1.Antimicrobial TherapyAntimicrobial Therapy Dr. Yahya Ibn Ilias

2. Antimicrobial agents Are effective in the treatment of infections because of their selective toxicity i.e the ability to kill an invading micro organism without harming the cells of the host. Antibiotic is the term used to describe any compound ( Synthetic / Natural) that inhibit of or kills micro organism. 3. Antimicrobial TherapyAntimicrobial Therapy Selective destruction of the microorganism. No or rare side effects on the host. Antimicrobial substances should have a specific action against molecules or enzymes or metabolism of the microorganism only. Criteria that determine the effectivenessCriteria that determine the effectiveness of antimicrobial agents:of antimicrobial agents: 4. Antibiotic Sensitivity TestAntibiotic Sensitivity Test During recent years, many bacteria have shown drug resistance against single or multiple drugs. Once the organism is isolated from clinical sample, it is necessary to identify them and to test them against various antibiotics so as to choose the most effective one and in turn, to treat the patient in most rational way. Main purpose of Antibiotic Sensitivity Test: To guide clinician in selecting the best antimicrobial agent in order to treat the patient. 5. Bacteriostatic Vs Bactericidal drugs Bacteriostatic drugs arrest the growth and replication of bacteria at serum levels achievable in the patient ,thus limiting the spread of infection while the bodys immune system attacks, immobilizes and eliminates the pathogens. Bacteriocidal drugs kill bacteria and decreases the total number of viable organism. Eg: Chloramphenicol is static against gram-ve rods and cidal against pnemococci. 6. Antimicrobial Spectra Antimicrobial spectra of a particular drug refers to the species of organisms affected by that drug. 1. Narrow spectrum: Antimicrobial agents acting only on a single or a limited group of micro organisms. Eg: isoniazid is active only against mycobacteria. Glycopeptides and bacitracin are only effective against Gram-positive bacteria, whereas polymixins are usually only effective against Gram negative bacteria. Aminoglycosides and sulfonamides are only effective against aerobic organisms, while nitroimidazoles are generally only effective for anaerobes. 7. 2. Broad Spectrum: Drugs that affect a wide variety of species . Eg: Tetracycline and chloramphenicol, fluoroquinolones, third- generation and fourth-generation cephalosporins. Administration of broad spectrum antibiotics can drastically alter the nature of the normal bacteria flora and can precipitate a super infection of an organism. 8. Extended expectrum: Applied to antibiotics that are effective against gram +ve organisms and also against a significant number of gram -ve bacteria. Eg: Ampicillin as it acts gram +ve and some gram-ve bacteria. 9. Combinations of Antimicrobial drugs It is therapeutically advisable to treat with the single agent that is most specific for the infecting oraganism. This strategy reduces the possibility of super infection, decreases the emergence of resistant organisms and minimizes toxicity. However situations in which combinations of drugs are employed do exist. Eg: Rx of tuberculosis benefits from drug combinations. 10. Advantages of drug combinations: Certain combinations of antibiotics such as b-lactams and aminogycosides show synergism i.e. combination is more effective than either of the drugs used separately. Disadvantages of drug combinations: A number of antibiotics act only when organisms are growing. Thus concomitant administration of a second agent that results in bacteriostatic may interfere with the action of the first drug that is bactericidal. 11. Drug Resistance Bacteria is said to be resistant if their growth is not halted by the maximal level of an antibiotic that is tolerated by the host. Some organisms are inherently resistant to an antibiotic. Eg: gram (ve) bacilli are resistant to Penicillin or M. Tuberculosis is insensitive to Tetracyclines. However, microbial species normally responsive to a particular drug may develop resistant strains. The emergence of these resistant strains has been ascribed to the inappropriate use of antibiotics in conditions that might resolve without treatment or which are amenable to antibiotic therapy. eg: Common cold. 12. Mechanism of Resistance Susceptible bacteria can acquire resistance to AMAs by either Genetic mutation or by accepting Antimicrobial resistance gene from other bacteria. 13. A. Genetic alteration leading to drug resistant: Resistance develops due to ability of DNA to: 1.Undergo spontaneous mutation 2.Move from one organism to another (resistance develop due to DNA transfer from one organism to another) B. Altered expression of proteins in drug resistant organisms: 1.Alteration of the target site through mutation can confer resistance as occurs with the penicillin binding proteins in methicillin-resistant S.aureus. 14. 2. Efflux systems : That pumps out the drugs (tetracycline) 3. The ability to destroy or inactivate the antimicrobial agent also can confer resistance on microorganisms. Eg:b-lactamase destroy many penicillins and cephalosporins, acetyltransferase can convert chloramphenicol to an inactive compound. C. Decreased penetrability of an agent can protect organisms against that antibiotic because it is unable to gain access to the site of action due to the presence of lipopolysaccharide layer (gram-ve bacteria). 15. Complications of Antibiotic Therapy 1.Hypersensitivity: Hypersensitivity reactions to antimicrobial drugs or their metabolic products frequently occur. Eg: Penicillins despite their almost absolute selective microbial toxicity can cause serious hypersensitivity problems, ranging from urticaria to anaphylactic shock. 2.Direct Toxicity: High serum levels of certain antibiotics may cause toxicity by affecting cellular processes in the host directly. Eg: Aminoglycosides can cause ototoxicity by interfering with membrane function in the hair cells of the organ of corti. 16. 