Antimicrobial Chemotherapy PDF

ANTIMICROBIAL CHEMOTHERAPY MATTHEW AIDOO Department of Phar macolog y and Toxicolog y School of Phar macy and Phar maceutical Sciences University for Development Studies, Tamale  OUTLINE ❑INTRODUCTION ❑ACTIVITY/SPECTRUM OF AMAs ❑CLASSIFICATION OF AMAs ❑PROBLEM OF AMAs ❑SELEC...

ANTIMICROBIAL CHEMOTHERAPY MATTHEW AIDOO Department of Phar macolog y and Toxicolog y School of Phar macy and Phar maceutical Sciences University for Development Studies, Tamale  OUTLINE ❑INTRODUCTION ❑ACTIVITY/SPECTRUM OF AMAs ❑CLASSIFICATION OF AMAs ❑PROBLEM OF AMAs ❑SELECTION OF AMAs ❑COMBINATION OF AMAs ❑FAILURE OF AMAs  INTRODUCTION ❑CHEMOTHERAPY: chemo + therapy The use of drug (chemical entity or substance derived form microorganisms) to eradicate pathogenic organisms or neoplastic cells in the treatment of infectious diseases or cancer ❖ANTIBIOTICS Antibiotics are natural substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms (at very low concentration)  INTRODUCTION ❑ANTIMICROBIAL AGENT (chemotherapeutic agent + Antibiotics) Any substance of natural, synthetic or semisynthetic origin which at low concentrations kill or inhibits the growth of microorganisms but causes little or no host damage ❑Chemotherapy is based on the principle of selective toxicity This requires utilization of metabolic or structural differences between normal human cells and disease-producing cells. The more closely related the disease-producing cells are to normal human cells, the more difficult to achieve selective toxicity  ANTIMICROBIAL ACTIVITY ❑Cidal - (bacteriocidal, vermicide, fungicidal, virucidal) Drug kills sensitive organisms so that the number of viable organisms falls rapidly after exposure to the drug ❑Static – (bacteriostatic, vermifuge, fungistatic, virustatic) Drug inhibits the growth of organisms but does not kill them. Hence, the number of viable organism remains relatively constant in the presence of a static drug, and immunologic mechanisms (host) are required to eliminate organisms during treatment of an infection with this type of drug  ANTIMICROBIAL SPECTRUM ❑Narrow spectrum Antimicrobial agents that are active against a single species or a limited group of pathogens. Preferred if the specific causative pathogen of an infection is known and non- serious infections. ❑Broad spectrum Antimicrobial agents that are active against a wide range of pathogens. Preferred when the pathogen is not yet known or multiple pathogens identified and serious infections.  CLASSIFICATION OF AMAs ❑Chemical structure Beta-lactams, triazoles, nucleoside/nucleotide reverse transcriptase inhibitors, nitroimidazoles, benzimidazoles, Aminoquinolines ❑Type of action (Cidal or static) Bacteriostatic, bactericidal, fungicidal , fungistatic, viricidal, virostatic, vermicidal, vermifuge. ❑Type of organisms (primary active against) Antibacterial, Antiviral, Antifungal, Antiprotozoal, Antihelminthic  CLASSIFICATION OF AMAs ❑Sources Fungi: penicillins, griseofulvin, Bacteria: polymyxin B, bacitracin, colistin, Actinomyces: amphotericin B, aminoglycosides, macrolides, tetracyclines, polyenes. ❑Mechanism/site of action Protease inhibitors, Integrase Inhibitors, Cell wall inhibitors, Protein synthesis inhibitors, Nucleic acid synthesis inhibitors etc. ❑Spectrum of activity Narrow spectrum, Broad spectrum, or Extended spectrum  PROBLEMS WITH AMAs ❑TOXICITY ❖Local toxicity Toxicity exerted at site of administration. E.g. gastric irritation, pain, abscess, thrombophlebitis at the site of injection. ❖Systemic toxicity Dose related organ damage. E.g. tetracycline –discoloration of teeth, aminoglycosides – nephrotoxicity and ototoxicity , chloramphenicol – grey baby syndrome etc.  