I B I T N A T O

I B I T N A T O d a. j e M n – oo k i. N R D S C I M . D H. P

The bacterial cell wall allows the microorganism to maintain its shape l The cell wall also provides structural support to withstand changes in osmotic pressure. l

Pharmacologic Classification of Antibiotics Betalactam agents Aminoglycosides Macrolides Tetracyclins Sulfonamides

Pharmacologic Classification of Antibiotics Quinolones Antimycobacterial Vancomycin Chloramphenicol Metronidazol

ﻣکﺎﻧیﺴﻢ ﺍﺛﺮ آﻨﺘی ﺑیﻮﺗیک ﻫﺎ -------- Cell Wall Ø Penicillins Ø Cepholosporins Ø Vancomycin Ø Bacitracin Ø Cyclocerin ﺗﺄﺜیﺮ ﺭﻭی 1 -

ﻣکﺎﻧیﺴﻢ ﺍﺛﺮ آﻨﺘی ﺑیﻮﺗیک ﻫﺎ DNA ﺍﺧﺘﻼﻝ ﺩﺭ ﺳﻨﺘﺰ پﺮﻭﺗﺌیﻦ ﻭ ﺳﺎﺧﺖ 4 DNA Replication Inhibition Ø Nalidixic acid Ø Ciprofloxacin Ø Ofloxacin Ø Metronidazole

Inhibition of DNA Dependent RNA Polymeras Ø Rifampin

Translation Inhibition Ø Aminoglycosids Ø Macrolides Ø Tetracyclins Ø Chloramphenicol

Betalactam agents Penicillins Cephalosporins Carbapenem ( Imipenem – Meropenem – Ertapenem ) Monobactam ( Azteronam )

Betalactam Inhibitors Clavulanic acid Sulbactam Tazobactam

Penicillins Natural Penicillin ( G - V ) Penicillinas Resistant Penicillins (PRP) Methicillin – Naficillin – Cloxacillin Aminopenicillin ( Ampicillin – Amoxycillin ) Antipseudomonas Penicillins ( Ticarcillin – Carbenicillin – Pipracillin – Azlocillin – Mezlocillin )

PENICILLIN-- G ØBenzyl penicillin ØNarrow spectrum antibiotic mainly against gram +ve. ØBacterial resistance is acquired mainly by production of penicillinase. PHARMACOKINETICS ØAcid labile. ØLess than 1/3 of an oral dose is absorbed in active form. ØDistributed mainly extracellularly. ØLittle metabolized because of rapid excretion. ØT 1/2 is ~30 min.

USES ØStreptococcal infections like pharyngitis, otitis media, scarlet fever, RF, etc. ØPneumococcal infections ØMeningococcal infections ØSyphilis ØDiphtheria ØTetanus & gas gangrene ØDOC for rare infections like anthrax, actinomycosis, trench mouth, etc. ØFor prophylactic uses of RF, gonorrhea, BE, Agranulocytosis pt’s & for surgical infections.

ADVERSE EFFECTS ØOne of the most nontoxic antibiotics. ØLocal irritancy & direct toxicity. ØHypersensitivity. Most common drug implicated in drug allergy. Features include rash, itching, urticaria, fever. Wheezing, angioneurotic oedema, serum sickness, exfoliative dermatitis are less common. ØAnaphylaxis is rare but fatal. ØTopical use of penicillin is highly sensitizing. ØSuper infections. ØJarisch-Herxheimer reaction.

SEMISYNTHETIC PENICILLINS ØProduced to overcome the shortcomings of Pn. G like Poor oral efficacy. Susceptibility to penicillinase. Narrow spectrum of activity. Hypersensitivity. B-lactamase inhibitors.

CLASSIFICATION • Acid resistant alternate to Pn. G– Phenoxy methyl penicillin • Penicillinase resistant– Methicillin, Oxacillin, Cloxacillin, Nafcillin • Extended spectrum– A) Aminopenicillins—Ampicillin, Amoxicillin, Becampicillin B) Caboxypenicillins– Carbenicillin, Ticarcillin C) Ureidopenicillins– Mezlocillin, Piperacillin • B-lactamase inhibitors– Clavulanic acid, Sulbactam

AMPICILLIN ØActive against all organisms sensitive to Pn. G in addition to gram_ve bacilli. ØNot acid labile. ØOral absorption is incomplete but adequate. Food interferes with absorption. ØMainly excreted by kidney & partly by bile but reabsorbed. ØPlasma t 1/2 is 1 hr. USES ØUTI, RTI. ØMeningitis, Gonorrhoea, Typhoid, Bacillary dysentry, Cholecystitis, SABE, Septicemias, etc.