3.Superinfections: Drug therapy, particularly with broad spectrum antimicrobials or combinations of agents, can lead to alterations of the normal flora of the upper respiratory, intestinal and genitourinary tracts, permitting the overgrowth of opportunistic organisms, especially fungi or resistant bacteria. These infections are often difficult to treat. An additional infection occurring during the course of an existing infection, usually caused by opportunistic microorganisms resistant to the antimicrobial agents used in treating the first infection 17. Misuses of Antibiotics TREATMENT OF NONRESPONSIVE INFECTIONS Most viral diseases are self-limited and do not respond to any of the currently available anti-infective compounds. Thus, antibiotic therapy of at least 90% of infections of the upper respiratory tract and many GI infections is ineffective. THERAPY OF FEVER OF UNKNOWN ORIGIN Fever of short duration in the absence of localizing signs usually is associated with undefined viral infections. Antimicrobial therapy is unnecessary, and resolution of fever usually occurs spontaneously within a week. Fever persisting for 2 or more weeks, commonly referred to as fever of unknown origin, has a variety of causes; only about one quarter of these are infections. Moreover, some of these infections (e.g., tuberculosis,disseminated fungal infections) may require antibiotics that are not typically used for bacterialinfections. Inappropriately administered antibiotics may mask an underlying infection, delay the diagnosis, and prevent the identification of the infectious pathogen by culture. 18. IMPROPER DOSAGE Dosing errors with antibiotics are common. Excessive dosing can result in significant toxicities, while too low a dose may result in treatment failure and is most likely to select for antibiotic resistance. INAPPROPRIATE RELIANCE ON CHEMOTHERAPY ALONE Infections complicated by abscess formation or the presence of necrotic tissue or a foreign body often cannot be cured by antibiotic therapy alone. Drainage, debridement, and removal of the foreign body are at least as important as the choice of antibiotic agent. As a general rule, when an appreciable quantity of pus, necrotic tissue, or a foreign body is present, the most effective therapy is an antimicrobial agent given in adequate dose plus a properly performed surgical procedure. 19. CLASSIFICATION AND MECHANISM OF ACTION Antimicrobial agents are classified based on proposed mechanism of action as follows: (1) Agents that inhibit synthesis of bacterial cell walls, including the b-lactam class and other agents such as Vancomycin; (2) Agents that act directly on the cell membrane to increase permeability and cause leakage of intracellular compounds; (3) Agents that disrupt function of ribosomal subunits to reversibly inhibit protein synthesis (e.g., chloramphenicol, the tetracyclines, erythromycin, and clindamycin); 20. (4) Agents that bind to the 30S ribosomal subunit and alter protein synthesis (e.g., the aminoglycosides); (5) Agents that affect bacterial nucleic acid metabolism by inhibiting RNA polymerase (e.g., rifampin) or Topoisomerase / DNA gyrase (e.g., the quinolones); (6) The antimetabolites, including trimethoprim and the sulfonamides, which block essential enzymes (PABA) of folate metabolism. 21. Summary of Targets 22. Inhibitors of Cell Wall Synthesis B-lactam Antibiotics: A. Penicillins (Penicillin G, Penicillin V, Methicillin, Nafcillin, Oxacillin, Cloxacillin, Ampicillin, Amoxycillin, Carbenicillin, Ticarcillin, Pipercillin, Azlocillin) B. Cephalosporins: Ist generation: cefazolin, cefadroxil, cephalexin 2nd generation: cefaclor, cefoxitin, cefuroxime 3rd generation: cefixime, ceftriaxone, cefotaxime 4th generation: cefepime 23. C. Carbapenems: Imipenem, Meropenem, Ertapenem D. Monobactams: Aztreonam Other Antibiotics: Vancomycin, Bacitracin B-Lactamase Inhibitors: Clavulanic acid, sulbactam and tazobactam 24. Penicillins Most widely effective antibiotics and are among the least toxic drugs known. Bactericidal Mechanism of action (MOA): Bacterial cell wall is cross linked polymer of polysaccharides and pent peptides. Penicillin interact with penicillin binding protein(PBP) on cytoplasmic membrane to inhibit transpeptidation reactions involved in cross linking of peptidoglycan chains, the final step in cell wall synthesis. 25. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi and viruses. Activation of autolytic enzymes(autolysins) that destroy the existing cell wall. 26. B-lactam ring is present in penicillin. B-lactamase is the enzyme that hydrolyzes the cyclic amide bond of the B- lactam ring, which results in loss of bactericidal activity. 27. Subgroups and Antimicrobial Activity: Narrow spectrum, B-lactamase sensitive: 1. Penicillin G (natural penicillins) Acid labile 2. Penicillin V (acid stable ) Spectrum: Streptococcal infection ( Pharyngitis, Otitis media, Rheumatic fever), Pneumococcal infection : Meningococcal infection : like meningitis, Gonorrhea** Gram + (ve) bacilli : B. Antharcis, C. Diphtheriae All clostridia are highly sensitive, so are Spirochetes. 28. Very narrow spectrum, b-lactamase resistant: Nafcillin, Methicillin, Cloxacillin Spectrum: known or suspected staphylococci Extended spectrum : - b-lactamase sensitive: ampicillin and amoxycillin Spectrum: gram +ve cocci (not staph), E.coli, H.influenza, listeria monocytogens. - Others b-lactamase sensitive: Ticarcillin, piperacillin, azlocillin Spectrum: gram ve rods including pseudomonas Beta lactamase inhibitors : Clavulanic acid, sulbactam, Tazobactam 29. Mechanisms of Resistance: 1. Production of beta- lactamase by the organism: Penicillin -- beta-lactamase ---------- penicillonic acid (no antibacterial activity) ---- break lactam ring structure. eg: staphylococcal 2. Structural change in PBPs: methicillin resistant s. aureus, penicillin resistant pneumococci. 3. Reduction in the permeability of the outer membrane of the bacteria to penicillins. 