ve organisms (E. anaerobic organisms. Antibiotics affect a wide variety of microbial species Eg. mycoplasma. coli) Broad-spectrum antibiotics . gram –ve rods (E. of gram -ve organisms.. Eg. coli). actinomyces..Spectrum of activity Terms Narrow-spectrum antibiotics Definitions Antibiotics acting only on a single or a limited group of microorganisms Eg..

Spectrum of activity .

Summary of antibiotic’s spectrum Narrow Spectrum • Aztreonam • Benzylpenicillin • Cloxacillin • Phenoxymethylpenicillin • Cephalexin Broad Spectrum •Amoxycillin •Aminoglycoside •Ciprofloxacin •Chloramphenicol •Imipenam •Tetracycline •Vancomycin •Carbenicillin •3rd generation cephalosporins .

bacteriostatic Bactericidal agents outright kill bacteria. They rely on body defenses to clear the infection. .Bactericidal vs. Penicillins Cephalosporins Macrolides Tetracyclines Bacteriostatic agents inhibit growth but don’t kill.

cephalosporins. tetracyclines. CMC Quinolones Rifampicin. metronidazole Sulfonamides.Mechanism of action      Inhibit cell wall synthesis  Penicillins. vancomycin Macrolides. Trimethoprim Inhibit protein synthesis  Inhibit DNA gyrase  Interfere with DNA function  Antimetabolites  .

Beta-lactam antibiotics 1) Penicillin derivatives 2) Cephalosporins 3) Monobactams 4) Carbapenems 2.Cell Wall Inhibitors 1. Beta-lactamase inhibitors 1) Clavulanic acid 2) Sulbactam . Glycopeptides 1) Vancomycin 1) Penicillin 2) Cephalosporins -lactam ring in red 3.

Cell wall inhibitors 1. Glycopeptide Vancomycin  Teicoplanin  Penicillin core structure. . -lactam antibiotics Penicillins  Cephalosporins  Carbapenems  Monobactams  2. "R" is variable group.

Bacterial cell wall -lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages Glycopeptides bind D-alanine and prevent crosslinkage .

shown as red lines linking the D-glutamine (L) to the Dalanine (A). The NAM and NAG sugars are shown as green and blue spheres respectively. Glycopeptides bind D-alanine and prevent crosslinkage -lactam antibiotics inhibit transpeptidases enzymes that form these crosslinkages .A schematic of peptidoglycan’s structure. The tetrapeptides linked to NAM are cross-linked by a pentaglycine peptide.

structure .Penicillins .

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 .

pharmacokinetics Given parenterally – well distributed  Crosses inflamed biological barrier  Mainly excreted via kidney   Inhibited by probenecid .Penicillins .

 Penicillin G  Gram +ve infection  Streptococci  Meningococci  Pneumococci  Clostridium  Syphilis Penicillins . otitis media  .indication  Penicillinase-resistant penicillins  Staph infection  Impetigo  Abcess Extended spectrum penicillin  Gram +ve & Gram –ve  Pneumonia.

01% patients A rash on the back of a person with anaphylaxis .will occur in approximately in 0.Penicillins – adverse reaction  Relatively non-toxic  Allergic reaction  Anaphylaxis .

Cephalosporins .

Cefoperazone 4. 4th generation cephalosporins -Good coverage for both Gram +ve & -ve . 2nd generation cephalosporins -best for Gram +ve & -ve -Extended Gram –ve coverage . Cephazoline 2. 3rd generation cephalosporins -best for Gram –ve -antipseudomonas .best for Gram +ve . Ceftazidime.1. Cefuroxime.eg.antipseudomonal activity -Eg. 1st generation cephalosporins . Ceftriaxone. Cefotaxime. Cefaclor 3.eg. Cefipime .eg. Cephalexin.

when caused by microorganisms that have become resistant to the antibiotics used earlier) . esp.Cephalosporins – adverse reactions  Fairly safe  Allergic reaction  Cross reaction with penicillin  Superinfection (an infection following a previous infection.