ADVERSE EFFECTS ØDiarrhoea is frequent after oral administration. ØProduces a high incidence of rashes. Concurrent administration of Allopurinol increases the incidence. INTERACTIONS ØHydrocortisone inactivates ampicillin if mixed in the i. v. sol. ØFailure of OCP. ØProbenecid retards renal excretion of ampicillin.

Sideffets of Penicillins Anaphylaxis Delayed hypersensivity Hemolytic anemia Cytopenia Sizure

Sideffets of Penicillins Intersitial nephritis Nephrotic SY Hemorrhagic cystitic Elevation of ALT, AST Diarrhea - Entrocolitis Skin rash

Cephalosporins First Generation : Cephalothin Cephazolin Cephalexin Cephradin Cephadroxil Cephapirin

Cephalosporins Second Generation : Cefaclor Cefamandol Cefoxitin Cefuroxime Cefonicid Cefotetan

Cephalosporins Third Generation : Cefotaxime Ceftizoxime Ceftriaxone Cefoprazone Ceftazidime Cefixime

Cephalosporins Fourth Generation : Cefepime Cefpirome

Cephalosporins l Cefazolin, cephalexin l l Cefuroxime, Cefaclor l l Covers some Gram-negative organisms Cefotaxime, Ceftriaxone l l Active vs. Gram-positive organisms including MSSA Broad spectrum, enhanced activity towards Gram-negative organisms Ceftazidime, Cefepime l Additive Pseudomonas coverage

EVOLUTION OF CEPHALOSPORINS Ø 1 st gen – developed in 1960’s have high activity against gram+ve bacteria. Ø 2 nd gen – more active against gram_VE with some active against anaerobes. Ø 3 rd gen – Introduced in 1980’s, have highly augmented action against gram_ve enterobactericeac, B-lactamases, less active on gram+ve cocci. Ø 4 th gen – developed in 1990’s spectrum of action similar to 3 rd gen. Highly effective in nosocomial pneumonia, febrile neutropenia, bacterimia, septicemia, etc.

Potential Adverse of Cephalosporins Rash, Urticaria, S. S. L. SY, Anaphylaxis Diarrhea , Nausea , Vomiting , Eosinophilia , Neutropenia , Thrombosytopenia, Hemolytic anemia

Potential Adverse of Cephalosporins Intersitial nephritis Seizure Glucosuria Drug fever Phlebitis

Oral Cephalosporins Cefalexin Cefaclor Cefuroxime Cefixime

Aminoglycosids Streptomycin Neomycin Kanamycin Gentamycin Amikacin Tobramycin Netilmycin Spectinomycin Paromomycin

Aminoglycosides Active vs. some Gram-positive and Gram-negative organisms l Gentamicin l l l Tobramycin l l l More active vs. Pseudomonas than gentamicin Shows less activity against certain other Gram-negative bacteria Amikacin l l Active vs. Pseudomonas More stable to enzymes, used in severe infections by gentamicin-resistant organisms Streptomycin l Used for tuberculosis

Sideffects of Aminoglycosids Nephrotoxicity Ototoxicity Neuromuscular blockade

Macrolides Erythromycin Clarithromycin Azithromy

Macrolides l Erythromycin l l l Clarithromycin l l Active vs. Gram-positive organisms, atypicals GI side effects Slightly greater activity than erythromycin Azithromycin l Slightly less active than erythromycin vs. Gram-positive but enhanced activity vs. some Gram-negative organisms

SPECTRUM ØNarrow spectrum. ØMostly gram+ve organisms. ØHighly active against Str. pyogenes, Str. pneumoniae, gonococci, clostridia, C. diptheria, listeria, etc. INTERACTIONS ØInhibits hepatic oxidation & causes rise in plasma levels of drugs like theophylline, carbamazepine, valproate, ergotamine, warfarin, terfanadine, astemizole & cisapride.

USES ØAs alternative to penicillins in streptococcal infections diptheria tetanus syphilis ØAs a first choice drug in atypical pneumonia caused by m. pneumoniae whooping cough chancroid (2 gm/day/7 days) ØAs a second choice drug in campylobacter enteritis (next to FQ) chlamydia trachomitis (500/6 hrs/7 days) penicillin resistant staphylococcal infections

ADVERSE EFFECTS ØRemarkably safer drug. ØGIT symptoms include mild to severe epigastric pain & ocassional diarrhea. ØVery high doses have caused reversible hearing impairment.