PROBLEMS WITH AMAs ❑HYPERSENTIVITY REACTION Inappropriate or exaggerated response to an antigen or allergen. These reactions are unpredictable and unrelated to dose. E.g. Penicillin, Nevirapine, Clindamycin. ❑SUPERINFECTION A new infection occur in a patient with preexisting infection due to use of AMAs (mostly in immunocompromised patients). Bacterial superinfection in viral respiratory disease Infection of a chronic hepatitis B carrier with hepatitis D virus Piperacillin-tazobactam may cause superinfection with candida  PROBLEMS WITH AMAs ❑DRUG RESISTANCE Unresponsiveness of a microorganism to an AMA, and is similar to the phenomenon of drug tolerance. Two (2) types Natural/Intrinsic resistance: Some microbes have resistant to certain AMAs. E.g. gram negative bacilli not affected by penicillin G; M. tuberculosis insensitive to tetracyclines. Acquired resistance: Development of resistance genes/mechanisms by microorganisms due exposure to AMAs.  SELECTION OF AMAs ❑PATIENT-PATHOGEN-DRUG RELATIONSHIP Pharmacokinetics – patient effect on drug Pharmacodynamics – drug effect on patient Immunity – patient effect on pathogen Sepsis – pathogen effect on patient Selective toxicity – drug effect on pathogen Resistance – pathogen effect on drug  SELECTION OF AMAs ❑PATIENT RELATED FACTORS Patient age – avoid certain AMAs (tetracycline in children) Renal and hepatic function – aminoglycoside- caution in renal failure; erythromycin, tetracycline – caution in liver failure History of drug allergy – Syphilis patient allergic to penicillin, use tetracycline – Fluoroquinolones cause erythema multiform Patient immunity – limit use of broad spectrum AMAs Pregnancy – caution/contraindication of certain AMAs Genetic factors – G6PD-deficiency and sulfonamides  SELECTION OF AMAs ❑DRUG RELATED FACTORS Type of activity – systemic vs non-systemic Spectrum of activity – Narrow vs broad spectrum Sensitivity of the organism – MIC, MBC Pharmacodynamic profile – Side effects/Adverse effects Pharmacokinetic profile – ADME Route of administration – enteral, parenteral, topical Cost – cost effectiveness  SELECTION OF AMAs ❑PATHOGEN RELATED FACTORS A clinical diagnosis Empirical choice of AMAs selected Specific choice of AMAs to be based on microbial examination (Antimicrobial Susceptibility Testing)  COMBINATION OF AMAs ❑AMAs may be combined for the ff reasons: To prevent resistance – combined antiretroviral agents, Amoxicillin/Clavulanic acid. To achieve synergism – Rifampin+ isoniazid for M. tuberculosis To broaden the spectrum of antimicrobial action (Cotrimoxazole: Trimethoprim/sulfamethoxazole) To reduce toxicity – Amphotericin B + rifampin (rifampin enhance the antifungal activity of amphotericin B).  FAIULRE OF AMAs ❑Common causes of AMAs failure include Improper selection of AMAs, and dosage Treatment begun too late Failure to take necessary precaution measures Poor immunity Trying to treat untreatable (viral) infections Presence of dormant or altered organisms which later give risk to a relapse. ANTIBACTERIAL AGENTS MATTHEW AIDOO Department of Phar macolog y & Toxicolog y School of Pharmacy and Phar maceutical Sciences University for Development Studies, Tamale  OUTLINE ❑STRUCTURE OF BACTERIAL CELL ❑BIOCHEMICAL REACTIONS OF BACTERIA ❑TARGETS OF ACTION OF ANTIBACTERIAL AGENTS ▪FOLATE SYNTHESIS ▪CELL WALL SYNTHESIS ▪PROTEIN STNTHESIS ▪NUCLEIC ACID SYNTHESIS ▪FORMED CELL  STRUCTURE OF BACTERIAL CELL ❑Bacteria are prokaryotes (cells without nuclei) ❖Cell wall – all contain peptidoglycan (except mycoplasma). Protects the cell membrane from damage. Supports cell membrane to resist high internal osmotic pressure. ❖Cell membrane – Functions as selectively permeable membrane with specific transport mechanisms for various nutrients. ❖Cytoplasm – contains macromolecules, ribosomes, chromosome (DNA). Protein synthesis, and energy generation takes place here.  