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 .

.Monobactam       Example Aztreonam Resistant against -lactamase Antipseudomonal activity Inactive against Gram +ve GIT side effects – diarrhea. nausea & vomiting IV – poorly absorbed when given via oral route.

.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 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) Macrolides 5) Fusidic Acid .

.

Aminoglycosides Bactericidal  From various Streptomyces species  Streptomycin  Neomycin  Amikacin  Gentamicin  Tobramycin  Netilmicin  .

Aminoglycosides – physical properties  Water soluble (polar)  Poorly absorbed from gut Given parenterally  Less able to cross biological barrier  More active at alkaline pH .

Aminoglycosides .MOA  Irreversible inhibitor of protein synthesis Passive diffusion via porin channels of outer membrane Actively transport into cytoplasm    Bind to 30S subunit ribosome 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 .

v.Aminoglycosides pharmacokinetic  Polar substance   Given i. or i. 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 .m.

Aminoglycosides: PK-PD   Concentration dependent killing  Post antibiotic effect  Rate of killing depend on concentration Antibacterial activity persist after the level reduce to below MIC  Can be given single daily dose Same efficacy  Reduce risk of toxicity  convenience  .

 Ototoxic   Aminoglycosides: toxicity Auditory damage Vestibular damage Potentiated by other nephrotoxic drugs  Nephrotoxic   Need to measure level (TDM)  Peak and trough Block neuromuscular junction  High dose  .

Streptomycin     Mainly use in the treatment of TB  Combine with other anti TB Resistance easily developed without combination Side effect  Fever. rashes  Impair vestibular function Contraindicated in pregnancy  Deafness in newborn .

klebsiella  No activity against streptococci and enterococci  But can enhance the effect of -lactam or vancomycin .Gentamicin  Active both in Gram +ve & -ve   Staphylococci  Resistance rapidly developed Pseudomonas.

Gentamicin – clinical uses Combine with cell wall inhibitor in severe infection  With penicillin G in Strep viridans endocarditis  Should not be used alone for pneumonia    Requires TDM  Poor penetration If use more than 5 days  Renal impairment .

Amikacin
Semi synthetic aminoglycoside  More resistant than genta towards inactivating enzymes  Active against MDR M. tuberculosis  Usually use as second line antibiotic

Spectinomycin
Structure related to aminoglycoside but lack of amino sugars  Given i.m.  Only use as an alternative to penicillin in gonorrhoea therapy

Penicillin sensitivity  Resistant gonococcal

Rarely nephrotoxic

Macrolides azithromycin erythromycin clarithromycin .

Macrolides • Streptomycin obtained from Streptomyces erythreus • Clarithromycin & azithromycin are semisynthetic  MOA  Bind reversibly to the 50S subunit  Inhibit elongation of the protein .

B pertussis. clamydia M.Erythromycin. streptococci. kansasii Atypical organism    Mycobacteria  Gram –ve   Treponema pallidum (syphilis) Neiserria sp. Corynebacteria . staph Mycoplasma.spectrum   Gram +ve  Pneumococci.

5 hours  Well distributed except CSF  Excreted in biles .pharmacokinetics   Destroyed by stomach acid  Enteric coated tablet Food interferes absorption  t1/2 = 1.Erythromycin .

uses  Corynebacterial infection  Diphteria     Clamydial infection Community acquired pneumonia Pertussis Syphilis  Penicillin allergy .Erythromycin.

vomiting.ADR  GIT  Nausea.Erythromycin.diarrhoea  Liver toxicity  Cholestatic jaundice  Drug interaction  Inhibit cytochrome P450 .

Clarithromycin Improved acid stability  Better absorption  Longer t1/2   BD dosing Metabolised by liver  More active against Mycobacterium avian complex  More expensive  .

