PGI-REVIEW-ANTIMICROBIAL-AGENTS-ANTIBIOTICS.pptx

antibiotics

1. ANTIMICROBIAL AGENTS: ANTIBIOTICS

2. Classification Inhibitors of Cell Wall Synthesis Penicillins Cephalosporins , Carbapenems , Vancomycin Inhibitors of Protein Synthesis Macrolides , Clindamycin , Tetracyclines , Chloramphenicol Aminoglycosides , Streptogramins , Linezolid Inhibitors of Folic Acid Synthesis Sulfonamides and Trimethoprim Inhibitors of Nucleic Acid Synthesis Fluoroquinolones Antimycobacterial Drugs Miscellaneous Antimicrobials

3. Inhibitors of Cell Wall Synthesis Penicillins Cephalosporins , Carbapenems , Vancomycin, Bacitracin

4. PENICILLINS

5. Classification Bactericidal β- lactam ring  antibacterial activity Subclasses (basis: antimicrobial activity and susceptibility to penicillinases ) Penicillinase -susceptible narrow-spectrum Pen G and V Penicillinase -resistant narrow-spectrum Methicillin , nafcillin Penicillinase -susceptible wider-spectrum Ampicillin , amoxicillin, ticarcillin

6. Mechanisms MOA Bind to penicillin-binding proteins on bacterial cytoplasmic membranes  inhibit transpeptidation (final step in cell wall synthesis) Activation of autolytic enzymes  cause lesions in bacterial cell membrane and wall

7. Mechanisms of Action

8. Mechanisms of Resistance Formation of penicillinases (by staph and gram neg bacilli) – MAJOR Changes in PBP structure (MRSA, NRSA, PRSP) Changes in porin structure – prevent access to cytoplasmic membrane ( ticarcillin -resistant Pseudomonas )

9. Pharmacokinetics Oral bioavailability Gastric acid inactivates Pen G Elimination Most – via active tubular secretion (half-lives less than 60 minutes) Nafcillin – eliminated in the bile Ampicillin – undergoes enterohepatic cycling Crosses placenta but not teratogenic Repository form Benzathine Pen G (half-life > 14 days)

10. Clinical Uses – depend on subclass Penicillin Infections Penicillin G Common streptococci, pneumococci (if susceptible), enterococci (synergy with aminoglycoside ), meningococci , Treponema pallidum (drug of choice), and related spirochetes Nafcillin , oxacillin , and related drugs Known or suspected staphylococcal infections (not MRSA) Amoxicillin and ampicillin Susceptible enterococci , Escherichia coli , Haemophilus influenzae , Moraxella catarrhalis , Listeria monocytogenes , Helicobacter pylori Ticarcillin and related drugs Gram-negative bacilli including Pseudomonas aeruginosa (synergy with aminoglycosides )

11. Toxicities Hypersensitivity – 5 – 6% incidence Assume complete cross- allergenicity between different penicillins GIT reactions Nausea, diarrhea Potential opportunistic infections Fungi – upper GIT Bacteria (antibiotic-associated colitis) Maculopapular rash – ampicillin Seizures (as GABA antagonist)

12. Penicillinase inhibitors Enhances antibacterial activity of certain penicillins Clavulanic acid, sulbactam Act as suicide inhibitors of bacterial penicillinases Ex. Amoxicillin ( penicillinase -susceptible) (+) clavulanic acid – active against penicillinase producing staph Ticarcillin / piperacillin + sulbactam – enhanced gram negative bacilli activity

13. CEPHALOSPORINS

14. Mechanisms Bactericidal beta-lactams MOA - identical to penicillins Resistance Cephalosporinase formation Changes in PBPs