STRUCTURE OF BACTERIAL CELL ❖ Outer membrane outside the cell wall in gram-negative bacteria is the outer membrane. It prevents penetration of some antibacterial agents and easy access of lysozyme to the cell wall. Gram-positive bacteria do not have OM.  BIOCHEMICAL REACTIONS A. Class I – utilization of glucose or alternative carbon source for generation of energy (ATP) and simple carbon compounds. B. Class II – utilization of energy (ATP) and simple carbon compounds to produce small molecules e.g. folate, amino aids, nucleotides, phospholipids, carbohydrates etc. C. Class III – assembly of small molecules into macromolecules e.g. proteins, nuclei acids (RNA, and DNA, peptidoglycan etc. TARGETS OF ACTION  FOLATE SYNTHESIS INHIBITORS ❑Bacteria synthesize folate (tetrahydrofolate) from paraaminobenzoic acid (PABA) and pteridine. Tetrahydrofolate is used as precursor for purine and DNA synthesis  FOLATE SYNTHESIS INHIBITORS ❑SULFONAMIDES Contain sulfanilamide; a structural analogue of PABA, which compete with PABA for the enzyme involved in folate synthesis.  FOLATE SYNTHESIS INHIBITORS ❑SULFONAMIDES (Bacteriostatic) E.g. Sulfamethoxazole, Sulphisoxazole Use during pregnancy only if potential benefit justifies potential risk to fetus (neural tube defects, oral clefts, club foot) Avoid breastfeeding during therapy due to potential risk of bilirubin displacement and kernicterus on breastfed child Avoid in G6PD deficient patients, sulfonamide group can act as oxidant and induce oxidative stress causing hemolytic anemia in patients with G6PD deficiency.  FOLATE SYNTHESIS INHIBITORS ❑SULFONAMIDES (Bacteriostatic) Hypersentivity reactions e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis [due to arylamine group at N4] Bone marrow suppression; anemia, leukopenia, thrombocytopenia (caution in aplastic anemia, SCD) Crystalluria (the acetylated metabolite can precipitate at neutral or acidic pH in urine causing crystalluria); take enough water to avoid crystalluria.  FOLATE SYNTHESIS INHIBITORS ❑TRIMETHOPRIM For the Bacteria to utilized folate, dihydrofolate has to converted to tetrahydrofolate (active form) by dihydrofolate reductase enzymes. Trimethoprim inhibits dihydrofolate reductase to prevent synthesis of tetrahydrofolate.  FOLATE SYNTHESIS INHIBITORS ❑TRIMETHOPRIM (bacteriostatic) It causes folate deficiency with resultant megaloblastic anemia – can be prevented by giving Folinic acid. Trimethoprim and Sulfonamide are both bacteriostatic. Trimethoprim + Sulfamethoxazole (Co-trimoxazole) is thought to be synergistic and may be bactericidal in certain cellular conditions.  CELL WALL SYNTHESIS ❑CELL WALL SYNTHESIS Peptidoglycan constitutes the cell wall of the bacteria. Gram-negative organisms have a single thickness whilst gram- positive organisms have up to 40 layers thick. Each layer consists of backbones of amino sugars, alternating: N-acetylglucosamine and N-acetylmuramic acid residue. N-acetylmuramic acid residue have short peptide side-chains that are cross-linked to form a polymeric lattice, which is strong enough to resist the high internal osmotic pressure. CELL WALL SYNTHESIS INHIBITION ❑Synthesis of peptidoglycan is a vulnerable step and can be blocked at several points by antibacterial agents. Drugs that inhibit cell wall synthesis are bactericidal agents CELL WALL SYNTHESIS INHIBITION ❑GLYCOPEPTIDES (Vancomycin, Teicoplanin) Inhibits cell-wall synthesis by blocking glycopeptide polymerization.  