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 .

MOA    Bind reversibly to the 30S subunit Misalignment of anticodons of the charged tRNAs with the codons of the mRNA.Tetracyclines . Failure of protein synthesis .

Tetracyclines    Introduced in 1948 (chlortetracycline) Bacteriostatic Coverage   Gram +ve & -ve Atypical bacteria Rickettsiae  Chlamydia  mycoplasma   Protozoa  Amoebas .

Ca2+) Ditributed widely except into CSF Crosses placenta Excreted both thru bile and urine T1/2  Short acting (6 hrs)  Tetracycline  Intermediate (12 hrs)  demeclocycline  Long (18 hrs)  doxycycline. minocycline .  minocycline (100%) Impaired by food (esp with Mg2+.  doxycycline (95%).Tetracyclines – P’kinetics       GI absorption  tetracycline (60-80%).

Pylori    Cholera Acne Lyme disease (Borelia burgdorferi) .uses    Drug of choice in atypical bacteria infection Ricketsiae Used in combination to treat gastric or duodenal ulcer  To eradicate H.Tetracyclines .

doxy/demeclocycline . diarrhoea   Increased during pregnancy  Damage growing bone & teeth    Due to Ca2+ chelating property Yellow discolouration Contraindicated in children < 8 years old Nephrotoxicity Photosensitization  Severe sunburn .Tetracyclines .ADR  GIT   Hepatic injury  Nausea. vomiting.

.

meningitidis   Broad spectrum (including rickettsiae) . influenza  N.Chloramphenicol Binds to 50 S ribosomal subunit  Mainly bacteriostatic  Bactericidal  H.

Chloramphenicol – P’kinetics IV (prodrug) or orally  Complete oral absorption  Excretion depends on conversion in liver to glucuronide. then secretion in kidney  Slow excretion in liver impairment  .

uses Staph brain abscess  Typhus  As an alternative in meningitis  Conjunctivitis – eye preparation  .Chloramphenicol .

Chloramphenicol .ADR  Blood dyscrasias  Idiosyncratic aplastic anemia  Gray baby syndrome  Neonates if doses not adjusted .

ANTIMETABOLITES 1) Trimethoprim 2) Sulfonamides .

MOA      Bacteria cannot transport folate into cells Tetrahydrofolate is a DNA precursor p-aminobenzoic acid (PABA) is a precursor for folate synthesis Sulfonamides are structurally similar to PABA Inhibits synthesis of dihydropteroate sythase (DHPS)  DHPS & DHFR absent in mammalian cells .Sulphonamide .

Sulfonamides .effect Bacteriostatic  Active against  Both Gram +ve & -ve  E. coli. Klebsiella. Salmonella  Clamydia  Some protozoa –   Pneumocystis carinii  Not active against rickettsiae .

Sulfonamides Pharmacokinetics  Preparation available Topical  Oral   Well absorbed from gut Distributed widely including CSF  Metabolized in liver  Excreted via kidney  .

uses  Topical  Sulfacetamide ophthalmic solution  Conjunctivitis  Trachoma  Silver sulfadiazine (SSD)  burns  Systemic  Use in combination .Sulfonamides .

Sulfonamides .ADR      Fever Skin rash Exfoliative dermatitis Steven Johnson syndrome Crystalluria .

combination  Sulfadiazine + pyrimethamine  Pyrimethamine inhibit protozoan DHFR  Synergistic  Penetrates CSF  1st line for acute toxoplasmosis Sulfadoxin + pyrimethamine (Fansidar)  Long acting  Prophylaxis & treatment for malaria  .Sulfonamides .

.

