Anti-Infective Agents PDF

WHAT IS AN ANTIBIOTIC? Antibiotics a chemical substance produced by a microorganism that inhibits the growth of or kills other microorganisms. Antimicrobial agents a chemical substance derived from a biological source or produced by chemical synthesis that kills or inhibits the growth of m...

WHAT IS AN ANTIBIOTIC? Antibiotics a chemical substance produced by a microorganism that inhibits the growth of or kills other microorganisms. Antimicrobial agents a chemical substance derived from a biological source or produced by chemical synthesis that kills or inhibits the growth of microorganisms. Antibiotics The current era of antimicrobial chemotherapy began in 1935 with the discovery of the sulfonamides. In 1940, it was demonstrated that penicillin, discovered in 1929, could be an effective therapeutic substance. During the next 25 years, research on chemotherapeutic agents centered largely on substances of microbial origin called antibiotics. CLASSIFICATION OF ANTIBIOTICS Chemical structure Mechanism of action Typed of organisms which primarily active Spectrum of activity Types of action Obtained from  SOURCE OF ANTIBACTERIAL AGENTS Organisms develop resistance faster to the natural antimicrobials Natural antibiotics are often more toxic than synthetic antibiotics Benzylpenicillin and Gentamicin are natural antibiotics Ampicillin and Amikacin are semi-synthetic antibiotics Moxifloxacin and Norfloxacin are synthetic antibiotics ROLE OF ANTIBIOTIC To inhibit multiplication Antibiotics have a bacteriostatic effect. At which drug concentration is the bacterial population inhibited? Minimal Inhibitory Concentration = MIC To destroy the bacterial population Antibiotics have a bactericidal effect. At which drug concentration is the bacterial population killed? Minimal Bactericidal Concentration = MBC CHOOSING THE RIGHT ANTI-INFECTIVE Is an antibiotic indicated? Use empirical therapy routinely Narrow spectrum Avoid toxicity and side effects Bactericidal vs bacteriostatic Cost Avoid allergies MAIN DIFFERENCE BETWEEN HUMANCELL AND MICROBIALCELL Microbial cell Human cell Cell is isolated and Independent. It is dependent on other cells. Thick protective cell wall is present. The wall is absent Cell membrane : No cytoplasmic Cytoplasmic bridges are present which bridges as there is only one cell. help in inter-cellular transport in between neighboring cells. Flagella for movement, pili for sexual Absent mostly. Except for ciliated cells reproduction. in respiratory tract & gut. Nucleus is Absent. Instead nuclear Prominent nucleus with nuclear content like DNA are present in membrane. So called as an eukaryote cytoplasm. No distinct nucleus, so type. called as prokaryote RNA : 70 s type with 50s and 30s type 80 s type with 60 s and 40 s sub units. sub units. WHAT PATHOGENS ARE WE DEALING WITH? Gram Positive? Gram Negative? Mixed Infection? Aerobes? Facultative? Anaerobes? WHAT TYPE OF ANTIBIOTIC SHOULD WE USE? Bacteriostatic? Bactericidal ? Narrow Spectrum? Broad Spectrum?  BACTERIOSTATIC VS BACTERICIDAL Bactericidal action necessary in endocarditis, meningitis, osteomyelitis,neutropenia Disadvantage of bactericidal: rapid bacterial lysis in meningitis with overwhelming inflammatory response with increased mortality Advantage of bacteriostatic: clindamycin in staph TSS( toxic shock syndrome) effective in inhibiting TSST-1( toxic shock syndrome toxin) production without excessive inflammatory response Cidal and static should not uses together  STRUCTURES OF BACTERIALCELL MEMBRANE Natural Resistance Enterococcus- PBP’s are different from other Gram-positives (also higher lipid content in cell wall), which causes a low level resistance to penicillins and resistance to C1G. STRUCTURES OFBACTERIAL CELL MEMBRANE Natural Resistance- Many Gram-negative organisms are naturally resistant to penicillin G and oxacillin because the drug is prevented from entering the cell by the LPS which blocks the porins. Gram-negatives are naturally resistant to vancomycin. WHAT TYPE OF ANTIBIOTIC SHOULD WE USE? Bactericidal ? Bacteriostatic? Narrow Spectrum? Broad Spectrum? INHIBITORS OF CELL WALL SYNTHESIS Beta-lactams Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins BETA-LACTAMS There are about 50 different Beta (ß)-lactams. They are all