Antimikroba, Antiparasit & Antivirus

Edy Junaidi

Antimikroba

Efek antibakterial :

Bakteriostatik Bakterisid Narrow spectrum Broad spectrum Natural resistance Acquired resistance

Spektrum efek antibakterial

Mekanisme resistensi

Selection of Antimicrobial agents

Optimal selection require :

Clinical judgement Detailed knowledge of pharmacological properties Microbiological factors Empirical therapy Definitive therapy Prophylactic therapy

General Use of Antibiotics :

Indications Combination of antibiotic agents

Empirical Therapy of Severe Infections in Which a Cause is Unknown Treatment of Polymicrobial Infections Enhancement of Antibacterial Activity in the Treatment of Specific Infections Prevention of the Emergence of Resistant Microorganisms Increased risk of toxicity Selection of multiple-drug-resistant microorganisms Eradication of normal host flora with subsequent superinfection Increased cost

Disadvantages :

Misuses of Antibiotics

Treatment of nonresponsive infections Therapy of fever of unknown origin Improper dosage Inappropriate reliance on chemotherapy alone Lack of adequate bacteriological information

General Mechanisms

Inhibitors of Cell Wall Synthesis

Structural stability of cell wall mainly constructed by murine (peptidoglycans) lattice, consist of:

N-acetylglucosamine N-acetyl muramic acid Penicillin & derivatives Cephalosporins Bacitracin Vancomycin

Formabuildingblockof cellwall

Inhibitors of cell wall synthesis bactericidal

Penicillins
DerivativesofPenicillinG

-lactamase inhibitors :

Clavulanic acid (the only available for oral use) Sulbactam Tazobactam

Combine with -lactam antibiotics to overcome penicillinase activity Ampicillin sulbactam, ticarcillin clavulanic acid, piperacillin tazobactam, amoxycillin clavulanic acid All except amoxycillin clavulanic acid are parenteral formulation

Cephalosporins

Semisynthetic antibiotics, classified according to antibacterial spectrum & stability to -lactamase The cephalosporins distribute in satisfactory concentrations to most tissues except the central nervous system.

Only cefepime, cefuroxime (Zinacef), cefotaxime (Claforan), ceftriaxone (Rocephin), and ceftazidime (Fortaz) achieve therapeutic concentrations in cerebrospinal uid

Inhibitors of Tetrahydrofolate Synthesis

Tetrahydrofolic acid (THF) a coenzyme in the synthesis of purine bases and thymidine constituents of DNA and RNA required for cell growth and replication Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim (bacteriostatic) Sulfonamide possess structural resemblence to PABA false substrate inhibit utilization of PABA Trimethoprim is a highly selective inhibitor of dihydrofolate reductase of lower organisms; ~100,000 times more drug is required to inhibit human reductase than the bacterial enzyme

Dihydrofolate reductase

Classification of Sulfonamides based on extend or rapidity of absorption and excretion Absorbed and excreted rapidly ( sulfisoxazole, Sulfamethoxazole and sulfadiazine)

Absorbed very poorly when administered orally and hence are active in the bowel lumen (sulfasalazine) Mainly used topically (sulfacetamide, mafenide, and silver sulfadiazine) Long-acting sulfonamides (Sulfadoxine)

Clinical Use

Urinary tract infections Nocardiosis Toxoplasmosis Bacterial Respiratory Tract Infections Gastrointestinal Infections Infection by Pneumocystis jiroveci Prophylaxis in Neutropenic Patients

Adverse Effects

May cause or precipitate megaloblastosis, leukopenia, or thrombocytopenia in folate-deficient patients narrowing safety margin Dermatologic reactions, severe cases primarily in older patients Transient jaundice with histological features of allergic cholestatic hepatitis Displacement of other plasma protein-bound drugs or bilirubin in neonates (danger of kernicterus : contraindication for the last weeks of gestation and in the neonate) Hypersensitivity reactions

Inhibitors of DNA Function

Synthesis of new DNA is a prerequisite for cell division inhibition of reading of genetic information at the DNA template damage the regulatory center of cell metabolism Interfere supercoiling of double helical configuration prevent specifically the resealing of opened strands bactericidal Nalidixic acid (older drug) attains effective concentrations only in urine urinary antiseptics, affects exclusively Gram-negative bacteria Other quinolones (Norfloxacin, Ofloxacin, ciprofloxacin, enoxacin, and others) achieve effective concentration systemically used for infections of internal organs

Gyrase Inhibitors

Quinolones damage epiphyseal chondrocytes and joint cartilages should not be used during pregnancy, lactation, and periods of growth Several reports on hepatic damage, prolongation of the QT-interval with risk of arrhythmias, and phototoxicity Reactive metabolites attack DNA damage DNA by complex formation or strand breakage Bactericidal effect Occurs in obligate anaerobic bacteria & shows antiprotozoal action (Trichomonas vaginalis, Entamoeba hystolitica) Potentially mutagenic, carcinogenic, and teratogenic in humans, it should not be used for longer than 10 days Avoid use during pregnancy and lactation