30. RESISTANCE TO ANTIBIOTICS- PENICILLIN NH O COOH CH3 CH3 NH O COOH CH3 CH3 +H20 -LACTAM RING PENICILLOIC ACID OH N NH Hydrolysis of -lactam bond -LACTAMASE 31. Pharmacokinetics Administration: oral (amoxycillin), iv (methicillin, ticarcillin, carbenicillin, piperacillin) or im route (procaine penicillin and benzathine penicillin). Absorption: most of the penicillins are incompletely absorbed after oral administration and reach the intestine in sufficient amount to affect the composition of the intestinal flora. Distribution: distribution of the drug throught the body is good. 32. Metabolism: metabolism of these drugs by the host is usually insignificant, but some metabolism of penicillin G has been shown to occur in patients with impaired renal function. Excretion: most are eliminated through active tubular secretion. Nafcillin and oxacillin eliminated largely in bile. Plasma half life : usually < 2 hours 33. Narrow spectrum Penicillins 34. Benzylpenicillin (penicillin G) Properties : Narrow spectrum Bactericidal in action and very high activity Destroyed by gastric HCL Destroyed by beta lactamase Short duration of action Highly water soluble Indications : Pneumococcal, streptococcal (infective endocarditis), meningococcal meningitis, tetanus, gas gangrene, syphillis, gonorrohea 35. Penicillin V (acid resistant) Properties : Same as penicillin G but Less potent activity Acid resistant (orally active) Short duration of action Destroyed by beta lactamase Indications : Boil, abscess Pneumonia Prophylaxis before and after surgery 36. Beta lactamase resistant penicillins The penicillins that are resistant to hydrolysis by beta lactamase (penicillinase) are called beta lactamase resistant penicillins. Properties : Narrow spectrum of activity, but less potent then benzylpenicillin Acid resistant (except methicillin) Food interferes absorption of drugs (administered 1 hour before or after meal) Indication is infections caused by penicillinase producing Staphylococci, for which they are the drug of choice except in area where methcillin resistant Staph. aureus (MRSA) 37. Flucloxacillin Narrow spectrum beta-lactam antibiotic Used to treat infections caused by susceptible Gram- positive bacteria Mode of action Acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria. 38. Indications 1. Staphylococcal skin infections and cellulitis including Impetigo,Otitis externa,folliculitis,boils,carbuncles, andmastitis 1. Pneumonia 2. Osteomyelitis, septic arthritis 3. Septicaemia 4. Empirical treatment for endocarditis 5. Surgical prophylaxis 39. Precautions/contraindications Previous history of allergy to penicillins, cephalosporins or carbapenems Should also not be used in the eye Used with caution in the elderly, patients with renal impairment, where a reduced dose is required; and those with hepatic impairment, due to the risk of cholestatic hepatitis. 40. Adverse effects An allergic reaction (shortness of breath; swelling of lips, face, or tongue; rash; or fainting); Seizures; Severe watery diarrhea and abdominal cramps; or Unusual bleeding or bruising. 41. Resistance Methicillin-resistant Staphylococcus aureus (MRSA) has developed resistance to flucloxacillin and other penicillins by having an altered penicillin binding protein Note : Oxacillin, Nafcillin, Cloxacillin and Dicloxacillin are similar to Flucloxacillin. 42. Cloxacillin Acid resistant Taken in empty stomach Plasma protein binding > 90% Elimination : kidney, partially by liver Plasma half life : about 1 hour 43. Broad spectrum penicillins Ampicillin, Amoxicillin, Carbenicillin, ticarcillin, azlocillin. Properties : These are semisynthetic penicillin Acid resistant (not destroyed by HCL) Destroyed by beta lactamase Less potent than benzylpenicillin Short duration of action (4 6 hours) and plasma t1/2 I hour Usually given with beta lactamase inhibitors Adverse effects : Superinfection, hypersensitivity, GI upset (loose motion) 44. Indications Respiratory tract infections (RTI): Sinusitis, Otitis media, tonsillitis, bronchitis Urinary tract infection (UTI) Meningitis due to H.influenza, meningococci Gonorrhoea Enteric fever Bacillary dysentry 45. Beta lactamase inhibitors Are family of enzymes produced by many gram + and gram bacteria that inactivates beta lactam antibiotics by opening the beta lactam ring . Clavulanic acid : Inhibits a wide variety of beta lactamase produce by both gram + and gram bacteria It is a progressive inhibitor: binding with beta lactamase is reversible initially, but becomes covalent later inhibition increasing with time and called sucide inhibitor. 46. Pharmacokinetics : Rapid oral absorption Bioavailability 60 % t1/2 1 hour Eliminated through kidney but not affected by probenecid. ADR : same as amoxicillin Uses : addition of clavulanic acid re- establishes the activity of amoxicillin against beta lactamase producing resistant Staph. Aureus, H. influenza, N. gonorrhoea, E. coli, proteus, Klebsiella, Salmonella, and shigella 47. Penicillin + Probenecid Probenecid inhibit the tubular secretion of penicillin, so probenecid causes : Raises the plasma concentration of penicillin Prolongation of the action of penicillin Penicillin +Aspirin Penicillin is excreted through kidney by tubular secretion, when aspirin is administered with penicillin, it inhibits the tubular secretion of penicillin, so prolonged the action (increased bioavailibility) 48. Adverse Reactions of penicillin 1. Hypersensitivity: most important adverse effect of the penicillins; ranges from maculopapular rash to angioedema and anaphylaxis. 2. GI Distress: nausea, vomitting and diarrhoea 3. Nephritis 4. Neurotoxicity 49. CEPHALOSPORINS B-lactams antibiotics that are closely related both structurally and functionally to penicillins. Like the penicillins, cephalosporins have a beta- lactam ring structure that interferes with synthesis of the bacterial cell wall and so are bactericidal. 50. To be continued 51. Mechanism of action (MOA): Cephalosporins are bactericidal agents and have the same mode of action as other beta-lactam antibiotics (as penicillins). All bacterial cells have a cell wall that protects them. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls, which causes the walls to break down and eventually the bacteria die. 52. CLASSIFICATION I Generation: Predominantly active against gram positive pathogens II Generation: Moderate activity against gram positive & gram negative pathogens III Generation: Predominantly active against gram negative pathogens IV Generation: wider spectrum 53. First Generation Cephalosporins Active against gram + cocci, pneumococci, streptococci and staphylococci. The first generation cephalosporins are: Cephradine Cefadroxil Cephalexin Cefazolin Cephalothin Cephapirin 54. Pharmacokinetics and dosage A. Oral : Cephalexin, cephradine, cefadroxil (500mg) Excretion by kidney and tubular secretion into the urine. Probenecid block the tubular secretion (increase the serum level) B. Parenteral : Cefazolin : only first generation parenteral 55. Clinical uses Relatively nontoxic. Oral drugs : UTI, cellulitis or soft tissue abscess Cefazolin penetrates the most tissues. Drug of choice for surgical prophylaxis. Streptococcal or staphylococcal infections who have history of penicillin allergy. Does not penetrate the CNS 56. Second generation cephalosporins Are active against organism inhibited by 1st generation drugs and extended gram negative coverage. The second generation cephalosporins are: Cefaclor, Cefuroxime, Cefonicid, Cefoxitin Ceforanide Cefprozil Cefmetazole, and cefotetan active against anaerobes. 