15. Classification and Clinical uses Cephalosporins Infections 1 st generation Cefazolin , cephalexin Gram (+) cocci (not MRSA), Escherichia coli, Klebsiella pneumoniae , some Proteus species 2 nd generation Cefotetan , cefaclor Gra m (-) bacilli including Bacteroides fragilis ( cefotetan ); Haemophilus influenzae and Moraxella catarrhalis ( cefaclor ) 3 rd generation Many gram (+) and gram (-) cocci and gram (-) bacilli including beta- lactamase -forming strains; individual drugs have activity against specific organisms including Pseudomonas ( ceftazidime ), anaerobes ( ceftizoxime ), and gonococci ( ceftriaxone , cefixime ) 4 th generation Cefipime combines the gram (+) activity of the 1 st generation drugs with the gram (-) activity of the 3 rd generation drugs Cefpirome

16. 5 th Gen Cephalosporins Ceftobiprole has powerful antipseudomonal characteristics and appears to be less susceptible to development of resistance Ceftaroline - covers MRSA, and Enterococcus faecalis — does not cover Pseudomonas *note: Katzung classifies this drug as a 4 th generation cephalosporin

17. 5 th Gen Cephalosporins* Cephalosporins Combined w/ β-lactamase Inhibitors developed to combat resistant Gram-negative infections Ceftolozane -tazobactam* and ceftazidime-avibactam treatment of complicated intra-abdominal infections and urinary tract infections (+) in vitro activity against Gram-negative organisms, including P aeruginosa and AmpC and extended-spectrum β-lactamase producing Enterobacteriaceae neither agent is active against organisms producing metallo -β-lactamases ceftazidime-avibactam is an option for carbapenemase -producing organisms

18. 5 th Gen Cephalosporins Cephalosporins Combined w/ β-lactamase Inhibitors Ceftolozane -tazobactam* and ceftazidime-avibactam limited activity against anaerobic pathogens  both should be combined w/ metronidazole when treating complicated intra-abdominal infections short half-lives (2–3 h); dosing: every 8 h primarily renally excreted  adjust dose in patients w/ impaired renal clearance * AmpC beta-lactamases - clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae and a few other organisms mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins , and beta-lactamase inhibitor-beta-lactam combinations

19. Pharmacokinetics Most are eliminated via active tubular secretion Half-lives of 1-2 hours Cefoperazone and ceftriaxone Eliminated in the bile 1 st and 2 nd generation drugs DO NOT enter the CNS 3 rd generation drugs can provide CSF levels adequate for the treatment of bacterial meningitis

20. Limitations 3 rd and 4 th gen – wide spectrum of antibacterial action HOWEVER, there are gaps None of the cephalosporins have activity against: methicillin-resistant staphylococci Listeria species Enterococci Mycoplasma pneumoniae Chlamydia

21. Toxicities Allergic reactions (1-2% incidence) Assume complete cross- allergenicity between different cephalosporins Partial cross- allergenicity between cephalosporins and penicillins Nausea and diarrhea Opportunistic infections Cefotetan, cefamandole, cefoperazone , ceftriaxone (rare) hypoprothrombinemia ( vit K antagonism) disulfiram -like reactions with ethanol inhibition of acetaldehyde dehydrogenase

22. Alternative Most authorities recommend avoiding cephalosporins in patients allergic to penicillins (for gram-positive organisms, consider macrolides; for gram-negative rods, consider aztreonam )

23. CARBAPENEMS

24. Carbapenems Imipenem , meropenem , doripenem , ertapenem Bactericidal, penicillinase -resistant, wide activity against gram (+) and (-) bacteria, including anaerobes IV agents eliminated by the kidneys reduce dose in renal dysfunction Imipenem + cilastatin  blocks metabolism by renal dihydropeptidases Toxicities - nausea, diarrhea, skin rash, and seizures (at high doses)

25. Monobactams Aztreonam β-lactam ring is not fused with another ring Narrow antimicrobial spectrum  not used for empirical therapy Resistant to β -lactamases

26. Monobactams Antibacterial Spectrum 1° - enterobacteria Aerobic gram (-) rods – Klebsiella , Pseudomonas, Serratia spp NO activity against gram (+) organisms and anaerobes Pharmacokinetics Administered via IV or IM Excreted in the urine; can accumulate in patients with renal failure