CELL WALL SYNTHESIS INHIBITORS ❑GLYCOPEPTIDES (Vancomycin, Teicoplanin) ❖VANCOMYCIN Used for pseudomembranous colitis, clostridium difficile- associated diarrhea, infective endocarditis, septicemia. Renally excreted (IV; 80–90% as unchanged drug) and oral primarily excreted in faeces. Dose reduction and monitoring of serum levels in renal impairment especially with IV. It is excreted in human milk, use with caution in lactation. CELL WALL SYNTHESIS INHIBITION ❑BETA-LACTAMs Inhibit the final transpeptidation that establishes the cross- links of peptidoglycan by forming covalent bonds with penicillin-binding proteins (PBP) via binding to the transpeptidase active site of PBP. This prevents cross-linking (i.e. binding between pentaglycine peptides and tetra-peptide side chains on NAM). E.g. Penicillins, Cephalosporins, Monobactams, Carbapenems CELL WALL SYNTHESIS INHIBITORS CELL WALL SYNTHESIS INHIBITORS CELL WALL SYNTHESIS INHIBITORS ❑PENICILLINS Diffuse well into body tissues and fluids but penetration into CNS is poor except when the meninges are inflamed Dose reduction may be essential in renal impairment – most penicillins primarily excreted renally. The most important side effect is hypersentivity reaction which causes rashes (non-severe) and anaphylaxis (severe life threatening). Penicillin skin test may be necessary. Treatment of hypersentivity reaction include antihistamines, or adrenaline, or corticosteroids. CELL WALL SYNTHESIS INHIBITORS ❑PENICILLINS Penicillins should not be given by intrathecal injection because they can cause encephalopathy. Penicillins can cause accumulation of electrolytes Some injectable penicillins contains sodium salts (caution in hypertensive patients) Some injectable penicillins contains potassium salts (caution in patients with hyperkalemia).  CLASSIFICATION OF PENICILLINS ❑NATURAL PENICILLINS These penicillins are most active against non-beta lactamase gram-positive bacteria and Enterococcus species. Examples ❖Benzylpenicilin [penicillin G] (benzathine and procaine penicillin) – inactivated by gastric acid and absorption from the gut is low, therefore it is given by injection. ❖Phenoxymethylpenicillin [penicillin V]– it is gastric acid stable, thus given orally. Has same activity as benzylpenicilin.  CLASSIFICATION OF PENICILLINS ❑PENICILLINASE SUSCEPTIBLE PENICILLINS Staphylococcus sp, Bacteroides sp, Neisseria gonorrhea, Moraxella catarrhalis and Heamophilus sp, produce penicillinase enzymes that hydrolyze beta-lactam rings. These penicillins are inactivated by the bacterial beta- lactamases (penicillinase) E.g. Benzylpenicilin , Phenoxymethylpenicillin, Amoxicillin, Ticarcillin, and Piperacillin.  CLASSIFICATION OF PENICILLINS ❑PENICILLINASE RESISTANT PENICILLINS These penicillins are not inactivated by beta-lactamases bacteria E.g. ampicillin, flucloxacillin, cloxacillin, dicloxacillin, [methicillin, and nafcillin, oxacillin – resistant to enterococci). Clavulanic acid, Tazobactam and Sulbactam (active against beta-lactamases) Avibactam, Vaborbactam, and Relebactam (active against carbapenemase)  CLASSIFICATION OF PENICILLINS ❑AMINOPENICILLINS These penicillins have broad spectrum activity (gram positive and negative) and some enterobcteriaceaes. ❖Ampicillin – absorption is decreased by the presence of food in the stomach. ❖Amoxicillin – a derivative of ampicillin and better absorbed orally, absorption not affected by presence of food in the stomach  CLASSIFICATION OF PENICILLINS ❑ANTIPSEUDOMONAL PENICILLINS These penicillins are active against pseudomonas aeruginosa. They are administered only parenterally. ❖Carboxypenicillins (e.g. Ticarcillin) – only available as Ticarcillin + Clavulanic acid (active against beta-lactamases) ❖Ureidopenicillins (Piperacillin, Mezlocillin, Azlocillin) – Piperacillin + Tazobactam. Piperacillin is more active than ticarcillin against pseudomonas aeruginosa.  