57. Cefaclor, Cefuroxime, cefamandole, cefonicid, and ceforanide ------- active against H. influenzae Cefoxitin and ----- active against B fragilis. 58. Pharmacokinetics and dosage : A . Oral : - Cefaclor, Cefuroxime, cefprozil,. Dosage : Adult (10-15mg/kg/d x 4 x divided dose; Children (20-40mg/kg/d up ot 1 g/d) Cefuroxime (not active against penicillin-resistant pneumococci) Cefaclor (susecptible to beta- lactamase hydrolysis) B. Parenteral : excreted by kidney I.M is very painful so I.V is used. 59. Clinical uses : Oral : beta-lactamase producing H influenzae, Moraxella catarrhalis. Tx of sinusitis, otitis or lower respiratory tract infections. Cefuroxime for community- acquired pneumonia. 60. Third generation cephalosporins Third generation cephalosporins have a broad spectrum of activity and expanded gram-negative coverage, and some are able to cross the BBB. Effective against beta lactamase producing strains of haemophilus and neisseria. Most enter CNS and are important in emperic management of meningitis and sepsis. 61. The third generation cephalosporins are: Oral Cefixime Cefdinir Cefpodoxime proxetil, Ceftibuten Moxalactam. Cefpodoxime proxetil Parenteral Ceftriaxone Cefotaxime, Cefoperazone, Ceftazidime, Ceftizoxime 62. Cefoperazone, ceftadizime are only two drugs with activity against P aeruginosa. Ceftizoxime and moxalactam (B. fragilis) 63. Pharmacokinetics Penetrate body fluids and tissues well . Half life : Ceftriaxone 15-50mg/kg/d (t1/2 : 7-8 hrs) x od 1g dose is sufficient for most serious infections 4g x od for meningitis Cefoperazone 25-100mg/kg/d (t1/2:2 hrs) x8-12hrs. Remaining drugs (t1/2 : 1-1.7hrs) Cefixime x p/o x 200mg (bd) or 400mg (od) for RTI or UTI. Excretion : renal except cefoperazone and ceftriaxone through biliary tract (no dose adjustment in renal disease) 64. Clinical uses Ceftriaxone and cefotaxime (meningitis)- caused by pneumococci, meningococci, H influenzae and suspected gram negative rods, but not by L monocytogenes. Sepsis of unknown cause. Ceftriaxone and cefotaxime for meningitis (cross the BBB) 65. 4th generation cephalosporins Fourth generation cephalosporins are extended spectrum agents with similar activity against gram-positive organisms as first generation cephalosporins. Many can cross blood brain barrier and are effective in meningitis. Highly active against haemophilus and neisseria. Plasma half life (2 hrs) and excreted by kiney. The fourth generation cephalosporins are: Cefepime Cefluprenam 66. Ceftobiprole,Ceftaroline has been described as "fifth-generation" cephalosporin, though acceptance for this terminology is not universal. Ceftobiprole has powerful anti pseudomonal characteristics and appears to be less susceptible to development of resistance. Ceftaroline has also been described as "fifth-generation" cephalosporin, but does not have the anti-pseudomonal coverage as Ceftobiprole . 67. Adverse reactions: Hypersensitivity reactions (anaphylaxis, fever, skin rashes, nephritis and hemolytic anemia) Patients with history of anaphylaxis to penicillins should not receive cephalosporins. Thrombophlebitis after IV and local irritation after IM Renal toxicity; interstitial nephritis common side effects involve mainly the digestive system: mild stomach cramps or upset, nausea, vomiting, and diarrhea. Incidence of resistance is lower than penicillins 68. Some common uses of cephalosporins Hospital-acquired pneumonias - Cefotaxime Meningitis - Cefotaxime, Ceftriaxone Sepsis (initial Tx) - 3rd and 4th generation cephalosporins Gonorrhoea Acute urinary tract infections (UTI) 69. Monobactams Aztreonam Used as IV every 8 hrly, 1-2 g Half life (1- 2 hrs) Narrow spectrum Gram(-) rods Highly resistant to -lactamases Penicillin allergic patients tolerate aztreonam. ADR: - May causes skin rashes. Alternative to aminoglycosides and 3rd generation cephalosporins 70. Carbapanems Imipenem, Meropenem, Ertapenem Antimicrobial Activity Imipenem, like other b-lactam antibiotics, binds to PBPs, disrupts bacterial cell wall synthesis, and causes death of susceptible microorganisms. It is very resistant to hydrolysis by most b-lactamases. The activity of imipenem is excellent for a wide variety of aerobic and anaerobic microorganisms. Streptococci (including penicillin-resistant S. pneumoniae), staphylococci (including penicillinase-producing strains), and Listeria are all susceptible. Although some strains of methicillin-resistant staphylococci are susceptible, many are not. Activity is excellent against the Enterobacteriaceae, including organisms that are cephalosporin-resistant. 71. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Consequently, it is administered together with an inhibitor of renal dehydropeptidase, Cilastatin, for clinical use. Therapeutic Uses Imipenemcilastatin is effective for a wide variety of infections, including urinary tract and lower respiratory infections; intra-abdominal and gynecological infections; and skin, soft tissue, bone, and joint infections. The combination appears to be especially useful for the treatment of serious infections caused by cephalosporin- resistant nosocomial bacteria, as may be seen in hospitalized patients who have recently received other b-lactam antibiotics. 72. Meropenem has slightly greater activity against gram-negative aerobes and slightly less activity against gram-positives. It is not significantly degraded by renal dehydropeptidase and does not require an inhibitor. Its toxicity and clinical efficacy are similar to imipenem, except that it may be less likely to cause seizures. Ertapenem is less active than meropenem or imipenem and it is not degraded by renal dehydropeptidase. 73. Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid. Cleared renally, and the dose must be reduced in patients with renal insufficiency. Imipenem Dose : 0.250.5 g given intravenously every 68 hours (half-life 1 hour). Meropenem Dose : 1 g intravenously every 8 hours. Ertapenem Dose : 1 g intravenously or intramuscularly ,half- life (4 hours) and is administered as a once-daily. 