1. Commonly Encountered Microbes and the Antibacterial Drugs used to treat them Felix Hernandez, M.D.

2. Gram Positive Cocci Appearance: Appearance: Blue and round by microscopy Blue and round by microscopy Have a thick peptidoglycan cell wall that surrounds the bacteria Have a thick peptidoglycan cell wall that surrounds the bacteria This wall is impermeable and is responsible for retention of the blue dye in gram staining This wall is impermeable and is responsible for retention of the blue dye in gram staining Penicillins, cephalosporins, bacitracin, vancomycin inhibit the synthesis of the peptidoglycan cell wall Penicillins, cephalosporins, bacitracin, vancomycin inhibit the synthesis of the peptidoglycan cell wall Common sites of invasion: Common sites of invasion: Staph aureus and staph epidermidis inhabit most people’s skin and can infect wounds, surgical sites and indwelling catheters. Staph aureus and staph epidermidis inhabit most people’s skin and can infect wounds, surgical sites and indwelling catheters. They may cause infective endocarditis They may cause infective endocarditis Streptococous pneumoniae is the cause of community acquired pneumonia and adult bacterial meningitis Streptococous pneumoniae is the cause of community acquired pneumonia and adult bacterial meningitis Group A Beta-hemolytic Streptococcus causes strep throat Group A Beta-hemolytic Streptococcus causes strep throat If untreated it can cause an immunologic reaction in the heart and joints known as rheumatic fever. If untreated it can cause an immunologic reaction in the heart and joints known as rheumatic fever.

3. Gram Negative Pathogens Can be divided into four groups: Can be divided into four groups: 1. enterics  normally inhabit the GI tract 1. enterics  normally inhabit the GI tract Ex: E. coli, Shigella, Salmonella, Enterobacter Ex: E. coli, Shigella, Salmonella, Enterobacter 2. Haemophilus influenzae 2. Haemophilus influenzae 3. Neisseria 3. Neisseria 4. Pseudomonas 4. Pseudomonas Have a thin layer of peptidoglycan that is surrounded by an outer membrane which is made of lipopolysacharrides (LPS) which acts as a toxin Have a thin layer of peptidoglycan that is surrounded by an outer membrane which is made of lipopolysacharrides (LPS) which acts as a toxin Some strains produce B-lactamase which is a penicillin destroying enzyme that is concentrated in the space between the outer membrane and cell wall Some strains produce B-lactamase which is a penicillin destroying enzyme that is concentrated in the space between the outer membrane and cell wall

4. Gram Negative Pathogens Common sites of invasion: Common sites of invasion: Enterics are responsible for UTI and aspiration pneumonia Enterics are responsible for UTI and aspiration pneumonia Neisseria gonorrhea is responsible for the STD gonorrhea Neisseria gonorrhea is responsible for the STD gonorrhea Neisseria meningitidis and H. influenzae both cause meningitis although H. influenzae more commonly causes pneumonia in the elderly Neisseria meningitidis and H. influenzae both cause meningitis although H. influenzae more commonly causes pneumonia in the elderly Pseudomonas aeruginosa is responsible for hospital acquired infections because if adequate moisture is available it can colonize any surface in the hospital and is resistant to many disinfectants Pseudomonas aeruginosa is responsible for hospital acquired infections because if adequate moisture is available it can colonize any surface in the hospital and is resistant to many disinfectants

5. Anaerobes Common organisms include Bacteriodes fragilis, Clostridium difficile, Clostridium botulinum, and Clostridium tetani Common organisms include Bacteriodes fragilis, Clostridium difficile, Clostridium botulinum, and Clostridium tetani C. botulinum causes botulism and C. tetani causes tetanus C. botulinum causes botulism and C. tetani causes tetanus Metronidazole, chloramphenicol and clindamycin are effective against anaerobic bacteria Metronidazole, chloramphenicol and clindamycin are effective against anaerobic bacteria Infections are frequently encased in an abscess wall and they produce foul smelling gas Infections are frequently encased in an abscess wall and they produce foul smelling gas They colonize the mouth, GI tract, and skin They colonize the mouth, GI tract, and skin Infections develop when they penetrate poorly oxygenated tissues such as the diabetic foot or normally sterile tissues like the peritoneum. Infections develop when they penetrate poorly oxygenated tissues such as the diabetic foot or normally sterile tissues like the peritoneum. With the use of broad spectrum antibiotics, C. difficile proliferates and releases a toxin that causes pseudomembranous colitis. With the use of broad spectrum antibiotics, C. difficile proliferates and releases a toxin that causes pseudomembranous colitis.