27. Monobactams Adverse Effects Relatively nontoxic Phlebitis, skin rash, occ. Elevation of LFTs Low immunogenic potential Little cross-reactivity with antibodies induced by other β -lactam antibiotics Safe alternative for px allergic to penicillins and/or cephalosporins

28. VANCOMYCIN

29. Vancomycin Bactericidal inhibitor of cell wall synthesis MOA Inhibits glycosylation reactions by binding to the D-Ala-D-Ala terminal of the pentapeptide chains of peptidoglycans Resistance (enterococci) Decreased binding of the drug via replacement of of the terminal D-Ala by D-lactate

30. Vancomycin Pharmacokinetics Not absorbed in the GIT Given parenterally, penetrates most tissues and undergoes renal elimination (reduce dose in renal dysfunction) Clinical uses Drug of choice for MRSA and back-up drug for enterococcal infections and pseudomembranous colitis Toxicities Chills, fevers, diffuse flushing (red man syndrome – due to histamine release), potential ototoxicity, nephrotoxicity

31. Bacitracin Mixture of polypeptides that inhibits bacterial cell wall synthesis MOA: inhibits the phosphorylation/ dephosphorylation cycling of the lipid carrier required in the transfer of peptidoglycan to the cell wall Restricted to topical use due to nephrotoxicity

32. PNEUMOCOCCAL RESISTANCE TO ANTIBIOTICS

33. Pneumococcal Resistance to Antibiotics Increasing prevalence of drug-resistant Streptococcus pneumoniae (DRSP) Resistance to penicillin = decreased susceptibility to most other beta-lactam antibiotics Involves changes in PBPs DRSP strains Resistant – macrolides, tetracyclines , co- trimoxazole Sensitive – newer fluoroquinolones (levofloxacin, sparfloxacin ) Vancomycin remains active against most pneumococci

34. Newer Cell Wall Synthesis Inhibitors Teicoplanin Glycopeptide Similar characteristics with vancomycin Daptomycin Lipopetide ; Inhibits cell wall synthesis by membrane depolarization Activity: like vancomycin but active against vancomycin -resistant enterococci and staphylococci Eliminated renally May cause myopathy  monitor CPK weekly

35. Inhibitors of Protein Synthesis Macrolides, Clindamycin, Tetracyclines , Chloramphenicol Aminoglycosides, Streptogramins , Linezolid

36. Macrolides , Clindamycin , Tetracyclines , Chloramphenicol

37. Buy AT 30, CELL at 50 A minoglycosides, T etracyclines – 30S C hloramphenicol , E rythromycin , L incomycin (Clindamycin), L inezolid – 50S

38. Mechanisms of Action and Resistance All are bacteriostatic inhibitors of protein synthesis acting at the ribosomal level

39. Mechanisms of Action Macrolides and clindamycin Bind to the 50S subunit to block translocation Chloramphenicol Bind to the 50S subunit, inhibits transpeptidation by preventing the binding of the aminoacyl moiety of charged tRNA Tetracyclines Bind to the 30S subunit to prevent binding of the charged tRNA to the acceptor site of the ribosomal-mRNA complex

40. Mechanisms of Resistance Gram (+) cocci Macrolides – methylation of the 50S “receptor” – preventing binding of antibiotics Chloramphenicol – formation of acetyltransferases that inactivate the drug Tetracyclines – decreased intracellular accummulation

41. MACROLIDES

42. Macrolides Examples – erythromycin, azithromycin, clarithromycin; - bacteriostatic Pharmacokinetics – all have good oral bioavailability Erythromycin ( biliary excretion) and clarithromycin (metabolism and renal clearance) – half-lives of less than 5 hours Azithromycin – accumulates in tissues and undergoes renal elimination Half-life > 3 days  single dose is adequate for the management of nongonococcal urethritis