74. Most common adverse effects : - Imipenemnausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites. Excessive levels of imipenem in patients with renal failure may lead to seizures. - Meropenem and Ertapenem are less likely to cause seizures than imipenem. - Patients allergic to penicillins may be allergic to carbapenems as well. 75. Vancomycin Is an antibiotic produced by Streptococcus orientalis With the single exception of flavobacterium, it is active only against gram-positive bacteria, particularly staphylococci. water-soluble and quite stable. 76. Mechanisms of Action Inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect. Antibacterial Activity : Vancomycin is bactericidal for gram-positive bacteria. Synergistic with Gentamicin and Streptomycin 77. Pharmacokinetics Poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by Clostridium difficile. 90% of the drug is excreted by kidney. Half-life of vancomycin is 610 days. Parenteral doses must be administered intravenously 78. Clinical Uses Indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin resistant staphylococci Combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy dosage is 30 mg/kg/d in two or three divided doses Children is 40 mg/kg/d in three or four divided doses. Oral vancomycin, 0.1250.25 g every 6 hours, is used to treat antibiotic-associated enterocolitis caused by Clostridium difficile. 79. Adverse Reactions In about 10% of cases Phlebitis at the site of injection Chills and fever Ototoxicity is rare and nephrotoxicity uncommon "red man" or "red neck syndrome (infusion-related flushing is caused by release of histamine) - prevented by prolonging the infusion period to 12 hours or increasing the dosing interval 80. Bacitracin Active against gram-positive microorganisms Inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. Markedly nephrotoxic if administered systemically, producing proteinuria, hematuria, and nitrogen retention Because of its marked toxicity when used systemically, it is limited to topical use Poorly absorbed and local antibacterial activity without significant systemic toxicity. Use :- irrigation of joints, wounds, or the pleural cavity. 81. Protein synthesis inhibitors The bacterial ribosome is composed of 30s and 50s subunits. 30s ribosomal subunit inhibitors: aminoglycosides and tetracyclines 50s ribosomal subunit inhibitors: Macrolides, chloramphenicol, clindamycin 82. AMINOGLYCOSIDES Bactericidal MOA: Inhibit protein synthesis ( 30 s subunit ) by interfering with the initiation complex of peptide formation induce misreading of mRNA, resulting in nonfuctional protein Eg: Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, Tobramycin, Sisomicin. 83. MECHANISM OF RESISTANCE: 1. Produce enzyme that inactivate the aminoglycoside (acetyltransferases, phosphotransferase) 2. Impaired entry of aminoglycoside into the bacteria. 3. Alteration of drug binding site (30s ribosomes) by chromosomal mutation. 84. Common properties of aminoglycosides Water soluble and more active at alkaline pH Extracellular distribution only, cannot cross the BBB Can cross the placenta (teratogenicity) Narrow therapeutic index All show common toxicities (ototoxicity, nephrotoxicity, neurotoxicity) 85. Indications Gram negative bacillary infections: 1. Septicaemia (gentamycin, amikacin) 2. Abdominal and pelvic sepsis Bacterial endocarditis (gentamycin + penicillin) Tuberculosis, plague, brucellosis Topical uses (Neomycin) 1. Conjunctival infection 2. Infection of external ear 3. Prior to bowel surgery (to reduce the intestinal flora) 86. Adverse effects 1. Hypersensitivity : rash, fever, eosinophilia, hemolytic anemia 2. Ototoxicity : 8th cranial nerve damage 3. Nephrotoxicity : 4. Neurotoxicity 5. Teratogenecity : risk of 8th cranial nerve damage 87. Common toxicities 1. Ototoxicity : Damage of 8th CN (vestibular and auditory damage) by toxic effects on sensory hair cells of cochlea and vestibular organ. a) Vestibular damage : comes earlier, usually reversible, headache (first), nausea, vomiting, dizziness, nystagmus, vertigo b) Auditory disturbance : comes lately; usually irreversible, tinnitus, deafness, headache 88. 2. Nephrotoxicity : excreted unchanged mainly by glomerular filtration; so attain high concentration in urine and accumulate in renal tubule : a) - damage to renal tubules (reversible) b) - proteinuria and haematuria c) - rising serum creatinin level 3. Neurotoxicity : Prevent release of acetylcholine. 89. Streptomycin Bactericidal (high dose) Bacterostatic (low dose) Second or third line drugs of tuberculosis Indications : Serious form of tuberculosis Plague, brucellosis Subacute bacterial endocarditis Urinary and respiratory tract infections 90. Gentamicin Sensitive strains : bactericidal against pseudomonas, proteus, klebsiella, enterobactor. More potent than streptomycin Spectrum: broad spectrum then streptomycin More nephrotoxic Indications : septicaemia, bacterimia, abdominal and pelvic abscess, bacterial endocarditis, infected burns, pneumonia, peritonitis Route of administration : IV, IM and topical (creams, ointments) 91. Neomycin Broad spectrum antibiotic Susecptible : E. coli, enterobacter, klebsiella pneuminiae, Staph. aureus, M. tuberculosis Poorly absorbed from the gut and excreted by kidney. Indications : Topical : infected burn, wound, ulcers Oral : preparation of the bowel for surgery 92. TETRACYCLINES Source : streptomyces grasius (soil organism) Broad spectrum antibiotics Bacterostatic in nature Acts by inhibiting bacterial protein synthesis Drugs : 1. Natural : oxytetracycline, chlortetracycline, demeclocyclin (short acting : 4-6hrs) 2. Semisynthetic : doxycycline, minocycline, methacycline, tetracycline (longer acting : 12- 24 hrs) 93. Mechanism of action Tetracyclines enter microorganisms ( by passive diffusion and active transport)------ Susceptible cells concentrate the drug intracellularly------- once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex .This prevents addition of amino acids to the growing peptide. 94. Pharmacokinetics Absorption after oral administration : 30% - chlortetracycline; 6070% - tetracycline, oxytetracycline, demeclocycline, and methacycline; and 95100% - doxycycline and minocycline Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+,Mg2+, Fe2+) ; by dairy products and antacids, which contain multivalent cations; and by alkaline pH 95. Distributed widely to tissues and body fluids . Minocycline reaches very high concentrations in tears and saliva. Tetracyclines cross the placenta and excreted in milk. As a result of chelation with calcium, tetracyclines are bound to and damagegrowing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline 50% by induction of hepatic enzymes that metabolize the drug. Excreted mainly in bile, feces and urine 96. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and contributes to maintenance of serum levels. Ten to 50 percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to 40 percent of the drug in the body is excreted in feces. Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms, does not accumulate significantly in renal failure, and requires no dosage adjustment, making it the tetracycline of choice for use in the setting of renal insufficiency. 97. Adverse Reactions Hypersensitivity reactions (drug fever, skin rashes) Gastrointestinal: - Nausea, vomiting, and diarrhea are the most common, direct local irritation of the intestinal tract, - Nausea, anorexia, and diarrhea can usually be controlled by administering the drug with food 98. Bony Structures and Teeth Tetracyclines are readily bound to calcium deposited in newly formed bone or teeth in young children. When the drug is given during pregnancy, it can be deposited in the fetal teeth, leading to discoloration, and enamel dysplasia. it can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods to children under 8 years of age, similar changes can result. 99. Liver Toxicity Especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g or more intravenously. Kidney Toxicity :Renal tubular acidosis and Fanconic syndrome (patient ingesting outdated and degraded tetracycline) resulting in nitrogen retention (except doxycycline) Local Tissue Toxicity: IV lead to venous thrombosis. IM painful local irritation 100. Photosensitization Systemic tetracycline administration, demeclocycline, can induce sensitivity to sunlight or ultraviolet light Vestibular Reactions :Dizziness, vertigo, nausea, and vomiting (doxycycline at doses above 100 mg). Superinfection : caused by Candida (angular stomatitis, sore throat; Proteus (UTI) 101. Indications Drug of first choice Chlamydial infections (PID) Mycoplasmal infection (pneumonia) Cholera Rickettsial infections (Typus, relapsing fever) Drug of second choice Diarrhoea (campylobacter) Dysentry (shigella) Abscess (actinomyces) Respiratory tract infection 102. Contraindications Children below 8 years of age Pregnancy : early (teratogenicity) ; late (fetal bone deformity, discoloration of teeth of offspring) Nursing mother Renal failure (except doxycycline) 103. Drug interactions Antacids : decrease effectiveness by chelating Iron : decrease absorption of tetracycline 104. Comparative study between Tetracycline 1. Natural 2. Irregularly absorbed from gut 3. Plasma half life : 12 hrs 4. Excretion : renal route 5. Renal failure : Contraindication Doxycycline 1. Semisynthetic 2. Completely absorbed from gut 3. Plasma half life : 16 hrs 4. Excretion : non renal route 5. Renal failure : effective 105. MACROLIDES Mechanism of action Inhibit protein synthesis by binding to the 50 s subunit Antibacterial activity Bactericidal or bacteriostatic, depending on the concentration and type of bacteria Example : Erythromycin, Azithromycin and clarithromycin, Roxythromycin Clarithromycin and azithromycin are semisynthetic derivatives of erythromycin. 106. Antibacterial spectrum: Erythromycin: Drug of choice in corynebacterial infections (Diphtheria, Corynebacterial sepsis); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment of community-acquired pneumonia Gram +ve cocci Atypical organisms (chlamydia, mycoplasma, ureaplasma species) Camphylobacter jejuni Azithromycin: Similar spectrum but more active in respiratory infections including mycobacterium avium Clarithromycin: has more activity against M.avium and H.pylori. 107. Pharmacokinetics: Erythromycin and Clarithromycin are metabolised by liver and excreted through the bile, they inhibit cytochrome p450 and are not safe in pregnancy. Azithromycin is excreted by the kidney, doesn't inhibit cytochrome p450 and is safer in pregnancy. Clarithromycin compared with Erythromycin are lower frequency of gastrointestinal intolerance. Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals. Azithromycin drug is slowly released from tissues (tissue half- life of 24 days). These unique properties permit once-daily dosing and shortening of the duration of treatment in many cases 108. Indication: Erythromycin : As alternative to Penicillin if allergic. Activity against atypical pneumonia organisms especially legionella, mycoplasma and chlamydia. Chancroid : 2g/day for 7 days is one of the drugs of choice, as effective as Azithromycin or Ceftriaxone. Clarithromycin: The antimicrobial spectrum is similar to Erythromycin; in addition, it includes MAC , other atypical mycobacteria and H. pylori. Indicated in URTI and LRTI, Sinusitis, Otitis media, skin infection due to Strep. Pyogens and some Staph. Aureus. Azithromycin: The antimicrobial spectrum is similar to Erythromycin. More active than other macrolids against H. influenzae but less active against Gm +ve cocci. Other indication Pharyngitis, tonsillitis, Otitis media, Chancroid and PPNG urethritis. 109. Resistance: Due to formation of methyl transferases that alter 50s drug binding site and acts as a drug inactivating enzymes. Side effects of Macrolides: Nausea, vomiting, abdominal pain & diarrhea Allergic reactions- urticaria, fever are infrequent. 110. CHLORAMPHENICOL MOA: binds reversibly to the 50S subunit of the bacterial ribosome ---- it inhibits the peptidyl transferase step of protein synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. Resistance is due to formation of acetyltransferases 111. Pharmacokinetics: Route of administration : oral , topical Absorption : completely absorbed from the GIT Distribution : throughout body tissue, CSF Plasma half life : 4 hours Metabolism : inhibit CYP P450 Excretion : kidney 112. Indications Salmonella infection (typhoid and paratyphoid fever): drug of choice in enteric fever Bacterial meningitis (H. influenzae) Brain abscess (chloramphenicol + penicillin) Septicaemia Occular infections (bacterial conjunctivitis) 113. Adverse Reactions Gastrointestinal Disturbances: Adults occasionally develop nausea, vomiting, and diarrhea Bone Marrow Disturbances: - commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 12 weeks Peripheral neuritis : prolonged use 114. Toxicity for Newborn Infants :- Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full-term infants and 25 mg/kg/d in premature infants 115. CLINDAMYCIN It is one of the lincosamide class antibiotic. It is usually used to treat infections with anaerobic bacteria, but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. 