CEPHALOSPORINS ❑Broad spectrum with similar activity to penicillins Principally excreted renally, thus dose modification is required in renal impairment. Cephalosporins penetrate the CNS poorly unless inflamed (exception; Cefotaxime) Cephalosporins most active against pseudomonas aeruginosa; Ceftazidime, Cefoperazone, Ceftriaxone, Cefepime. Principal SE is hypersentivity reactions, and about 3% of penicillin-sensitive patients will also be allergic to CPS.  CEPHALOSPORINS CLASSFICATION CLASS 1ST GEN 2ND GEN 3RD GEN 4TH GEN 5TH GEN Gram+ +++ ++ + +++ ++++ bacteria Gram- + +++ ++++ ++++ ++++ bacteria E.g. Cefazolin Cefuroxime Ceftriaxone Cefepime Ceftaroline Cephalothin Cefprozil Ceftazidime (Not active Cephapirin Cefaclor Cefotaxime against Cephradine Cefpodoxime P. aeruginosa) Cephalexin Cefmetazole Cefixime Active against Cefadroxil Cefoxitin Ceftibuten MRSA Cefotetan Cefoperazone  CEPHALOSPORINS ❑CEFTRIAXONE Avoid in premature neonates and in neonatal jaundice – ceftriaxone can displace bilirubin from albumin-binding sites, causing hyperbilirunemia in premature neonates. Use with caution in breastfeeding women – ceftriaxone can displace bilirubin from albumin-binding sites, increasing risk of kernicterus in the baby. Do not give ceftriaxone concurrently with calcium containing products (e.g. ringers lactate) – risk of calcium- ceftriaxone precipitant formation in the lungs, and kidneys of term and preterm neonates.  CARBAPENEMS ❑Broad spectrum agents with activity against anaerobes They are NOT active against MRSA Some may NOT be effective against gram-negative bacteria like enterococcus faecium, klebsiella pneumoniae, pseudomonas aeruginosa because these produce different class of beta-lactamases called carbapenemases. Imipenem-Cilastatin-Relebactam Meropenem-Vaborbactam  CARBAPENEMS ❑IMIPENEM It is partially inactivated in the kidney by enzymatic activity (dihydropeptidase) It is therefore administered with Cilastatin (a specific inhibitor of dihydropeptidase) and thus blocks renal inactivation of Imipenem. Neurotoxicity has been observed at very high dosage, in renal failure or in patients with CNS disease  CARBAPENEMS ❑MEROPENEM It is similar to Imipenem in activity It is stable to renal enzyme which inactivates imipenem and can thus be given without Cilastatin. It has less seizure-inducing potential and can be used for CNS infections  CARBAPENEMS ❑DORIPENEM Similar in activity to Imipenem and Meropenem It also stable to renal enzymatic inactivation. Active against pseudomonas aeruginosa. ❑ERTAPENEM It also stable to renal enzymatic inactivation. It is not active against P. aeruginosa unlike meropenem and imipenem.  MONOBACTAM ❑AZTREONAM Monocyclic beta-lactam (monobactam) with activity against gram-negative aerobic bacteria e.g. P. aeruginosa, N. meningitides and H. influenza. It is a narrow-spectrum antibacterial agent It should not be used alone for blind treatment because it is not active against gram-positive and anerobic bacteria. Aztreonam binds poorly to PBP sites of gram-positive and anerobic bacteria and thus has relatively poor inhibitory effects against them.  PROTEIN SYNTHESIS ❑Protein synthesis is an essential requirement of any cell. In eukaryotes, protein synthesis occurs with the 40S (Svedberg) and 60S subunits. In prokaryotes, such as bacteria, protein synthesis occurs in 30S and 50S ribosomal subunits. The differences in the ribosomes in prokaryotes (70S) and eukaryotes (80S), provides the basis for selective toxicity. The ribosome [50S subunit] has three binding site for tRNA; the A (aminoacyl), P (peptidyl) and E (exit), and [30S subunit] has a binding site for mRNA. PROTEIN SYNTHESIS  PROTEIN SYNTHESIS INHIBITION ❑TETRACYCLINES (bacteriostatic) Binds to the 30S RSU, and possibly 50S RSU. They compete with tRNA for the A site of the ribosome. E.g. Tetracycline, Oxytetracycline, Demecycline, Doxycycline, Minocycline, Methacycline, Demeclocycline, Tigecycline, Eravacycline.  