6. Cell Wall Synthesis Peptidoglycan chains are synthesized in the cytoplasm and get transferred across the plasma membrane and linked to other peptidoglycan chains Peptidoglycan chains are synthesized in the cytoplasm and get transferred across the plasma membrane and linked to other peptidoglycan chains This results in a chain link that surrounds the bacteria This results in a chain link that surrounds the bacteria Human cells don’t have cell walls so cell wall synthesis inhibitors don’t have many side effects Human cells don’t have cell walls so cell wall synthesis inhibitors don’t have many side effects

7. Cell Wall Synthesis Inhibitors Penicillins Penicillin G (IV/IM) and Penicillin V (PO) Penicillin G (IV/IM) and Penicillin V (PO) Narrow Spectrum, Penicillinase Sensitive Narrow Spectrum, Penicillinase Sensitive MOA: inhibit cross linking of cell wall components MOA: inhibit cross linking of cell wall components DOC for: Staph and Strep, N. meningitidis, C. tetani, Syphilis DOC for: Staph and Strep, N. meningitidis, C. tetani, Syphilis Side Effects: hypersensitivity reactions, neutropenia, nephrotoxicity Side Effects: hypersensitivity reactions, neutropenia, nephrotoxicity Naficillin Naficillin Narrow Spectrum, Penicillinase Resistant Narrow Spectrum, Penicillinase Resistant MOA: has a bulky side group that protects it from penicillinase MOA: has a bulky side group that protects it from penicillinase DOC for: penicillinase producing Staph DOC for: penicillinase producing Staph Side Effects: severe thrombophlebitis and liver toxicity with elevated LFTs Side Effects: severe thrombophlebitis and liver toxicity with elevated LFTs

8. Cell Wall Synthesis Inhibitors Penicillins Broad Spectrum Broad Spectrum Ampicillin Ampicillin MOA: are hydrophilic and can penetrate the porins in Gram – MOA: are hydrophilic and can penetrate the porins in Gram – Are not effective against pencillinase producers Are not effective against pencillinase producers DOC for: listeria and enterococcus DOC for: listeria and enterococcus Side Effects: Diarrhea Side Effects: Diarrhea Amoxicillin Amoxicillin MOA: same MOA: same DOC for: empiric therapy in otitis media, sinusitis and pneumonia DOC for: empiric therapy in otitis media, sinusitis and pneumonia Side Effects: Diarrhea Side Effects: Diarrhea Amoxicillin and Clavulanate (Augmentin) Amoxicillin and Clavulanate (Augmentin) MOA: same but the clavulanate inhibits penicillinases MOA: same but the clavulanate inhibits penicillinases DOC for: Moraxella catarrhalis (OM), H. influenza DOC for: Moraxella catarrhalis (OM), H. influenza Side Effects: Diarrhea Side Effects: Diarrhea

9. Cell Wall Synthesis Inhibitors Penicillins Anti-Pseudomonals Anti-Pseudomonals Ticarcillin Ticarcillin MOA: has a side chain that makes it more resistant to penicillinases from gram – species MOA: has a side chain that makes it more resistant to penicillinases from gram – species DOC for: Pseudomonas DOC for: Pseudomonas Side Effects: None Side Effects: None Piperacillin Piperacillin MOA: same MOA: same DOC for: enterobacteria and gram + cocci DOC for: enterobacteria and gram + cocci Side Effects: Neutropenia and hematologic abnormalities Side Effects: Neutropenia and hematologic abnormalities