43. Clinical Uses For infections caused by gram (+) cocci (not MRSA, and some pneumococcal strains are also resistant), Mycoplasma pneumoniae, chlamydial species, Ureaplasma urealyticum , and Legionella pneumophila Azithromycin - also for Haemophilus influenzae and Moraxella catarrhalis Clarithromycin – for Helicobacter pylori

44. Toxicities Erythromycin GIT distress Estolate form may cause cholestasis (avoid in pregnancy) Erythromycin and clarithromycin Inhibit CYT P450  may enhance the effects of other drugs (carbamazepine, theophylline, warfarin) Azithromycin (-) enzyme inhibition; safe in preganancy

45. CLINDAMYCIN ( Lincosamide )

46. Clindamycin Pharmacokinetics Effective orally, with good tissue penetration Eliminated by metabolism, biliary excretion and renal clearance Clinical Uses Active versus gram-positive cocci (not MRSA) and anaerobes including Bacteroides strains Prophylactic against enterococcal encocarditis in penicillin-allergic patients Back-up drug against Pneumocystis carinii and Toxoplasma gondii

47. Clindamycin Toxicities GIT distress, skin rash, opportunistic infections including pseudomembranous colitis (d/t Clostridium difficile overgrowth)

48. TETRACYCLINES

49. Tetracyclines Ex. Tetracycline, doxycycline, demeclocycline Pharmacokinetics (+) good oral bioavailability (AVOID antacids) Most are eliminated via the kidney, but a large fraction of doxycycline appears in the feces

50. Tetracyclines Clinical Uses – Mycoplasma pneumoniae, chlamydial species, Rickettsia, and Vibrio Back-up drugs in syphillis , and are used prophylactically in chronic bronchitis and acne Tetracycline – against Helicobacter pylori Doxycycline – drug of choice for Lyme disease Demeclocycline – for SIADH

51. Toxicities GIT disturbances, opportunistic infections, tooth enamel dysplasia, bone growth irregularities in children, phototoxicity and dizziness Hepatic dysfunction in overdose (rare) Fanconi’s syndrome (from of renal tubule acidosis; seen in older tetracyclines)

52. CHLORAMPHENICOL

53. Chloramphenicol Pharmacokinetics Orally effective with wide tissue penetration Metabolized by glucoronyl transferase (deficient in neonates) Clinical uses Back-up drug in bacterial meningitis, typhoid fever, rickettsial diseases, and Bacteroides infections

54. Chloramphenicol Toxicities Nausea, diarrhea, opportunistic infections, bone marrow suppression (dose-dependent and reversible) and aplastic anemia (very rare) “gray baby”syndrome – cyanosis and cardiovascular collapse Occurred in neonates with inadequate glucoronyltransferase

55. Aminoglycosides, Streptogramins , Linezolid

56. Mechanisms of Action Aminoglycosides Bactericidal inhibitors of protein synthesis Intracellular accumulation is oxygen-dependent – anaerobes are INNATELY resistant Bind to 30S ribosomal subunit  block formation of the initiation complex, prevent translocation, and cause misreading of mRNA

57. Mechanisms of Action Streptogramins Bactericidal (based on Katzung ; bacteriostatic in Kaplan reviewers) Binding to a site on the 50S subunit and blocking extrusion of nascent polypeptides; also inhibit tRNA synthetase Linezolid Bacteriostatic Also binds to 50S subunit site to block initiation

58. Mechanisms of Resistance Resistance to aminoglycosides – common in gram-positive bacteria Occur via plasmid-mediated formation of inactivating transferases Streptogramins and linezolid Resistance patterns still being determined

59. Pharmacokinetics of Aminoglycosides Absorption and distribution As polar compounds not absorbed orally or widely distributed Parenteral adminstration is required for systemic and most tissue infections Elimination Renal clearance of ALL aminoglycosides is proportional to glomerular filtration rate Major dose reductions are required in glomerular dysfunction Elimination half-lives of 2-3 hours