116. CLINDAMYCIN It is toxic and no longer used MOA is similar to that of macrolides. Narrow spectrum: gram +ve cocci and anaerobes Most serious adverse effect is potentially fatal pseudomembranous colitis caused by over growth of clostridium difficile. 117. Antifolate drugs 118. Sulfonamides Sulfonamide drugs were the first antimicrobial agents effective against pyogenic bacterial infections. Basic formula of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA) Sulfonamides tend to be much more soluble at alkaline than at acid pH. 119. Antimicrobial Activity Susceptible microorganisms require extracellular PABA in order to form dihydrofolic acid, an essential step in the production of purines and the synthesis of nucleic acids. Sulfonamides are structural analogs of PABA that competitively inhibit dihydropteroate synthase. inhibit growth by reversibly blocking folic acid synthesis. Sulfonamides inhibit both gram positive and gram- negative bacteria, Chlamydia trachomatis, and some protozoa. 120. Some enteric bacteria, such as E coli, klebsiella, salmonella, shigella, and enterobacter, respond but majority are resistant. Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis. 121. Resistance As a result of mutations that : 1. Cause overproduction of PABA, 2. Cause production of a folic acid synthesizing enzyme that has low afinity for sulfonamides, or 3. Impair permeability to the sulfonamide. 122. Pharmacokinetics Divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical The oral, absorbable sulfonamides can be classified as short-, medium-, or long-acting on the basis of their half-lives. 123. Absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Absorbed sulfonamides become bound to serum proteins (20% to over 90%). 124. Peak blood levels occur 26 hours after oral administration A portion of absorbed drug is glucuronidated in the liver. Sulfonamides and inactivated metabolites are then excreted into the urine, mainly by glomerular filtration. In renal failure, the dosage of sulfonamide must be reduced. 125. Clinical Uses Sulfonamides are infrequently used as single agents Drugs of choice : - Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis 126. Oral Absorbable Agents Sulfadiazine: (Short acting ) Achieves therapeutic concentrations in cerebrospinal fluid and in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis Sulfisoxazole and sulfamethoxazole (intermediate) urinary tract infections. Adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily. 127. Sulfadoxine is the only long-acting sulfonamide currently available. Available only in a combination formulation with pyrimethamine, which is used as a second-line agent in treatment for malaria Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression. 128. Oral Nonabsorbable Agents Sulfasalazine (salicylazosulfapyridine) : -widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease 129. Topical Agents Sodium sulfacetamide ophthalmic solution or ointment ---- for bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, Mafenide acetate is used topically to prevent bacterial colonization and infection of burn wounds. Mafenide is absorbed from burn sites, and systemic levels are produced. The drug and its primary metabolite also inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds. 130. Adverse Reactions Most common adverse effects : - fever, skin rashes, exfoliative dermatitis, photosensitivity, nausea, vomiting, diarrhea Stevens-Johnson syndrome, although relatively uncommon (ie, less than 1%), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects : - stomatitis, conjunctivitis, arthritis, hepatitis. 131. Urinary Tract Disturbances: Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine (large doses), particularly if fluid intake is poor, can cause crystalluria (treated by administration of sodium bicarbonate to alkalinize the urine and fluids to maintain adequate hydration). Hematopoietic Disturbances : Sulfonamides may provoke hemolytic reactions in patients whose red cells are deficient in glucose-6-phosphate dehydrogenase. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns. 132. Cotrimoxazole Fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole. Trimethoprim, inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA. Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, inhibits the activity of dihydrofolic acid reductase of protozoa more than that of mammalian cells. 133. Trimethoprim or pyrimethamine, given together with sulfonamides, produces sequential blocking in this metabolic sequence, resulting in marked enhancement (synergism) of the activity of both drugs. Combination often is bactericidal, compared to the bacteriostatic activity of a sulfonamide alone 134. Resistance Result from reduced :- 1. cell permeability, 2. overproduction of dihydrofolate reductase, or 3. production of an altered reductase with reduced drug binding. 135. Pharmacokinetics Given orally, alone or in combination with sulfamethoxazole, because it has a similar half-life. Trimethoprim-sulfamethoxazole can also be given IV. Absorbed efficiently from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole ,the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs 136. About 6570% of each participant drug is protein- bound, and 3050% of the sulfonamide and 5060% of the trimethoprim are excreted in the urine within 24 hours. Trimethoprim concentrates in prostatic fluid and in vaginal fluid, therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs. 137. Clinical Uses Oral Trimethoprim : 100 mg twice daily in acute urinary tract infections Oral Trimethoprim-Sulfamethoxazole : effective treatment for P jiroveci pneumonia, shigellosis, systemic salmonella infections complicated urinary tract infections, prostatitis Two double-strength tablets (trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections and prostatitis. For children treated for shigellosis, urinary tract infection, or otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 12 hours 138. Intravenous Trimethoprim- Sulfamethoxazole Choice for: moderately severe to severe pneumocystis pneumonia, gram-negative bacterial sepsis, shigellosis; typhoid fever; or urinary tract infection, patient is unable to take the drug by mouth. 