Tetracyclines Drug of choice in infections caused by Chlamydia, Rickettsia, Brucella and Lyme disease l Value has decreased due to increasing bacterial resistance l Tetracycline l l l Doxycycline l l Role in Helicobacter pylori eradication (less frequently used than other antibiotics) Once daily Minocycline l Broader spectrum

Antimicrobial spectrum • Many gram+ve & gram_ve cocci especially Neisseria. • Most gram+ve bacilli except Mycobacteria. • Sensitive gram_ve bacilli include H. ducreyi, V. cholera, Yersinia, H. pylori Brucella, Campylobacter, etc. • All chlamudiae & Rickettsiae are highly sensitive. • Spirochetes & Borrelia are quite sensitive. • Enterobacteriaceae are now largely resistant.

ADVERSE EFFECTS • Irritative effects like epigastric pain, nausea, diarrhoea, esophageal ulceration. DOSE RELATED • Liver damage– acute hepatic necrosis in pregnant women. • Kidney damage– Fancony syndrome is produced by outdated tetracyclines due to proximal tubular damage. • Phototoxicity – more with Demeclocycline & Doxycycline. • Teeth & bones. • Superinfection.

PRECAUTIONS • Should not be used in pregnancy, lactation & in children. • Avoided in pt’s on diuretics as blood urea may rise. • Used cautiously in renal or hepatic insufficiency. • Inactivation if mixed with penicillins. • May reduce insulin requirements. • Addition of tetracyclines with the anticoagulants may lead to serious bleeding episodes.

USES • First DOC in LGV Granuloma inguinale Chalmydial infections Atypical pneumonia Cholera Brucellosis Rickettsial infections • Second DOC to penicillins for anthrax, actinomycosis, etc ciprofloxacin for gonorrhoea cotrimoxazole for chancroid streptomycin for tularemia

Quinolones Nalidixic acid Ciprofloxacin Ofloxacin Pefloxacin Norfloxacin

Quinolones l Ciprofloxacin l l Levofloxacin l l Active vs. MSSA, Gram-negative and Pseudomonas Has activity vs. Streptococcus pneumoniae, but slightly less active towards Pseudomonas compared to ciprofloxacin Moxifloxacin l Has activity vs. anaerobes but less active towards Pseudomonas

Flouroquinolon interaction üPlasma conc. of Theophylline, caffiene, & warfarin are increased by C. floxacin. üNSAID’s may enhance CNS toxicity. üAntacids, Sucralfate, & Fe salts if given concurrently reduce absorption. USES: • UTI’s • Gonorrhoeas • Chacroid – 500 mg/BD/3 days. Excellent alt. To Cotrimoxazole. . CONTD……

FIRST CHOICE DRUGS IN Typhoid Bone, soft tissue, gynecological & wound infections Diabetic foot In combination therapy for T. B ADVERSE EFFECTS: üGIT symptoms like Nausea, Vomitting, Bad taste. üCNS – dizziness, headache, anxiety, insomnia, impairment of concentration and dextereit. (CAUTION WHILE DRIVING).

Carbapenems l Imipenem l l Meropenem l l Broad spectrum, covers Gram-positive, Gram-negative (including ESBL -producing strains), Pseudomonas and anaerobes Less seizure-inducing potential, can be used to treat CNS infections Ertapenem l l Lacks activity vs. Acinetobacter and Pseudomonas Has limited activity against penicillin-resistant pneumococci

Other antibiotics l Clindamycin l l Metronidazole l l l Vs. Gram-positive cocci and anaerobes Vs. anaerobes Preferred therapy in antibiotic associated diarrhoea (Clostridium difficile) than oral vancomycin, although unlicenced Vancomycin, teicoplanin l For Gram-positive organisms (including MRSA)

METRONIDAZOLE • Prototype Nitroimidazole with broad spectrum cidal activity. • A tissue amoebicide & highly active against anaerobic bacteria. • Probably acts by damaging DNA & cause cytotoxicity. • Selectively high activity against anaerobic organisms has suggested interference with e- transport from NADPH. • Found to inhibit cell mediated immunity, to induce mutagenesis & to cause radiosensitization.

PHARMACOKINETICS • Completely absorbed from small intestine. • Widely distributed in the body & various body fluids. • Metabolized in liver primarily by oxidation & Glucuronide conjugation. • Excreted in urine. CONTRAINDICATIONS • In neurological diseases, blood dyscrasias, 1 st trimester of pregnancy and chronic alcoholism.

ADVERSE EFFECTS ØRelatively frequent but non serious. ØAnorexia, Nausea, Metallic taste & Abdominal cramps are the most common. ØHeadache, Glossitis, Dryness of mouth & transient neutropenia are less frequent side effects. ØThrombophlebitis of injected vein. INTERACTIONS ØA disulfiram like intolerance to alcohol. ØEnzyme inducers like phenobarbitone & rifampin may reduce its therapeutics. ØCimetidine can reduce its metabolism. So dose to be decreased.