10. Cell Wall Synthesis Inhibitors Cephalosporins First Generation- Narrow Spectrum, sensitive to B-Lactamase First Generation- Narrow Spectrum, sensitive to B-Lactamase Cephalexin (Keflex), Cefazolin (Kefzol) Cephalexin (Keflex), Cefazolin (Kefzol) MOA: Binds penicillin binding proteins and inhibits cell wall synthesis MOA: Binds penicillin binding proteins and inhibits cell wall synthesis Resistance: bacteria reduce drug permeability, mutate penicillin binding proteins and produce B-lactamase Resistance: bacteria reduce drug permeability, mutate penicillin binding proteins and produce B-lactamase Spectrum: Gram + cocci except for MRSA and some Gram –, Cefazolin is used in surgical prophylaxis and for treating skin and soft tissue infections by Staph or Strep. Spectrum: Gram + cocci except for MRSA and some Gram –, Cefazolin is used in surgical prophylaxis and for treating skin and soft tissue infections by Staph or Strep. Side Effects: hypersensitivity reaction, GI disturbances, possible seizures and confusion with Cefazolin, Nephrotoxicity Side Effects: hypersensitivity reaction, GI disturbances, possible seizures and confusion with Cefazolin, Nephrotoxicity

11. Cephalosporins Second Generation- Broader Gram – Activity Second Generation- Broader Gram – Activity Cefaclor (Ceclor), Cefuroxime (Cefitin), Cefoxitin, Cefotetan Cefaclor (Ceclor), Cefuroxime (Cefitin), Cefoxitin, Cefotetan MOA: same as first gen but resistance to Lactamase MOA: same as first gen but resistance to Lactamase Spectrum: Gram+ cocci with extended Gram – activity with H. influenza, Enterobacter, Proteus and Neisseria Spectrum: Gram+ cocci with extended Gram – activity with H. influenza, Enterobacter, Proteus and Neisseria None are effective against pseudomonas None are effective against pseudomonas Clinical Uses: otitis media, pharyngitis, sinus, skin and respiratory infections Clinical Uses: otitis media, pharyngitis, sinus, skin and respiratory infections Cefuroxime is used as a single dose therapy for N. gonorrhea Cefuroxime is used as a single dose therapy for N. gonorrhea Side Effects: Same as first gen Side Effects: Same as first gen Cefaclor is associated with serum sickness (delayed allergic response) Cefaclor is associated with serum sickness (delayed allergic response)

12. Cephalosporins Third Generation- Broad Spectrum, Resistant to cephalosporinases Third Generation- Broad Spectrum, Resistant to cephalosporinases Ceftriaxone (Rocephin), Ceftazidime, Cefepime Ceftriaxone (Rocephin), Ceftazidime, Cefepime MOA: same as first gen but more resistant to lactamases MOA: same as first gen but more resistant to lactamases Spectrum: gram- bacilli, some pseudomonas, gram+ cocci (staph and strep) Spectrum: gram- bacilli, some pseudomonas, gram+ cocci (staph and strep) Clinical Uses: penetrate the CSF so can be used for CNS infections Clinical Uses: penetrate the CSF so can be used for CNS infections Side Effects: same as first gen and acalculous cholestasis Side Effects: same as first gen and acalculous cholestasis

13. Cell Wall Synthesis Inhibitors Vancomycin Vancomycin MOA: prevents transfer of cell wall precursors from plasma membrane to cell wall MOA: prevents transfer of cell wall precursors from plasma membrane to cell wall Clinical Use: DOC for penicillin or methicilliin resistant staph and strep Clinical Use: DOC for penicillin or methicilliin resistant staph and strep Side Effects: thrombophlebitis, ototoxicity, nephrotoxicity, Red Man Syndrome (IV)  tachy, flushing, parethesias, hypotension and severe nephrotoxicity Side Effects: thrombophlebitis, ototoxicity, nephrotoxicity, Red Man Syndrome (IV)  tachy, flushing, parethesias, hypotension and severe nephrotoxicity Bacitracin Bacitracin MOA: inhibits recycling of the carrier which transports cell wall precursors across the plasma membrane MOA: inhibits recycling of the carrier which transports cell wall precursors across the plasma membrane Clinical Use: Gram + infections in the skin and eye Clinical Use: Gram + infections in the skin and eye Side Effects: severe nephrotoxicity when administered IM Side Effects: severe nephrotoxicity when administered IM Seen in combo with neomycin in Neosporin Seen in combo with neomycin in Neosporin