PROTEIN SYNTHESIS INHIBITORS ❑TETRACYCLINES (bacteriostatic) Absorption of tetracyclines are impaired by food in the gut. Except minocycline and doxycycline. Antacids, aluminum, calcium, iron, magnesium, zinc salts and milk decrease absorption of tetracyclines. Deposition in growing bones (reversible inhibition of bone growth) and teeth (permanent discoloration and dental hypoplasia) by binding to calcium. Thus, tetracyclines should not be given to children below 12 years, pregnant woman and breastfeeding women.  PROTEIN SYNTHESIS INHIBITION ❑TETRACYCLINES (bacteriostatic) These tetracyclines should be used with caution in patients with hepatic impairment: (Minocycline, Doxycycline, Tigecycline, and Eravacycline). Primarily eliminated hepatically (in bile; feces). These tetracyclines should be used with caution in patients with renal impairment: (Minocycline, Tetracycline, Oxytetracycline, Methacycline, Demeclocycline). Primarily eliminated renally  PROTEIN SYNTHESIS INHIBITION ❑AMINOGLYCOSIDES (Bactericidal) Binding to the 30S ribosomal subunit, distorting its structure and causing misreading of mRNA. Their penetration into bacteria cell membrane, depends partly on an oxygen-dependent active transport by a carrier system and thus have minimal action against anaerobic organisms. Their transport into cell membrane is blocked by Chloramphenicol and enhanced by agents that interfere with cell wall synthesis (Beta-lactams).  PROTEIN SYNTHESIS INHIBITION ❑E.g. Gentamicin, Amikacin, Neomycin, Streptomycin, Tobramycin, Netilmicin.  PROTEIN SYNTHESIS INHIBITION ❑AMINOGLYCOSIDES They are highly polar cations and therefore poorly absorbed from the GIT, thus given parenterally for systemic therapy. They should preferably not be given concurrently with ototoxic diuretic (e.g. furosemide) if not possible separate dosing by a practicable long period. Aminoglycosides have require serum monitoring to avoid supra or sub therapeutic levels especially in renal disease.  PROTEIN SYNTHESIS INHIBITORS ❑AMINOGLYCOSIDES Excretion is principally by the kidney and accumulation occurs in renal impairment, hence dose reduction in renal impairment and elderly patients The important side effects are ototoxicity and nephrotoxicity; they occur commonly in the elderly and in patients with renal failure. Nephrotoxicity and ototoxicity are dose and duration dependent. Paralysis may occur when given concurrently with NMBA PROTEIN SYNTHESIS INHIBITION ❑MACROLIDES (bacteriostatic/bactericidal) Bind to the 50S ribosomal subunit This blocks the transfer of peptidyl tRNA from the A-site to the P-site of the ribosome, thus preventing the elongation of the polypeptide chain. The binding site of macrolides is the same as Chloramphenicol and Clindamycin and thus these agents could compete if given concurrently. PROTEIN SYNTHESIS INHIBITION ❑MACROLIDES Erythromycin, Azithromycin, Clarithromycin, Roxithromycin Spectinomycin PROTEIN SYNTHESIS INHIBITION ❑MACROLIDES Macrolides should not be given concurrently with Chloramphenicol and Clindamycin – these agents bind to the same site (50S ribosomal subunit of bacteria). Caution in hepatic disease – hepatic dysfunction or cholestatic jaundice associated with use of macrolides. Avoid in patients with cardiac arrhythmias – prolongs cardiac repolarization and QT interval. Clostridium difficile associated diarrhea (CDAD) has been reported with macrolides.  