USES • Amoebiasis • Giardiasis • Trichomonas vaginitis • Many anaerobic infections • Pseudomembranous enterocolitis • Ulcerative gingivitis & trench mouth • H. pylori infections • Guinea worm infestations

MISCELLANEOUS ANTIBIOTICS CLINDAMYCIN üLincosamide antibiotic with mechanism of action & spectrum of activity similar to erythromycin. üInhibits most gram+ve cocci including penicillinase producing staph. , C. diptheria, nocardia, Actinomyces & Toxoplasma. üHighly active against anaerobes especially Bact. fragilis. üGood oral absorption & does not cross BBB. üAccumulates in neutrophils & macrophages. üMetabolised in liver & excreted in urine and bile. üT 1/2 – 3 hrs

üMajor adverse effect is diarrhea & pseudomembranous enterocolitis caused by C. difficle super infection. üEmployed for prophylaxis in colorectal/pelvic surgeries. üIn AIDS pt. , with pyrimethamine for toxoplasmosis, with primaquine for P. carinii pneumonia. üTopically used for infected acne vulgaris. üClindamycin, Erythromycin & Chloramphenicol exhibit mutual antagonism. üPotential neuromuscular blockers.

VANCOMYCIN ØGlycopeptide antibiotic discovered in 1956 as a penicillin substitute due to efficacy against MRSA, Str. viridans, Enterococcus, Cl. difficle. ØBactericidal. ØActs by inhibiting bacterial cell wall synthesis by binding to terminal D-ala-D-ala sequence. ØNot absorbed orally. ØAfter i. v, it is widely distributed , penetrates serous cavities, inflammed meninges & is excreted by urine.

ØT 1/2 of 6 hrs. ØToxicity cuses plasma conc. Dependent permanent deafness. kidney damage is also dose related. ØRapid i. v injection causes chills, fever, urticaria, & intense flushing this is REDMAN SYNDROME.

Other antibiotics l Cotrimoxazole l l l Nitrofurantoin l l Role in uncomplicated UTI, UTI prophylaxis, acute exacerbations of chronic bronchitis Pneumocystis carinii (now jiroveci) infections For UTI, prophylaxis vs. UTI Fusidic acid, rifampin l l For penicillin-resistant staphylococci Not for monotherapy due to risk of emergence of resistance

Linezolid (Zyvox®) l An oxazolidinedione l Spectrum of activity and indications l l l Vancomycin-Resistant Enterococcus faecium infections, including cases with concurrent bacteremia Nosocomial pneumonia caused by MSSA or MRSA or Strep pneumoniae (including MDRSP) Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, caused by MSSA or MRSA, Strep pyogenes, or Strep agalactiae Uncomplicated skin and skin structure infections caused by MSSA or Strep pyogenes. Community-acquired pneumonia caused by Strep pneumoniae (including MDRSP), including cases with concurrent bacteremia, or MSSA

MICROORGANISMS NOT SEEN ON GRAM STAIN Chlamydia SPP Mycoplasma SPP Legionella Pneumoniae Mycobacteriums Rickettsiae Spirochets

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - POSITIVE COCCI - AEROBIC Ø Ø Ø Staph. aureus Staph. epidermidis Strep pyogenes Strep pneumonia Strep viridans Enterococcus

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - POSITIVE BACILLI - AEROBIC Ø Listeria monocytogenes Ø Bacillus antheracis Ø Corynebacterium diphtheriae

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - NEGATIVE COCCI - AEROBIC Ø Neisseria. gonorrhoeae Ø Neisseria meningitidis Ø Moraxella catarrhalis

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - NEGATIVE BACILLI - AEROBIC Ø Ø Ø Ecoli Klebsiella. P Proteus. M Pseudomonas. A Enterobacter SPP Haemophilus. influenzae

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - POSITIVE COCCI - ANAEROBIC Ø Peptostreptococcus SPP Ø Peptococcus SPP

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - POSITIVE BACILLI - ANAEROBIC Ø Ø Ø Clostridium difficile Clostridium tetani Clostridium perfringens Propionibacterium acnes Actinomyces SPP

CATEGORIZATION OF MICROORGANISMS BY GRAM STAINING CHARACTERISTICS & OXGGEN TOLERANCE GRAM - NEGATIVE BACILLI - ANAEROBIC Ø Bacteroides fragilis Ø Fusobacterium SPP

ANTIBIOTIC SELECTION BASED ON MICROBIOLOGY G. P. C G. N. B G. P. B Penicillins - Cephalos Porins Aminoglycosides ( ) - Macrolides Penicillins - Cephalos Porins Macrolides Aminoglycosides - Cephalosporins Penicillins - Cephalosporin

ANAEROBIC MICROORGANISMS Penicillins Clindamycin Metronidazole Cefoxitin