14. Cell Wall Synthesis Inhibitors Carbapenem Carbapenem Imipinem/Cilastatin, Meropenem Imipinem/Cilastatin, Meropenem MOA: inhibits cross linking of cell wall components MOA: inhibits cross linking of cell wall components Cilastatin inhibits renal metabolism of imipinem Cilastatin inhibits renal metabolism of imipinem Clinical Uses: DOC for Acinetobacter, used to treat Gram + and – including lactamase producers and pseudomonas Clinical Uses: DOC for Acinetobacter, used to treat Gram + and – including lactamase producers and pseudomonas Side Effects: hypersensitivity. Doesn’t cause sterile bowel because of low concentration in the bowel Side Effects: hypersensitivity. Doesn’t cause sterile bowel because of low concentration in the bowel

15. Cell Wall Synthesis Inhibitors Monobactam Monobactam Aztreonam Aztreonam MOA: Inhibits cross linking of cell wall components MOA: Inhibits cross linking of cell wall components Clinical Use: Excellent coverage of Gram – including P. aeruginosa. Not active against Gram + Clinical Use: Excellent coverage of Gram – including P. aeruginosa. Not active against Gram + Side Effects: hypersensitivity, seizures, and hepatitis Side Effects: hypersensitivity, seizures, and hepatitis Lipopeptides Lipopeptides Daptomycin Daptomycin MOA: Depolarizes bacterial cell membrane MOA: Depolarizes bacterial cell membrane Clinical Uses: skin infections caused by S. aureus, MRSA and Strep Clinical Uses: skin infections caused by S. aureus, MRSA and Strep Side Effects: Hepatotoxicity, diarrhea, and rash Side Effects: Hepatotoxicity, diarrhea, and rash

16. DNA Inhibitors Quinolones Quinolones Nalidixic Acid (NegGram) Nalidixic Acid (NegGram) MOA: blocks a subunit of DNA gyrase therefore preventing supercoiling and inhibiting DNA synthesis MOA: blocks a subunit of DNA gyrase therefore preventing supercoiling and inhibiting DNA synthesis Clinical Uses: enteric Gram – but not Pseudomonas Clinical Uses: enteric Gram – but not Pseudomonas Side Effects: hypersensitivity rxn, photosensitivity, seizure, HA. Side Effects: hypersensitivity rxn, photosensitivity, seizure, HA. Displaces oral anticoagulants from plasma proteins Displaces oral anticoagulants from plasma proteins Causes growth plate arrest so not used in children Causes growth plate arrest so not used in children

17. DNA Inhibitors Fluroquinolones Fluroquinolones Norfloxacin Norfloxacin MOA: inhibits DNA gyrase and topoisomerase activity MOA: inhibits DNA gyrase and topoisomerase activity Clinical Uses: good gram – coverage Clinical Uses: good gram – coverage Side Effects: cartilage damaged so children is a CI Side Effects: cartilage damaged so children is a CI Ciprofloxacin (Cipro) Ciprofloxacin (Cipro) MOA: same as above MOA: same as above Clinical Uses: excellent Gram – coverage with some Gram + Clinical Uses: excellent Gram – coverage with some Gram + Side Effects: Same as above Side Effects: Same as above Levofloxacin (Levaquin) Levofloxacin (Levaquin) MOA: Same as above MOA: Same as above Clinical Uses: excellent gram – coverage and improved Staph. Coverage, treat legionella and chlamydia atypical pneumonia Clinical Uses: excellent gram – coverage and improved Staph. Coverage, treat legionella and chlamydia atypical pneumonia Side Effects: same as above Side Effects: same as above

18. DNA Inhibitors Metronidazole (Flagyl) Metronidazole (Flagyl) MOA: enters the bacteria and is activated by reduction of the nitro group. Binds DNA and inhibits its synthesis MOA: enters the bacteria and is activated by reduction of the nitro group. Binds DNA and inhibits its synthesis Clinical Uses: Bacteriodes, Clostridium and Protozoans such as E. histolytica, Trichomonas, and Giardia Clinical Uses: Bacteriodes, Clostridium and Protozoans such as E. histolytica, Trichomonas, and Giardia Side Effects: Disulfiram-like reaction with alcohol (flushing, vomiting and headache), CNS disturbance, bloating and cramping Side Effects: Disulfiram-like reaction with alcohol (flushing, vomiting and headache), CNS disturbance, bloating and cramping Nitrofurantoin (Macrodantin) Nitrofurantoin (Macrodantin) MOA: mechanism unclear but may damage DNA MOA: mechanism unclear but may damage DNA Clinical Uses: kills many urinary pathogens but not pseudomonas Clinical Uses: kills many urinary pathogens but not pseudomonas Side Effects: hepatotoxicity, pulmonary fibrosis, neuropathy Side Effects: hepatotoxicity, pulmonary fibrosis, neuropathy