PROTEIN SYNTHESIS INHIBITORS ❑MACROLIDES Azithromycin and clarithromycin more acid stable, and erythromycin is acid labile. Concurrent use with ergotamine or dihydroergotamine can cause vasospasm and ischemia of extremities and CNS symptoms (i.e. Ergotism) Erythromycin, and Clarithromycin are enzyme inhibitors and increases serum levels of drugs that are metabolized by CYP3A4 (e.g. simvastatin, colchicine, benzodiazepines) INHIBITION OF PROTEIN SYNTHESIS ❑CHLORAMPHENICOL (Bacteriostatic) It is primarily bacteriostatic but can be bactericidal in high concentrations against some bacteria. Binding to the 50S subunit of the bacterial ribosome It inhibits the action of peptidyl transferase, thus preventing transpeptidation (i.e. transfer of peptide chain from peptidyl tRNA to aminoacyl tRNA)  PROTEIN SYNTHESIS INHIBITORS ❑CHLORAMPHENICOL (Bacteriostatic) Serious and fetal blood dyscrasias, (including aplastic anemia, thrombocytopenia, and granulocytopenia). Grey baby syndrome in premature neonates – due to under- developed UDP-glucuronyl transferase enzyme to metabolize excessive drug levels for excretion (serum levels > 50 mcg/mL after repeated dose). Furthermore, there is insufficient renal excretion of the unconjugated chloramphenicol. Avoid chloramphenicol in lactation or do not nurse Use with caution in pregnancy, and premature neonates.  PROTEIN SYNTHESIS INHIBITION ❑LINCOSAMIDES (Clindamycin) Binding to the 50S subunit (23S RNA) of the bacterial ribosome. It prevents peptide formation (translation of amino acids to longer chain) thereby inhibits protein synthesis. Bacteriostatic or bactericidal depending on the drug concentration, organism and infection site. Active against gram positive organisms, anerobic organism and minimal effect on gram-negative organisms.  PROTEIN SYNTHESIS INHIBITION ❑LINCOSAMIDES (Clindamycin)  PROTEIN SYNTHESIS INHIBITORS ❑LINCOSAMIDES (Clindamycin) Poor penetration into cerebrospinal fluid and thus should not be used for CNS infections (meningitis) Clindamycin has good penetration into joints and bones, and it is thus use for infections at these sites. Use with caution in hepatic impairment, monitor for hepatic abnormalities. Severe skin reaction including toxic epidermal necrolysis, and Stevens-Johnson syndrome can occur. Discontinue drug permanently if reactions occurs.  PROTEIN SYNTHESIS INHIBITION ❑STREPTOGRAMINS (Quinupristin/Dalfopristin ) They are two types of chemically different compounds, group A (Dalfopristin) and group B (Quinupristin). Individually they exhibit only very modest bacteriostatic activity but their combination offer bactericidal effect. Dalfopristin changes the structure of the ribosome so as to promote the binding of Quinupristin. The combination is effective against MRSA and vancomycin-resistant enterococcus faecium.  PROTEIN SYNTHESIS INHIBITION ❑STREPTOGRAMINS (Quinupristin/Dalfopristin ) Binds sequentially to the 50S ribosomal subunit. They block the translation of mRNA into protein. Both group A and group B bind to peptidyl-transferase domain of the bacterial ribosome. Group A streptogramin inhibits the elongation of the polypeptide chain. Group B streptogramin stimulates the dissociation of peptidyl-tRNA from the ribosome.  PROTEIN SYNTHESIS INHIBITION ❑LINEZOLID (OXALIZIDONONES) Binds to 50S ribosomal subunit. They block the translation of mRNA into protein. Useful for methicillin-resistant satph. aureus, penicillin- resistant streptococcus pneumonia, and vancomycin resistant enterococci.  