139. Oral Pyrimethamine with Sulfonamide Pyrimethamine and sulfadiazine : - used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine. 140. Adverse Effects Megaloblastic anemia, leukopenia, and granulocytopenia. This can be prevented by the simultaneous administration of folic acid, 68 mg/d. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances. 141. DNA Gyrase Inhibitors 142. Quinolones Active against gram negative bacteria , though newer fluorinated compounds also inhibit gram positive. First member Nalidixic acid : limited to urinary tract g.i tract infections because of low potency, modest blood and tissue levels, limited spectrum and high frequency of bacterial resistance. 143. Nalidixic acid Active against gram- negative bacteria, like E.coli, proteus, Klebsiella, Enterobacter, Shigella but not pseudomonas. Mechanism of action (MOA) : acts by inhibiting DNA gyrase and is bactricidal. 144. Pharmacokinetics Absorbed orally. Highly plasma protein bound and partly metabolized in liver. Excreted : kidney. Plasma half life : 8 hours. Note : concentration of the free drug in plasma and most tissues attained with usual doses is non therapeutic for systemic infections. High concentration attained in urine (20 50 times that in plasma) is lethal to the common urinary pathogens. 145. Adverse effects G.I upset (nausea, vomiting and diarrhoea) rashes Most important toxicity is neurological : - headache, drowsiness, vertigo, visual disturbances, occasionally seizure (in children) Hemolysis (G 6 PD) Contraindication : in infants 146. Uses Urinary tract infection (Nitrofurantoin should not be given concurrently antagonism occurs) Diarrhoea (Proteus, E.coli, Shigella, Salmonella) 147. Fluoroquinolones : active against a variety of gram-positive and gram-negative bacteria. First generation Norfloxacin Ciprofloxacin Ofloxacin Pefloxacin Second generation Lomefloxacin Levofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Trovafloxacin 148. Mechanism of action (MOA) Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. 149. Antibacterial Activity Ciprofloxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin has excellent gram-negative activity and moderate to good activity against gram positive bacteria. 150. Gatifloxacin, moxifloxacin, sparfloxacin, and trovafloxacin group of fluoroquinolones with improved activity against gram-positive organisms, particularly S pneumoniae and to some extent staphylococci. 151. Resistance Due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism e.g E coli. With the increasing use of fluoroquinolones for a variety of infections, including respiratory tract infections, fluoroquinolone resistance has emerged among strains of Streptococcus pneumoniae. 152. Pharmacokinetics Fluoroquinolones are well absorbed (bioavailability of 80 95%) and distributed widely. Serum half-lives range from 3 hours (norfloxacin and ciprofloxacin) up to 10 (pefloxacin) or longer (sparfloxacin). Long half-lives of levofloxacin, moxifloxacin, sparfloxacin, and trovafloxacin permit once-daily dosing. Oral absorption is impaired by divalent cations, including those in antacids. 153. Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Alatrovafloxacin is the inactive, prodrug form of trovafloxacin for parenteral administration. Dose adjustment for renal failure is not necessary for trovafloxacin or moxifloxacin. Nonrenally cleared fluoroquinolones are contraindicated in patients with hepatic failure. 154. Adverse Effects Most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests. Hemolysis (G 6 PD) 155. Ciprofloxacin (prototype) Highly susceptible : E.coli, K. pneumoniae, Enterobacter, Salmonella typhi, Shigella, Proteus, N. gonorrhoeae, N. meningitidis, Campylobacter, Vibrio cholerae Moderately susceptible : Pseudomonas, Staph. aureus, Staph. epidermidis. Note : less active at acidic pH. 156. Pharmacokinetics Absorption : faster but food delays High penetrability : concentration in lung, sputum, muscle, bone, prostate but CSF are lower. Excretion : kidney Note : urinary and biliary concentrations are 10 50 fold higher than plasma. 157. Side effects Occurs in 10 % patients G.I.T : bad taste , nausea, vomiting, and diarrhea (less common: gut flora not affected). Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests. Hemolysis (G 6 PD) Tendonitis and tendon rupture. 158. Interactions Plasma concentration of theophylline, caffeine and warfarin increased (due to inhibition of metabolism) Antacids, sucralfate and iron : reduced absorption 159. Uses : Urinary tract infections Gonorrhoea (single dose 500 mg) Chancroid (500mg x tds x 3 days) Bacterial gastroenteritis Typhoid (first drug of choice due to resistance of chloramphenicol, ampicillin and cotrimoxazole) Bone, soft tissue and wounds infections Tuberculosis (MDR TB) Conjunctivitis (topical) 160. Norfloxacin Less potent than ciprofloxacin MIC values for most gram negative bacteria are 2 4 times higher Lower concentration in tissues Metabolized in liver and excreted by kidney Used for urinary and GIT infections because high concentration are present in the gut and gut flora is not disturbed. 161. Spectrum: Active against gram-positive pathogens including. Staphylococcus aureus. Staphylococcus epidermidis. Streptococcus agalactiae. Enterococcus faecalis. Gram-negative spectrum notable for activity against. Escherichia coli. Klebsiella pneumoniae. Enterobacter aerogenes. Proteus mirabilis. Proteus vulgaris. 162. Ofloxacin Intermediate between ciprofloxacin and norfloxacin in activity against gram negative bacteria, but more potent than ciprofloxacin for gram positive and certains anaerobes. Good activity against Chlamydia and Mycoplasma (alternative drug of choice for cervicitis, urethritis and atypical pneumonia) M. leprae (for alternative multidrug therapy regimens) 163. Pharmacokinetics Relatively lipid soluble Oral bioavailability is high: attains higher plasma concentrations. Food does not interfere with its absorption Excreted by kidney 164. Uses Systemic infections Chronic bronchitis Gonorrhoea (single dose 200mg) 165. Levofloxacin Oral bioavailability : nearly 100% (as i.v) Slower elimination Drug interaction : Plasma concentration of theophylline, cyclosporine and warfarin remains unchanged. First drug of choice : community acquired pneumonia and exacerbations of chronic bronchitis (87 96% cure). High cure rates : sinusitis, enteric fever, pyelonephritis. 166. To be continued..