19. Antimetabolites Sulfonamides Sulfonamides Sulfadiazine Sulfadiazine MOA: structurally similar to para-amino benzoic acid (PABA) and compete with it and prevent it from being incorporated into folate so you block DNA, RNA or protein synthesis MOA: structurally similar to para-amino benzoic acid (PABA) and compete with it and prevent it from being incorporated into folate so you block DNA, RNA or protein synthesis Clinical Uses: both gram + and -, used to treat uncomplicated UTI, chancroid, and prophylaxis against rheumatic fever Clinical Uses: both gram + and -, used to treat uncomplicated UTI, chancroid, and prophylaxis against rheumatic fever Side Effects: bone marrow depression, renal toxicity, photosensitivity, hemolysis, Steven-Johnson syndrome (serum sickness), Kernicterus (compete with bilirubin for albumin sites resulting in bilirubin deposited in brain nuclei) Side Effects: bone marrow depression, renal toxicity, photosensitivity, hemolysis, Steven-Johnson syndrome (serum sickness), Kernicterus (compete with bilirubin for albumin sites resulting in bilirubin deposited in brain nuclei) Trimethoprim/Sulfamethoxazole (TMP/SMZ, Cotrimoxazole, Septra, Bactrim) Trimethoprim/Sulfamethoxazole (TMP/SMZ, Cotrimoxazole, Septra, Bactrim) MOA: same as above plus prevents reduction of dihydrofolate to tetrahydrofolate by inhibiting dihydrofolate reductase MOA: same as above plus prevents reduction of dihydrofolate to tetrahydrofolate by inhibiting dihydrofolate reductase Clinical Uses: enteric gram -, Salmonella, effective for UTI, acute otitis media and traveler’s diarrhea, used for PCP prophylaxis in immunocompromised Clinical Uses: enteric gram -, Salmonella, effective for UTI, acute otitis media and traveler’s diarrhea, used for PCP prophylaxis in immunocompromised Side Effects: same as above Side Effects: same as above

20. Protein Synthesis Inhibitors Aminoglycosides (bacteriocidal) Aminoglycosides (bacteriocidal) Gentamycin, Streptomycin, Tobramycin Gentamycin, Streptomycin, Tobramycin MOA: bind at the 30s/50s subunit interface and results in abnormal reading of mRNA and defective protein synthesis MOA: bind at the 30s/50s subunit interface and results in abnormal reading of mRNA and defective protein synthesis Resistance: mutation of binding sites, inhibition of transport and permeability of the drugs Resistance: mutation of binding sites, inhibition of transport and permeability of the drugs Clinical Uses: aerobic and faculative gram – bacilli, anaerobic bacteria are resistant because transport into the organism is oxygen dependent Clinical Uses: aerobic and faculative gram – bacilli, anaerobic bacteria are resistant because transport into the organism is oxygen dependent DOC for E.coli, Proteus and Pseudomonas DOC for E.coli, Proteus and Pseudomonas Side Effects: nephrotoxicity (high troughs) and ototoxicity (high peaks) Side Effects: nephrotoxicity (high troughs) and ototoxicity (high peaks) Amikacin Amikacin MOA is the same as above but it has a different resistance profile so it is reserved for use in Gram – infections that are resistant to other aminoglycosides MOA is the same as above but it has a different resistance profile so it is reserved for use in Gram – infections that are resistant to other aminoglycosides

21. Protein Synthesis Inhibitors Chloramphenicol Chloramphenicol MOA: reversibly binds to the 50s subunit and prevents the tRNA from associating with peptidyl transferase MOA: reversibly binds to the 50s subunit and prevents the tRNA from associating with peptidyl transferase Resistance: Acetyl transferases inactivate the drugs Resistance: Acetyl transferases inactivate the drugs Clinical Uses: excellent coverage of most gram+ and gram – including anaerobes. Clinical Uses: excellent coverage of most gram+ and gram – including anaerobes. DOC for typhoid fever, H. flu meningitis or epiglottitis DOC for typhoid fever, H. flu meningitis or epiglottitis Side Effects: reversible bone marrow suppression, aplastic anemia, gray baby syndrome (in newborns abdominal distention, vomiting, cyanosis, hypothermia, collapse and death (40%) Side Effects: reversible bone marrow suppression, aplastic anemia, gray baby syndrome (in newborns abdominal distention, vomiting, cyanosis, hypothermia, collapse and death (40%) Linezolid (Zyvox) Linezolid (Zyvox) MOA: binds to 50s subunit MOA: binds to 50s subunit Clinical Uses: vancomycin resistant gram + Clinical Uses: vancomycin resistant gram + Side Effects: None Side Effects: None