PROTEIN SYNTHESIS INHIBITION ❑FUSIDIC ACID (Bactericidal) It bind to the 50s RSU similar to the macrolides It inhibits translocation It is narrow spectrum mostly against gram-positive bacteria (e.g. staphylococcus) It is well absorbed from the gut and distributed widely in the tissues  NUCLEIC ACID SYNTHESIS ❑It is possible to interfere with nucleic acid synthesis in the following ways; ▪Inhibiting the synthesis of the nucleotides (e.g. fluorouracil, mercaptopurine) ▪Altering the base-pairing properties of the template (e.g. acriflavin) ▪Inhibiting DNA or RNA polymerase (e.g. dactinomycin, rifampicin) ▪Inhibiting topoisomerases (e.g. fluoroquinolones) ▪Direct effects on DNA itself (e.g. mitomycin)  NA SYNTHESIS INHIBITION ❑QUINOLONES (Bactericidal) It blocks bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents relaxation of supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV probably interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division.  NA SYNTHESIS INHIBITORS ❑CIPROFLOXACIN Use with caution in patients with history of epilepsy – decrease seizure threshold and may induce convulsions. Caution in pediatrics – risk of tendonitis or tendon rapture. Caution in pregnancy but contraindicated in lactation Do not use concurrently with antacids (magnesium, aluminum), milk, dairy products interfere with absorption of quinolones. Avoid in G6PD deficiency (full defect) – Ciprofloxacin and Nalidixic acid  NA SYNTHESIS INHIBITION ❑CIPROFLOXACIN Phototoxicity reactions occur, Avoid excessive sunlight or UV radiation exposure during treatment and for 48 hours after stopping treatment. Caution in renal impairment, dose reduction required Prolongation of QT interval avoid concomitant use with macrolides especially Azithromycin. Ciprofloxacin increases the level of theophylline via inhibition of CYP3A45 enzymes, Avoid or use alternative drug.  QUINOLONES CLASSIFICATION Class 1ST GEN 2ND GEN 3RD GEN 4TH GEN Gram - + ++ +++ positive Gram ++ , but not +++ +++ +++ negative Pseudomonas Examples Nalidixic acid Ciprofloxacin Levofloxacin Trovofloxacin Oxolinic acid Norfloxacin Spafloxacin Cinoxacin Ofloxacin Moxifloxacin Rosoxacin Enoxacin Gatifloxacin Lomefloxacin Pefloxacin  NA SYNTHESIS INHIBITION ❑NITROIMIDAZOLE The MOA involves reduction of the nitro group on these drugs by nitroreductases produced by susceptible organisms. This results in the formation of a highly reactive intermediates that disrupts the organism’s DNA. These antimicrobial agents are only active in anaerobic conditions because oxygen will compete with antibiotic for electrons necessary in the nitroreductases reaction  NA SYNTHESIS INHIBITION ❑NITROIMIDAZOLE Effective against gram-positive or gram-negative anaerobic bacteria, and also against Entamoeba histolytica, Giardia lamblia. Examples Metronidazole Tinidazole Secnidazole Nimorazole Ornidazole  NA SYNTHESIS INHIBITION ❑METRONIDAZOLE Contraindicated in pregnancy (causes cleft lip/palate), Except, 1st trimester in trichomoniasis and bacterial vaginosis infection. Caution in lactation – potential tumorigenicity in animal studies, discontinue lactating or discontinue drug. Contradicted – Use of alcohol during therapy or 3 days of discontinuing therapy; use of disulfiram within past 2 weeks. Caution in hepatic impairment, dose reduction required. Blood dyscrasia; agranulocytosis, leukopenia, and neutropenia have been associated with use.  PROTEIN & NUCLEIC ACID SYNTHESIS INHIBITION ❑NITROFURANTOIN (Bactericidal) It inactivates bacterial proteins synthesis and other macromolecules that may interfere with metabolism and cell wall synthesis. It is converted by bacterial nitroreductases to electrophilic intermediates which inhibit the citric acid cycle as well synthesis of protein, DNA, and RNA It is broad spectrum. It’s use is confined to the treatment of urinary tract infections. Avoid in G6PD deficient patents. FORMED STRUCTURE OF THE CELL ❑CELL MEMBRANE (bactericidal) ❖POLYMIXINS Cationic detergents that have selective effect on bacterial cell membranes. They interact with the phospholipids of bacteria cell membrane and disrupts its structure They mostly used for antibacterial topical infection. THANK YOU