60. Once Daily Dosing of Aminoglycosides Despite short half-lives As effective as conventional dosing regimens Results in less nephrotoxicity Postantibiotic effect (PAE) occurs Killing action continues when plasma levels have fallen below expected MICs Concentration-dependent, rather than time-dependent killing action, BUT nephrotoxicity appears to be dependent on both dosage and time

61. Clinical Uses of Aminoglycosides Gentamicin, tobramycin, amikacin For aerobic gram-negative bacilli, including Escherichia coli and species of Enterobacter, Klebsiella , Proteus, Pseudomonas, and Serratia Synergism with penicillins against enterococci and Pseudomonas strains Streptomycin – regimens for TB, cholera, tularemia Neomycin – very nephrotoxic  restricted to topical use

62. Toxicities of Aminoglycosides Nephrotoxicity Acute tubular necrosis (6-7% incidence) Once-daily dosing decreases toxic effects Ototoxicity Auditory or vestibular dysfunction 2-3% incidence May not be fully reversible Contact dermatitis Frequent with neomycin

63. Streptogramins and Linezolid Streptogramins Quinupristin , dalfopristin IV; for MRSA, vancomycin -resistant Staphylococcus aureus (VRSA) , and vancomycin -resistant enterococci (VRE) Linezolid Similar clinical indications with streptogramins Also active against penicillin-resistant pneumococci No cross-resistance with other protein synthesis inhibitors

64. Streptogramins and Linezolid Streptogramins Arthralgia and myalgia Potent inhibitors of cytochrome P-450 enzymes involved in drug metabolism

65. Inhibitors of Folic Acid Synthesis Sulfonamides and Trimethoprim

66. Mechanisms of Action Sulfonamides Structurally similar to para-aminobenzoic acid (PABA) – precursor used by microorganisms in folate synthesis Inhibit dihydropteroate synthetase  1 st step of folic acid synthesis Trimethoprim Structural analog of dihydrofolic acid Inihbits dihydrofolate reductase in bacteria Pyrimethamine – inhibits DHFR in protozoans

67. Mechanisms of Action Sequential blockade Combination of sulfamethoxazole and trimethoprim  sequential blockade of folic acid synthesis  antibacterial synergy Individually – static Combined – cidal

68. Mechanisms of Resistance Sulfonamides Changed sensitivity of dihydropteroate reductase Increased PABA production Decreased intracellular accumulation of drug Trimethoprim Change in DHFR sensitivity

69. Pharmacokinetics Sulfonamides – most are orally effective Intact drug or acetylated metabolites are eliminated via the kidney  may cause CRYSTALLURIA in acidic urine Bind to plasma proteins and displace other bound drugs (phenytoin, warfarin) and bilirubin Trimethoprim Well-absorbed orally; penetrates tissues effectively Eliminated largely unchanged by the kidney

70. Clinical Uses Individual drugs Sulfonamides Silfisoxazole – simple UTI Sulfacetamide – ocular chlamydial infections Sulfadiazine – burn dressings Sulfazalazine – ulcerative colitis Trimethoprim-Sulfamethoxazole UTIs Respiratory, ear and sinus infections Haemophilus influenzae and Moraxella catarrhalis Drug of choice for prevention and treatment of Pneumocystis carniii pneumonia

71. Toxicities Sulfonamides Hypersensitivity reactions (4-6% incidence), nausea and diarrhea, hemolysis in G6PD patients, phototoxicity , crystalluria , drug interactions TMP-SMX Those above PLUS Hematotoxicity (anemia and granulocytopenia ) Esp. in malnourished or immunodeficient patients TMP – Treats Marrow Poorly

72. METHICILLIN-RESISTANT STAPHYLOCOCCUC AUREUS Resistant to ALL beta-lactam antibiotics Also usually resistant to macrolides, older fluoroquinolones, and TMP-SMX Vancomycin presently has activity against most MRSA strains, but resistance is increasing Alternative drugs for MRSA Quinupristine-dalfopristin Linezolid

