Antimikroba, Antiparasit & Antivirus

Edy Junaidi

Antimikroba

● Efek antibakterial :– Bakteriostatik

– Bakterisid

● Spektrum efek antibakterial– Narrow – spectrum

– Broad – spectrum

● Mekanisme resistensi– Natural resistance

– Acquired resistance

Selection of Antimicrobial agents● Optimal selection require :

– Clinical judgement

– Detailed knowledge of pharmacological properties

– Microbiological factors

● General Use of Antibiotics :– Empirical therapy

– Definitive therapy

– Prophylactic therapy

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

DisadvantagesDisadvantages :

● Increased risk of toxicity

● Selection of multiple-drug-resistant microorganisms

● Eradication of normal host flora with subsequent superinfection

● Increased cost

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 SynthesisInhibitors of Cell Wall Synthesis

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

– N-acetylglucosamine

– N-acetyl muramic acid

● Inhibitors of cell wall synthesis → bactericidal– Penicillin & derivatives

– Cephalosporins

– Bacitracin

– Vancomycin

Form a building block of cell wall

PenicillinsDerivatives of Penicillin G

● β-lactamase inhibitors :– Clavulanic acid (the only available for oral use)

– Sulbactam

– Tazobactam● Combine with Combine with ββ-lactam antibiotics to overcome -lactam antibiotics to overcome

penicillinase activitypenicillinase 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 β-lactamase

● The cephalosporins distribute in satisfactory concentrations to most tissues except the central nervous system.

– Only cefepime, cefuroximecefepime, cefuroxime (Zinacef), cefotaximecefotaxime (Claforan), ceftriaxoneceftriaxone (Rocephin), and ceftazidimeceftazidime (Fortaz) achieve therapeutic therapeutic concentrationsconcentrations in cerebrospinal fluid

Inhibitors of Tetrahydrofolate SynthesisInhibitors of Tetrahydrofolate Synthesis● Tetrahydrofolic acid (THF) → a coenzymecoenzyme in the synthesis

of purine bases and thymidine ⇒ constituents of DNA and RNA ⇒ required for cell growthrequired for cell growth and replicationreplication

● Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim (bacteriostatic)

● Sulfonamide possess structural resemblence to PABA → false substratefalse substrate → inhibit utilization of PABA

● Trimethoprim is a highly selective inhibitor of highly selective inhibitor of dihydrofolate reductase of lower organismsdihydrofolate reductase of lower organisms; ~100,000 times more drug is required to inhibit human reductase than the bacterial enzyme

Dihydrofolate Dihydrofolate reductasereductase

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 lumenactive 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 contraindication for the last weeks of gestation and in the neonatefor 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

Gyrase InhibitorsGyrase Inhibitors

● 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 quinolonesquinolones (Norfloxacin, Ofloxacin, ciprofloxacin, enoxacin, and others) achieve effective concentration systemically → used for infections of internal organs

● 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

Nitroimidazole derivatives (Metronidazole, Timidazole)Nitroimidazole derivatives (Metronidazole, Timidazole)● 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 lactationAvoid use during pregnancy and lactation

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

Tetracycline & Its derivativesTetracycline & Its derivatives● Inhibit the binding of tRNA–AA complexes

● Bacteriostatic effect

● Broad spectrum

Aminoglycosides Aminoglycosides (Gentamycin, amikacin, streptomycin, etc)

● Induce the binding of “wrong” tRNA–AA complexes, resulting in synthesis of false proteins

● Bactericidal ( concentration-dependent), mainly Gram-negative 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 insoluble complexescomplexes → 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)

Resistance mechanismsResistance mechanisms :

● 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

ChloramphenicolChloramphenicol● 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 Macrolides (Prototype : Erythromycin)● Binding reversibly to 50S ribosomal subunits at or very near the

site that binds chloramphenicol

● Inhibits the translocation stepInhibits 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

LincosamidesLincosamides● 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

LinezolidLinezolid● Synthetic antimicrobial agent of the oxazolidinone class● Binding to the P site of the 50S ribosomal subunit and

preventing formation of the larger ribosomal-fMet-tRNA 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 vancomycin-resistant strains

● Resistance generally requires mutations in two or more copies of 23S rRNA genes

Antifungal AgentsImidazole derivativesImidazole 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 antibioticsPolyene 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

FlucytosineFlucytosine● Converted in candidal fungi to 5-fluorouracil by the action of a

specific fungal cytosine deaminase

● Antimetabolite, disrupts DNA and RNA Synthesis → fungicidal effect

CaspofunginCaspofungin● 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

GriseofulvinGriseofulvin● 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)