Trimethoprim + sulfamethoxazole (TMP + SFX = co-trimoxazole)  TMP   Inhibit DHFR Synergistic when combined with SFX  Combination is bactericidal .

prostate  Excreted in urine  Usually given BD dose  .co-trimoxazole – p’kinetics TMP:SFX = 1:5  Available in IV and oral  Oral  Well absorbed  T1/2 = 10 hrs (both)  Penetrates well into CSF.

co-trimoxazole .uses  Infection caused by    UTI   Shigella Salmonela   Community acquired pneumonia PCP pneumonia (P. jiroveci)   Treatment prophylaxis Treatment prophylaxis .

ADR Sulfonamides ADR  Megaloblastic anaemia  Leukopenia  Granulocytopenia  .Co-trimoxazole .

Inhibit DNA gyrase Quinolones .Fluoroquinolones Essential structure of all quinolone antibiotics Interfere with DNA function Metronidazole .

Fluoroquinolones Synthetic fluorinated analogs of nalidixic acid  Inhibit bacterial DNA synthesis  Inhibit DNA gyrase & topoisomerase  Examples  Ciprofloxacin  Norfloxacin  Perfloxacin  .

Inhibition of topoisomerase IV prevents separation of replicated DNA Required for normal transcription and replication .

M. avian .Fluoroquinolones Spectrum depend on drugs  Earlier fluoroquinolones (ciprofloxacin)     Later drug (gatifloxacin)  Mainly cover Gram –ve Also useful in  Better coverage for Gram +ve Atypical pneumonia  TB.

uses Usually used in multidrug resistant infection  UTI  Bacterial AGE  Gonorrhea  Eradication of meningococci from carriers  .Fluoroquinolones .

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 by susceptible organisms, particularly anaerobic bacteria and protozoa. - It is used to treat ameobic dysentry, giardiasis, gangrene, pseudomonas coitis & various abdominal infections, lung abscess & dental sepsis.

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

Metronidazole - anaerobes
Side Effects
•Nausea & vomiting
•Peripheral neuropathy •Convulsions, headaches •Hepatitis
PK

It is well absorbed after oral or rectal administration

Pathogen Gram +ve cocci
Pneumococcus Streptococcus (common) Staphylococcus (penicillase-producing) Staphylococcus (methicillin resistance) Enterococcus

Drug (s) of first choice
Penicillin G, Ampicillin Penicillin G Augmentin®, Unasyn®, Cloxacillin, Methicillin, Nafcillin, Timentin® Vancomycin Penicillin G plus gentamicin

Alternative Drug (s)
Erythromycin, Cephalosporin Erythromycin, Cephalosporin Cephalosporin TMZ-SMZ Vancomycin plus gentamicin

Gram -ve cocci
Gonococcus Meningococcus Cetrriaxone Penicillin G, Ampicillin Penicillin G, Ampicillin, Spectinomycin Cefotaxime, Cefuroxime, Chloramphenicol

Gram -ve rods
E.coli, Proteus, Klebsiella Shigella Enterobacter, Citrobacter, Serratia Hemophilus spp Pseudomonas aeruginosa Bacteroides fragillis Aminoglycosides, 3rd generation cephalosporin Fluoroquinolone Imipenam, Fluoroquinolone Cefuroxime or 3rd generation cephalosporin Aminoglycosides plus extended spectrum penicillin Metronidazole, Clindamycin TMZ-SMZ, Fluoroquinolone, extended spectrum penicillin TMZ-SMZ, Ampicillin TMZ-SMZ, extended spectrum penicillin TMZ-SMZ, Ampicillin, Chloramphenicol Ceftazidime, Aztreonam, Imipenam Imipenam, Chloramphenicol, Ampicillin/sulbactam

To avoid complication due to postoperative infection. the surgeon will pretreat this patient with an antibiotic. Which of the following antibiotics should the surgeon select? • • • • • A. Cefazolin .A patient with degenerative joint disease is to undergo insertion of a hip prosthesis. This hospital has a significant problem with MRSA. Vancomycin E. Imipenem/cilastatin C. Ampicillin B. Gentamicin/piperacillin D.

THANK YOU .