Nitroimidazole derivatives (Metronidazole, Timidazole)

Inhibitors of Protein Synthesis

Protein synthesis involves amino acid assembly to form peptides protein, occurs at ribosomes Antibiotics of different groups affecting protein synthesis by interfering steps amino acid incorporation into peptide chains Inhibit the binding of tRNAAA complexes Bacteriostatic effect Broad spectrum

Tetracycline & Its derivatives

Aminoglycosides (Gentamycin, amikacin, streptomycin, etc)

Induce the binding of wrong tRNAAA complexes, resulting in synthesis of false proteins Bactericidal ( concentration-dependent), mainly Gramnegative organisms

GIT absorption differ among derivatives of tetracycline, nearly complete for doxycycline & minocycline The most common unwanted effect is GI upset:
Direct mucosal irritant

Damage to the natural bacterial gut flora (broad-spectrum antibiotics)

Concurrent ingestion of antacids or milk form insoluble complexes inactivation The ability to chelate Ca2+ makes tetracyclines accumulates in growing teeth (irreversible discoloration) & bone (reversible growth inhibition) Other Adverse effects include photosensitivity, hepatic damage (mainly after IV administration) Decreased accumulation of tetracycline (acquisition of an energy-dependent efflux pathway) Production of a ribosomal protein that displaces tetracycline from its target Enzymatic inactivation of tetracyclines

Resistance mechanisms :

Chloramphenicol

Inhibits peptide synthetase Binds reversibly to the 50S ribosomal subunit prevent binding amino acyl tRNA to acceptor site inhibiting peptide bond formation Broad spectrum Bacteriostatic, may be bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae Completely absorbed after oral ingestion; Readily crosses diffusion barriers Danger of bone marrow damage

Dose-dependent, toxic, reversible form manifested during therapy Non dose-dependent, frequently fatal, occurs after several weeks of latency

Macrolides (Prototype : Erythromycin)

Binding reversibly to 50S ribosomal subunits at or very near the site that binds chloramphenicol Inhibits the translocation step from the acceptor site on the ribosome to the peptidyl donor site Predominantly bacteriostatic mainly against Gram-positive organisms Effective orally Suitable as a substitute in allergy or resistance to penicillin Clarithromycin, roxithromycin and azithromycin have similar activity with slower elimination reduce dosing & frequency of administration Inhibitors of CYP isozymes potential for drug interactions

Lincosamides

Clindamycin possess antibacterial activity erythromycin Bacteriostatic effect mainly on Gram-positive aerobic Clindamycin is a semisynthetic chloro analogue of Lincomycin

Better absorbed Greater antibacterial efficacy

Both penetrate well into bone tissue Macrolide resistance due to ribosomal methylation also may produce resistance to clindamycin Clindamycin is not substrate of efflux pumps microbial resistance to macrolides by this mechanisms might susceptible to Clindamycin

Linezolid

Synthetic antimicrobial agent of the oxazolidinone class Binding to the P site of the 50S ribosomal subunit and preventing formation of the larger ribosomal-fMettRNA complex that initiates protein synthesis Unique mode of action no cross-resistance with other drug classes Active againts bacteria resistance to other drugs, including penicillin resistance, methicillin resistance, vancomycin-intermediate and vancomycinresistant strains Resistance generally requires mutations in two or more copies of 23S rRNA genes

Antifungal Agents
Imidazole derivatives

Inhibit synthesis of ergosterol, an integral constituent of cytoplasmic membranes of fungal cells Fungistatic or fungicidal Poorly absorbed and poorly tolerated systemically

Most imidazoles are suitable only for topical use (Clotrimazole, Econazole, Oxiconazole and other azoles)

Fluconazole and itroconazole are newer orally effective triazole derivatives Fluconazole water-soluble injectable solution

Polyene antibiotics
(Amphotericin B and nystatin)

Cause formation of hydrophilic channels Amphotericin B is active against most organisms responsible for systemic mycoses polyene antimycotics are nonabsorbable it must be given by infusion poorly tolerated

Chills, fever, CNS disturbances, impaired renal function, phlebitis at the infusion site

Flucytosine

Converted in candidal fungi to 5-fluorouracil by the action of a specific fungal cytosine deaminase Antimetabolite, disrupts DNA and RNA Synthesis fungicidal effect

Caspofungin

Inhibits synthesis of the fungal cell wall Water-soluble, parenteral injection; can be used in systemic mycoses due to aspergillus fungi when amphotericin B or itroconazole cannot be employed well tolerated, with the exception of phlebitis at the infusion site Acts as a spindle poison to inhibit fungal mitosis The time required for the eradication of dermatophytes corresponds to the renewal period of skin, hair, or nails Its clinical use become obsolete because of its cumbersome application (require parenteral administration in the therapy of dermatophytoses)

Griseofulvin