73. Inhibitors of Nucleic Acid Synthesis Fluoroquinolones

74. Fluoroquinolones Fluoroquinolones – derivatives of nalidixic acid Norfloxacin and ciprofloxacin are prototypes Latter – (+) extensive use and increasing resistance Newer agents (+) activities against specific organisms (+) distinct toxicities

75. Mechanisms of Action Bactericidal inhibitors of nucleic acid synthesis Inhibit topoisomerase II (DNA gyrase)  block relaxation of supercoiled DNA, Inhibit topoisomerase IV - prevent separation of replicated DNA

76. Mechanisms of Resistance Especially seen in gram (+) cocci Decreased intracellular accumulation Changes in sensitivity to inhibition of the topoisomerases

77. Pharmacokinetics Antacids interfere with oral bioavailability Renal clearance via active tubular secretion Dose reductions needed in renal dysfunction (+) short half-lives

78. Clinical Uses General Wide spectrum of activity – infections of the GUT, GIT, and URT Specific Ciprofloxacin and ofloxacin – single dose in gonorrhea (but resistance is increasing) Levofloxacin and sparfloxacin Mycoplasma pneumoniae , PRSP, community-acquired pneumonia Moxifloxacin and trovafloxacin Newer drugs with broad activity that includes Drug-resistant oneumococci , Mycoplasma pneumoniae , a naerobes, Chlamydia

79. Toxicities Common to all GIT distress, skin rash, tendinitis, headache, dizzines Seizures in overdose and susceptible agents NOT recommended in pregnancy and in small children  affects collagen metabolism Phototoxicity ( eg . Sparfloxacin ) Some my prolong the QT interval Travofloxacin – (+) hepatotoxic potential

80. Antimycobacterial Drugs

81. Concepts Drug combinations – rationale: Delay development of resistance Enhance activity DOT – directly observed therapy For patient compliance Major drugs Isoniazid, rifampicin, ethambutol , pyrazinamide, streptomycin Fluoroquinolones , and several older anti-TB drugs For MDR-TB Prophylaxis Isoniazid and rifampicin for latent TB infection

82. Isoniazid MOA INH is converted by mycobacterial catalase to a metabolite that inhibits mycolic acid synthesis High-level resistance Deletions in the katG gene  codes for catalase Low-level resistance Deletions in the inhA gene  codes for the target acyl carrier protein

83. Isoniazid Pharmacokinetics Metabolized by N-acetyltransferase Genotypic variability exists  fast acetylators need high doses of INH Toxicities Neurotoxicity (offset by vitamin B6) hepatitis (age-dependent) Hemolysis in G6PD deficiency Lupus-like reactions (rare)

84. Isoniazid INH I njures N eurons and H epatocytes

85. Rifampicin MOA Inhibits DNA-dependent RNA polymerase Resistance Via changes in polymerase sensitivity to inhibition Pharmacokinetics Undergoes hepatic metabolism to red-orange colored metabolites

86. Rifampicin Toxicities MOST COMMON  Light-chain proteinuria, GIT distress, rash Flu-like syndrome at high doses Induces drug metabolizing enzymes (less so for rifabutin ) May decrease the effectiveness of Anticonvulsants Contraceptive steroids warfarin

87. Ethambutol Inhibits arabinogalactan synthesis (component of mycobacterial cell walls) MOST DISTINCTIVE TOXICITY Retrobulbar neuritis Dose-dependent reversible

88. Pyrazinamide Requires bioactivation for activity, but the precise target undetermined Minimal cross-resistance with other agents May be valuable in short course treatment regimens Toxicities Polyarthralgia Hyperuricemia Phototoxicity Exacerbation of porphyria

