Antimicrobial Drugs PDF

Chemotherapeutic drugs (the part of antimicrobial agents) a. Principles of Anti-microbial Therapy b. Cell Wall Inhibitors, Penicillin c. Cell Wall Synthesis Inhibitors, Cephalosporins d. Cell Wall Synthesis Inhibitors, others e. Protein Synthesis Inhibitors: e. Quinolone & Sulfonamides...

Chemotherapeutic drugs (the part of antimicrobial agents) a. Principles of Anti-microbial Therapy b. Cell Wall Inhibitors, Penicillin c. Cell Wall Synthesis Inhibitors, Cephalosporins d. Cell Wall Synthesis Inhibitors, others e. Protein Synthesis Inhibitors: e. Quinolone & Sulfonamides f. Antimycobacterials g. Anti-fungal agents h. Antiparasitic Drugs i. Antiviral Agents  Anti-infective Therapy, Antimicrobial Drugs Modern age – Discovery of sulfanilamide in 1936 – Commercial introduction of penicillin in 1941 Antimicrobial Therapy – Original antimicrobials: derived from microorganisms – Newer agents: chemically synthesized 7-2  Factors Leading to Infection Age: young and elderly Increased exposure to pathogenic organisms Disruption of the normal barriers (↓ immunity) & Inadequate immunological defenses Impaired circulation (e.g. diabetes) Poor nutritional status 7-3  Sources of Infection Antimicrobials are active against: 1.Bacteria 2.Fungi 3.Viruses 4.Others: (e.g. Parasites, worms) 7-4  Overuse Overuse of antimicrobial agents can lead to the development of severely resistant organisms. – Promoted the development of organisms that are not affected by any of the available therapies 7-5 Principles of Anti-microbial Therapy  Selection of Antimicrobial Agents Requires knowledge of 1) the organism's identity 2) the organism's susceptibility to a particular agent 3) the site of the infection 4) patient factors 5) the safety of the agent 6) the cost of therapy. 7  Empiric therapy: immediate administration of drug(s) prior to bacterial identification and susceptibility testing. Broad-spectrum therapy may be needed: – initially for serious infections when the identity of the organism is unknown or – the site makes a polymicrobial infection likely. Pathogen-directed therapy: drug administration after bacterial identification according to susceptibility testing 8  Bacteriostatic vs. Bactericidal drugs Bacteriostatic drugs arrest the growth and replication of bacteria. Bactericidal drugs kill bacteria at drug serum levels achievable in the patient. 9 10  Minimum inhibitory concentration (MIC) (for bacteriostatic agents) MIC: the lowest concentration of antibiotic that inhibits bacterial growth. To provide effective antimicrobial therapy, the clinically obtainable antibiotic concentration in body fluids should be greater than the MIC. 11  Minimum bactericidal concentration (MBC) (for bactericidal agents) MBC: determines the minimum concentration of antibiotic that kills the bacteria under investigation. The tubes that show no growth in the MIC assay are subcultured into antibiotic-free media. 12 Effect of the site of infection on therapy The blood-brain barrier The penetration and concentration of an antibacterial agent in the CSF is particularly influenced by the following: 1. Lipid solubility of the drug: – quinolones and metronidazole VS b–latam antibiotics 2. Molecular weight of the drug: – high molecular weight (for example, vancomycin) penetrates poorly. 3. Protein binding of the drug 13 Patient factors Attention must be paid to the condition of the patient. For example: – the status of the patient's immune system – Kidneys – Liver – circulation – age In women: – pregnancy – breastfeeding 14 A. Immune system: and bacteriostatic antimicrobials Immunosuppression due to: – Alcoholism – Diabetes – infection with the HIV – Malnutrition – advanced age – immunosuppressive drugs. 15 B. Renal dysfunction: Poor kidney function causes accumulation of antibiotics in the body. – Adjusting the dose or the dosage schedule. 16 C. Hepatic dysfunction: Erythromycin & Tetracycline D. Poor perfusion: Diabetes E. Age: Renal or hepatic elimination processes F. Pregnancy: All antibiotics cross the placenta. – Tetracyclines: tooth dysplasia and inhibition of bone growth – Some anthelmintics are embryotoxic and teratogenic. – Aminoglycosides are ototoxic to the fetus. Lactation: the concentration of an antibiotic in breast milk is usually low, the total dose to the infant may be enough to cause problems 17 Safety of the agent Many of the antibiotics are safe due to selective toxicity. Others are very toxic (for example, chloramphenicol) – reserved for life-threatening infections – Less selectivity Cost of therapy Often, several drugs may show similar efficacy 18 in treating an infection but vary widely in cost.  Route of Administration 1. Oral route: – mild infections and can be treated on an outpatient basis. – In patients requiring a course of intravenous therapy initially, the switch to oral agents occurs as soon as possible. 2. Parenteral: – Antimicrobials that are poorly absorbed from the GI tract – Treatment of patients with serious infections – Patient is not capable of swallowing. 19  Combinations of Antimicrobial Drugs A. It is advisable to treat patients with the single agent that is most specific for the infecting organism. – This strategy: 1. reduces the possibility of superinfection 2. decreases the emergence of resistant organisms 3. minimizes toxicity. B. Combinations therapy may be advisable in certain situations. For example, the treatment of tuberculosis benefits from drug combinations. 20  Drug Resistance Bacteria are said to be resistant to an antibiotic if the maximal level of that antibiotic that can be tolerated by the host does not halt their growth. Some organisms are inherently resistant to an antibiotic. – For example, gram-negative organisms are inherently resistant to vancomycin. 21 22  Complications of Antimicrobial Therapy A. Hypersensitivity – Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. – For example, Penicillins. B. Direct toxicity – High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. – For example, aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of Corti. 