bactericidal. They are non-toxic. They are relatively inexpensive. organic acids and most are soluble in water. inactivation by beta-lactamases Some more common Beta-lactamase enzymes include: Penicillinases Cephalosporinases ESBL’s Cephamycinases Carbapenemases BETA-LACTAMASE INHIBITORS(BLI) have a beta(ß)-lactam ring, but have weak or poor antibacterial activity. They have a very high affinity for ß-lactamases They act as a trap, and are hydrolyzed in preference to the ß-lactam drug. The drug is left intact to act on the bacteria (cell wall) Should be called penicillinase inhibitors, because they are active against: ƒ Staphpenicillinase, Penicillinase of K. pneumoniae  BETA-LACTAMASE INHIBITORS(BLI) ESBL (to a greater or lesser degree)- if the penicillinase is being overproduced, the inhibitor effect may be diluted (Inoculum Effect) Inhibitors are active against all penicillinase but never on cephalosporinase NEW ISSUE- BLI can act as inducers and actually stimulate enzyme (betalactamase) production. It ispossible to see the following: Pseudo monas Ticarcillin = S Ticarcillin/Clavulanic = R Enterobacteriaceae Piperacillin = S Piperacillin/Tazobactam = R INHIBITORS OF CELL WALL SYNTHESIS Penicillins Cephalosporins Monobactams Carbapenems Glycopeptides Fosfomycins  aztreonam differs from those of other β-lactam antibiotics and more closely resembles that of an aminoglycoside. Aztreonam has activity only against gram-negative bacteria Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Aminoglycosides: Spectrum of Action Rapid bactericidal effect Broad spectrum of action Gram-negative infections Gram-positives, except Streptococus and Enterococcus. Must combine an aminoglycoside (Gentamicin or Streptomycin) with a penicillin, ampicillin or vancomycin for severe enterococcal infections (Synergy Testing). In serious infection, used in association with beta- lactams or fluoroquinolone Nephrotoxic and toxic for ears AMINOGLYCOSIDE Mode of action: Target = Ribosome in cytoplasm Aminoglycosides are positively charged molecules The negative charge of bacteria is due to LPS in the outer membrane and the peptidoglycan (notably the teichoic acid). The drugs cross the cytoplasmic membrane via respiratory enzymes(involved in aerobic respiration). AMINOGLYCOSIDE Aminoglycosides bind to the RNA of the 30S ribosomal sub-unit. Release of incomplete, toxic proteins The bactericidal activity of aminoglycosides ultimately stops protein synthesis and dramatically damages the cytoplasmic membrane. Bacteriostatic Their spectrum of activity is limited to Gram-positive cocci such as Streptococci and Staphylococci. These antibiotics are also active against anaerobes. Clindamycin used in osteomyelitis of the jaws. Clindamycin dose not in routine of odontogenic infection  The drugs enter a Gram-positive cell without any problem. In Gram-negative bacteria there is no entry because MLSK are lipophilic molecules. They cannot cross the outer membrane which is hydrophilic. “Oil and water don’t mix”. MLSK are also large molecules that cannot pass through the porins (which are also aqueous channels) – impermeability. Most Gram-negatives are naturally resistant to MLSK Antibiotics MLSK group are structurally distinct but have a similar mode of action by binding the 50S ribosomal subunit  Inhibitors of Protein Synthesis Aminoglycosides MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides) Tetracyclines Glycylcyclines Phenicols Oxazolidinones Ansamycins Tetracyclines: Spectrum of Action: Broad spectrum, resistance is common Primarily for treatment of genital infections (chlamydiae) and atypicals (Rickettsiae, Mycoplasma).Growth promotor in animal husbandry. Toxicity: Diffuse well in cells and bones. Not recommended for pregnant women and children (less than 2 years old) because of the toxicity on bones and teeth of the fetus.  