22. Protein Synthesis Inhibitors Macrolides Macrolides Erythromycin Erythromycin MOA: prevents translocation of polypeptide chain by binding the P site of the 50s subunit MOA: prevents translocation of polypeptide chain by binding the P site of the 50s subunit Resistance: mutation of binding site by methylation Resistance: mutation of binding site by methylation Clinical Uses: bacteria lacking cell walls (mycoplasma, legionella and chlamydia), gram + aerobes, gram – aerobes except campylobacter and H. flu. Poor anaerobic coverage Clinical Uses: bacteria lacking cell walls (mycoplasma, legionella and chlamydia), gram + aerobes, gram – aerobes except campylobacter and H. flu. Poor anaerobic coverage DOC for Mycoplasma pneumonia, neonate with chlamydia pneumonia, pertusis DOC for Mycoplasma pneumonia, neonate with chlamydia pneumonia, pertusis Side Effects: GI upset, injections are painful due to venodestruction Side Effects: GI upset, injections are painful due to venodestruction

23. Protein Synthesis Inhibitors Clarithromycin (Biaxin) Clarithromycin (Biaxin) MOA: same MOA: same Resistance: same Resistance: same Clinical Uses: Mycobacterium avium, Strep throat and URI and some anaerobes Clinical Uses: Mycobacterium avium, Strep throat and URI and some anaerobes Side Effects: GI upset and headache but less frequently than Erythromycin Side Effects: GI upset and headache but less frequently than Erythromycin Azithromycin (Zithromax) Azithromycin (Zithromax) MOA: same MOA: same Resistance: same Resistance: same Clinical Uses: combined erythro and clarithro. Used to treat same things and also uncomplicated chlamydia Clinical Uses: combined erythro and clarithro. Used to treat same things and also uncomplicated chlamydia Side Effects: GI upset and abdominal pain but less frequently than erythro Side Effects: GI upset and abdominal pain but less frequently than erythro

24. Protein Synthesis Inhibitors Lincosamides Lincosamides Clindamycin (Celocin) Clindamycin (Celocin) MOA: binds to the 50s subunit and prevents chain elongation by blocking transpeptidation MOA: binds to the 50s subunit and prevents chain elongation by blocking transpeptidation Resistance: alteration of ribosome binding site and enzymatic inactivation of the drug Resistance: alteration of ribosome binding site and enzymatic inactivation of the drug Clinical Uses: covers gram + and most anaerobes. DOC for severe anaerobic GI infections Clinical Uses: covers gram + and most anaerobes. DOC for severe anaerobic GI infections Side Effects: abdominal cramps, diarrhea, reversible LFT elevation, classically associated with pseudomembranous colitis (due to C. diff resistance) Side Effects: abdominal cramps, diarrhea, reversible LFT elevation, classically associated with pseudomembranous colitis (due to C. diff resistance)

25. Protein Synthesis Inhibitors Tetracycline, Doxycycline Tetracycline, Doxycycline MOA: Inhibits protein synthesis by binding to the 30s subunit and blocking amino-acid linked tRNA from binding to the A site of the ribosome MOA: Inhibits protein synthesis by binding to the 30s subunit and blocking amino-acid linked tRNA from binding to the A site of the ribosome Resistance: proteins that transport drugs out of the cell Resistance: proteins that transport drugs out of the cell Clinical Uses: acne and chlamydia. Also used for Borrelia Burgdorferi (Lyme Disease) Clinical Uses: acne and chlamydia. Also used for Borrelia Burgdorferi (Lyme Disease) Side Effects: GI distress, reversible nephrotoxicity, hepatotoxicity, photosensitivity, dental staining (gray line) Side Effects: GI distress, reversible nephrotoxicity, hepatotoxicity, photosensitivity, dental staining (gray line)