23 C. Super-infections With – broad-spectrum antimicrobials – combinations of agents May result in alterations of the normal microbial flora permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. 24  Antibacterials 25  Classifications Antibacterial agents are classified based on the following factors: – Bactericidal or bacteriostatic – Site of action – Narrow or broad spectrum 7 - 26 27  Sites of Antibacterial Actions 28  Cell Wall Inhibitors 29 30  I. Overview The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. 31  Crosslinks Teichoic acid From: Goodman and Gilman, 9th ed. Transpeptidease Reaction Transpeptidease Inhibition  To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. The most important members of this group of drugs are: 1. b-lactam antibiotics (named after the b-lactam ring that is essential to their activity) 2. vancomycin. 35  II. Penicillins A. Mechanism of action The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur - These drugs are bactericidal. - Penicillins are only effective against: – rapidly growing organisms – synthesize a peptidoglycan cell wall. 36 Penicillins Mechanisms of resistance 1. Alter the affinity of transpeptidases for binding to penicillin 2. enzymatically cleave the beta-lactam ring and prevent binding to transpeptidase 3. active transport out of cell (efflux pumps) 4. poor penetration into cell (intrinsic resistance) 37 Pharmacology of Select Penicillins A. the naturals - penicillin G and penicillin V 1. antimicrobial activity a) both share antimicrobial spectra for aerobic G+ organisms but penicillin G is more active against Neisseria sp. and anaerobes b) 90% of staphylococci are resistant, most gonococci are too 38 3. Fate after absorption 4. Excretion – 60% of penicillin G is – eliminated rapidly (i.e., bound to albumin 30 minutes) from the – significant amounts are body by kidneys found in liver, bile, – in neonates and infants, kidney, semen, joint clearance is much less fluid, lymph, and because renal function intestine hasn’t been fully – penetration into CSF is established poor unless there is – in patients with renal inflammation failure, liver will inactivate penicillin G at the rate of 10% per hour 39 Therapeutic uses: a. Streptococcus pneumoniae infections (pneumonia and meningitis b. Streptococcus pyogenes infections (pharyngitis, Scarlet Fever, toxic shock, necrotizing fascititis, arthritis, meningitis, etc); also given prophylactically c. viridans streptococcal endocarditis (also given prophylactically) d. anaerobes except Bacteroides fragilis group e. meningococcal infections f. syphilis and other diseases caused by spirochetes 40 B. Antistaphylococcal penicillins: Isoxazolyl penicillins Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin, & Methicillin 1. Antimicrobial activity 3. excretion – these drugs were made to resist – rapidly excreted by kidneys staphylococcal penicillinases – significant hepatic elimination into – activity against staph not bile guaranteed with rise of MRSA 4. therapeutic uses 2. Absorption – community acquired MSSA – oxacillin, cloxacillin, and infections dicloxacillin are – not effective against enterococci pharmacologically similar or Listeria – stable in gastric acid and readily absorbed after oral administration – can also be administered parenterally for serious cases of staphylococcal disease – food interferes with absorption – nafcillin is inactivated by acid pH so its given parenterally 41  C. Extended-spectrum penicillins: Aminopenicillins – Ampicillin and Amoxicillin 1. Antimicrobial activity 2. Absorption a. broad spectrum? a. both are acid resistant b. do not work against but more amoxicillin is beta-lactamase absorbed by the producers (i.e. intestinal tract than Pseudomonas, Proteus, ampicillin after an oral Klebsiella, etc) dosage c. beta-lactamase b. food interferes with inhibitors (clavulanate, absorption of ampicillin sulbactam) extend the but not amoxicillin spectrum somewhat 42 43 3. fate after absorption 5. therapeutic uses a. upper respiratory tract infections 20% bound to plasma b. otitis media proteins c. uncomplicated urinary 4. excretion tract infections a. both are excreted from d. acute bacterial the kidneys meningitis in children e. typhoid fever 44  D. Antipseudomonal penicillins: Carbenicillin, a carboxypenicillin (ticarcillin) and a ureidopenicillin (piperacillin) 1. Antimicrobial activity 5. Therapeutic uses a. ticarcillin is an anti- a. for immunocompromised pseudomonal drug patients with serious G- b. piperacillin plus infections tazobactam (a beta- b. bacteremias, UTI, lactamase inhibitor) has pneumonias the broadest spectrum of all penicillins 2. Absorption – given parenterally 3. Fate after absorption – same as other penicillins 4. Excretion – kidneys 45 46 Toxicity/Contraindications A. hypersensitivity reactions (uncommon) 1. in order of decreasing frequency: maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, anaphylaxis 3. rashes will disappear when drug is withdrawn, can use antihistamines or glucocorticoids 4. for patients with allergies, use a different drug or try to desensitize 47 B. other adverse reactions 1. pain and sterile inflammatory reactions at sites of IM injections 2. large doses (>20 million IU/day) given to patients with renal failure can cause lethargy, confusion, twitching, and seizures 3. dizziness, tinnitus, headache, hallucinations are side effects sometimes seen with penicillin G procaine injections for venereal disease due to sudden release of procaine 4. pseudomembranous colitis due to Clostridium difficle overgrowth 48  b-Lactamase Inhibitors b-Lactamase inhibitors: Instead, they bind to and 1. clavulanic acid inactivate b-lactamases, 2. Sulbactam thereby protecting the 3. Tazobactam antibiotics that are normally substrates for contain a b-lactam ring these enzymes. do not have significant The b-lactamase antibacterial activity. inhibitors are therefore formulated in combination with b- lactamase sensitive antibiotics. 49 50