TETRACYCLIN Tetracycline = Short acting Minocycline and Doxycycline = Long acting Minocycline and Doxycycline are more active than Tetracycline. Used extensivly in periodontitis and periodontal disease tetracycline exists as a mixture of two forms - lipophillic and hydrophillic, Helps the antibiotic gain entry in to the Gram-pos. TETRACYCLIN it’s target - the 30s ribosome Gram-positives have no natural resistance to the tetracyclines. Of the Gram-negative organisms only Proteus mirabilis is naturally resistant  1st Generation Quinolones: Only for Gram-negatives, used to treat urinary tract infections Fluoroquinolones: Ciprofloxacin,Levofloxacin, Norfloxacin, Ofloxacin) More effective (lower MIC values). Spectrum extended to cover Staphylococci, Streptococci and Pneumococci (sparfloxacin). DO IT , OVERCOME THE PROBLEM Bacteria never die Be happy  Anthelminthic drugs ❖These drugs are active against helminths (worms) Acts by: ✓Kills the worm (Vermicidal) ✓Expels the worm (Vermifuge) ❖Classified on the basis of organism susceptible Anthelminthic drugs: classification ❖For roundworm, hookworm, pinworm Albendazole, mebendazole, pyrantel pamoate, piperazine, levamisole ❖For threadworm Ivermectin, albendazole ❖For whipworm, Trichinella spiralis Albendazole, Mebendazole Anthelminthic drugs: classification ❖For Filariasis Diethylcarbamazine, Ivermectin, Albendazole ❖ForTapeworm Praziquantel, Niclosamide,Albendazole ❖For Hydatid disease Albendazole, Mebendazole  Albendazole ❖Broad spectrum anthelmintic ❖Acts by: Binds to microtubular protein β-tubulin of the parasite Inhibits polymerization of microtubules ✓Microtubules gradually lost and paralysed  Albendazole ❖Additional actions: Blocks glucose uptake by parasite Depletes glycogen stores by inhibiting mitochondrial enzymes Albendazole: Uses ❖Drug of choice: Roundworm (Ascaris lumbricoides) Hookworm (Ancyclostoma duodenale) Tapeworm (Neurocysticercosis) Pinworm (Enterobius vermicularis) Hydatid disease (Echinococcous sps.) Cutaneous larva migrans (Ancyclostoma caninum) Trichinella spiralis Albendazole: Uses ❖Alternative drug for: Threadworm (Strongyloides stercoliasis) Whipworm (Trichuris trichiura) Filaria (Wuchereria bancroftii, Brugia malayi) Tapeworm (Taenia sps., Hymenolepsis nana) Albendazole: Side effects ❖Excellent tolerability ❖Gastrointestinal side effects: Nausea, diarrhoea, abdominal pain ❖Dizziness ❖On prolonged use: Headache, fever, alopecia, jaundice, neutropenia Anti-protozoal drugs ❖These agents are active against protozoa Unicellular Non-photosynthetic Belongs to the phylum Protozoa ❖Acts by killing the organism ❖Classified according to the organism susceptible and site of action Anti-protozoal drugs: Classification ❖Anti-amoebic drugs Tissue amoebicides, Luminal amoebicides (diloxanide furoate or paromomycin) ❖Drugs for giardiasis Metronidazole, Nitazoxanide,Quiniodochlor, Furazolidine ❖Drugs for trichomonas Metronidazole, Diiodohydroxyquin, Quiniodochlor, Povidone-iodine ❖Drugs used in Leishmaniasis Amphotericin B, Miltefosine, Sodium stibogluconate,Paromomycin  Anti-amoebic drugs: Classification ❖ Tissue amoebicides: For intestinal + extraintestinal amoebiasis ✓Nitroimidazoles (-dazole) ▪Metronidazole, Tini-, Secni-,Orni-, Satrani- Anti-amoebic drugs: Classification ❖ Tissue amoebicides: For intestinal + extraintestinal amoebiasis ✓Alkaloids: ▪Emetine, Dihydroemetine Anti-amoebic drugs: Classification ❖Tissue amoebicides: For intestinal amoebiasis only ▪Chloroquine  Anti-amoebic drugs: Classification ❖Luminal amoebicides: Amides ▪Diloxanide furoate, Nitazoxanide 8-hydroxyquinolines ▪Quinidochlor, Iodoquinol Antibiotics ▪Tetracyclines, Paromomycin Metronidazole ❖Broad spectrum amoebicidal drug ❖Not effective in aerobic bacteria and aerobic environment  Metronidazole ❖Acts by: Enters into cells by diffusion Gets reduced to highly reactive nitro radical ✓Competes with biological electron acceptors for electrons generated by pyruvate oxidation (PFOR pathway) ✓Cells become energy deficient and dies Metronidazole: Uses ❖Amoebiasis (Entamoeba histolytica) ❖Giardiasis (Giardia lambia) ❖Trichomonas (Trichomonas vaginalis) ❖Anaerobic bacterial infection ❖Pseudomembranous enterocolitis ❖Acute necrotizing ulcerative gingivitis (Trench mouth) ❖H. pylori gastritis Metronidazole: Adverse effects ❖Frequent and unpleasant, but not serious Anorexia, nausea, metallic taste, abdominal cramps Thrombophlebitis of injected vein ✓Dilute solution properly Allergic reactions  Metronidazole: Adverse effects ❖Frequent and unpleasant, but not serious Headache, glossitis, dryness of mouth and impairment of concentration Peripheral neuropathy and CNS effects on prolonged administration ✓Seizures in high dose ✓Leukopenia on repeated doses