89. Order of Degree of Hepatotoxicity (least to most) Isoniazid < Rifampicin < Pyrazinamide

90. Drugs for Mycobacterium intracellulare infection Prophylaxis Azithromycin or clarithromycin Treatment Clarithromycin + ethambutol with or without rifampicin or rifabutin

91. Drugs for Leprosy Dapsone Most active against Mycobacterium leprae Back-up drug for Pneumocystis carinii pneumonia Toxicities GIT irritation, skin rash, methemoglobinemia , hemolysis in G6PD deficiency Alternative Drugs Rifampicin or clofazimine  used in resistance or dapsone intolerance

92. Miscellaneous Antimicrobials

93. Metronidazole and Tinidazole MOA: undergoes reductive metabolism in anaerobes  forms a metabolite that interferes with nucleic acid synthesis Clinical uses Drug of choice for: amebiasis , giardiasis, trichomoniasis , infections caused by Bacteroides fragilis , Clostridium difficile, Gardnerella vaginalis Also used in the eradication of Helicobacter pylori in PUD Toxicities GIT irritation, headaches, dizziness, dark-colored urine Disulfiram-like reactions with alcohol

94. Fosfomycin MOA: Inhibits enolpyruvate transferase, preventing the formation of N- acetylmuramic acid needed for bacterial cell wall synthesis Resistance Via decreased intracellular accumulation Clinical Use UTIs

95. Urinary Antiseptics Nitrofurantoin MOA: activated by bacterial flavoproteins ( nitrofuran reductase) to active reduced reactive intermediates that are thought to modulate and damage ribosomal proteins or other molecules, especially DNA, causing inhibition of DNA, RNA, protein, and cell wall synthesis Oral administration  result in urinary levels adequate for eradication of most UTI pathogens EXCEPT Proteus and Pseudomonas; MOA not clear Toxicities GIT distress, skin rash, phototoxicity , hemolysis in G6PD deficiency

96. Urinary Antiseptics Nalidixic acid Quinolone; antibacterial activity identical to nitrofurantoin Toxicities Glycosuria, skin rash, phototoxicity , ocular dysfunction

97. Fidaxomicin Macrolide Inhibits bacterial RNA polymerase; bactericidal Used for C. difficle colitis Administered orally Not absorbed  blood levels are negligible

98. Urinary Antiseptics Methenamine Urinary acidifier Releases formaldehyde below pH 5.5 Insoluble complexes form if given with sulfonamides

99. Disinfectants and Antiseptics Acids, alcohols, aldehydes 70% ethanol Formaldehyde Acetic acid Salicylic acid Halogens – iodine and hypochlorous acid Halozone – for water purification Sodium hypochlorite (household bleach) Disinfection of blood spills that may contain HIV or HBV

100. Disinfectants and Antiseptics Oxidizing agents Hydrogen peroxide, potassium permanganate Heavy metals Merbromin, silver sulfadiazine Chlorinated phenols Hexachlorphene and chlorhexidine – used in surgical scrub routines Lindane – mite or lice infestation Cationic surfactants Benzalkonium chloride and cetylpyridinium chloride  for disinfection of surgical instruments BUT may foster growth of gram (-) bacteria

101. Antibacterial Drugs and Phototoxicity Manifestation Delayed erythema and edema  skin hyperpigmentation and desquamation Common agents Fluoroquinolones, sulfonamides, tetracyclines  localized to regions exposed to UV light Other agents Griseofulvin, lincomycin, nalidixic acid, pyrazinamide, trimethoprim

102. ANTIBIOTICS TO BE AVOIDED IN PREGNANCY Aminoglycosides – ototoxicity Clarithromycin – embryotoxic in animal studies Erythromycin estolate – cholestasis in pregnancy Fluoroquinolones – deleterious effects in collagen metabolism Tetracycline – interfere with bone and tooth formation via calcium chelation Sulfonamides (3 rd trimester) – may displace bilirubin from plasma proteins in the fetus and neonate  kernicterus Metronidazole – mutagenic (via Ames test)