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Module 6 July 2016

6.2 Antibiotics
Lecturer: Nico Fabian
III. Pharmaceutical Microbiology: Antibiotics  Food retards transit (↓abs) except Amoxicillin
- product of microorganisms or chemical synthesis  Poor penetration in eyes, prostate, & CNS
- Inhibit other organisms even in small quantities
o BACTERIOSTATIC- retard growth o Excretion via the kidneys
o BACTERICIDAL- kill ALL  Probenecid ↓tubular secretion of penicillin  ↑penicillin;
o RESISTANCE: no response to antibiotic hence ↓dose of penicillin
o SUPERINFECTION: e.g Clostridium difficile - PENICILLINS
- TB  MDR  XDR 1. Natural penicillin
o 1stline  2nd line  trial and error; gen. or broad spectrum - Susceptible to β-lactamase
o May be bacterial, viral 2.1 Penicillin G/ benzylpenicillin
o Complication: meningitis - Acid-labile; IV
- G(+,-), spirochete, anaerobe (eg. Clostridium), x Bacillus
A. CELL WALL SYNTHESIS INHIBITORS - Depot formulations; aqueous
- MOA: (-) Transpeptidation  Benzathine Pen G (IM)
- Hx: Alexander Fleming  I: syphilis; prophylaxis for rheumatic
o Discovered penicillin by serendipity heart fever
o Isolated by Florey and co-workers  Procaine Pen G (IM): procaine ~ local anesthetic
- β-lactam ring 1.2 Penicillin V/ phenoxymethylpenicillin
- Acid stable; PO
2. β-lactamase resistant/ anti-staphylococcal penicillins
- active against Staphylococci & other G(+)
- disadv: not for G(-)
2.1 Methicillin
- Nephrotoxic (out of the market)
- MRSA (methicillin-resistant Staphylococcus aureus) &
MRSE (methicillin-resistant Staphylococcus epidermidis) 
o bactericidal activity & antigenic determinant VANCOMYCIN
o penicillin beta-lactamase penicilloic acid 2.2 Oxacillin
- Stability - I: soft tissue infections
o In crystalline/ powder form 2.3 Nafcillin
o Solutions/ suspensions are freshly prepared 3. Extended-spectrum
o Stored in amber bottles - G(+), improved G(-) activity; susceptible to β-lactamase
- Special precautions 3.1 Aminopenicillin
o All penicillins are cross-sensitive w/ cephalosporins (5-16% cross- - x Klebsiella, enterobacter, pseudomonas, serratia, proteus
sensitizing) - cause morbilliform rashes
- Pregnancy category B - Ampicillin
- Drug-drug interactions  Prototype; lowest BA
o Allopurinol + ampicillin  rash  (+) Sulbactam  Unasyn®
o Penicillin + bacteriostatic  ↓bactericidal act., antagonistic  S/E: pseudomembranous colitis
o Penicillin + β-blocker  anaphylaxis - Bacampicillin
 Physiologic Histamine antagonist: epinephrine
 prodrug; highest BA
- Pharmacokinetics - Amoxicillin
o Absorption varied except in acid-labile like Pen G, Methicillin
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Module 6.2 Antibiotics
 Absorption not affected by food
 (+) K Clavulanate  Co-amoxiclav (Augmentin®)
 S/E: rash o
3.2 Anti-pseudomonals ANAEROBIC ACTIVITY
- Serious infections caused by G(-) 2ND GEN 3RD GEN
- Active against Pseudomonals, Klebsiella Cefoxitin Cefotaxime
- Synergistic when used with Aminoglycosides Cefotetan Ceftriaxone
- Combined w/ β-lactamase inh. Ceftizoxime
 Resemble β-lactam  suicide inh.
 Potentiation o
- Carboxypenicillins Ceph Except - Staph and Strep

1st gen
 Carbenicillin Cefadroxil
 Ticarcillin: (+) clavulanate  Timentin® Cefazolin
- Ureidopenicillins
 Mezlopenicillin Cef-vowel Cefmetazole - Community-acquired pneumonia (CAP)
 Piperacillin: (+) tazobactam  Piptaz®, Zosyn® Cefprozil - Crosses BBB

2nd
 Azlocillin Loracarbef - activity against gram + and gram – (including
- CEPHALOSPORINS Haemophilus, Klebsiella, Proteus, E.coli
o ↑generation ~ ↑G(-) act; bactericidal - x act. vs Pseudomonas
o Greater efficacy against resistant microorganisms Cef- Cefixime - Crosses BBB (except ceftibuten,
o Stable vs β-lactamase consonant Cefotaxime cefpodoxime, cefixime, cefoperazone): can
o No act. vs enterococci & listeria Cefoperazone be used for meningitis

3rd
o Special precautions Moxalactam - x reliable vs. enterobacter: x UTI (e.coli)
 Pseudomembranous colitis Proxetil - Ceftazidime, Cefoperazone: Pseudomonas
 Coagulation abnormality: compromise CF formation - Ceftriaxone: lyme, gonorrhea
 Nephrotoxic - Pseudomonas
 Preg. Cat. B Cefepime - Atypical organism

4th
 Pharmacokinetics Cefpirome - MRSA
i. Well-absorbed in GIT (PO) - Enterobacter
ii. Absorption delayed by food but amount absorbed is Ceftobiprole -  MRSA, pseudomonas

5th
unaffected Ceftaroline -  MRSA
 Drug Interactions
i. (+) aminoglycosides  severe nephrotoxicity - OTHER β-LACTAMS
ii. (+) anticoagulants  ↑risk hyperprothrombinemia 3.1 Monobactams
iii. (+) probenecid  ↑cephalosporin plasma level - active against G(-)
iv. Alcohol + 2nd/3rd gen  Disulfiram(Antabuse®) effect; - Aztreonam
*disulfiram inh aldehyde dehydrogenase
 Chromobacterium violaceum
acetaldehyde  A/E
 Weakly immunogenic, resistant to β-lactamase
o
 Reserved for very serious infection
Gram (+) Gram (-)
3.2 Carbapenems
1st +++ +
- Share allergic potential w/ penicillin
2nd ++ ++ - Imipenem
3rd + +++  G(+,-), anaerobe
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Module 6.2 Antibiotics
 Inh by dehydropeptidases in renal tubules - 30 s
 (+) Cilastatin w/c inh renal dehydropeptidase - Bactericidal, only for g(-), not preferred for (+) & anaerobes
- Meropenem - More active in alkaline pH
 More g(-) but less g(+) than imipenem - SToKeNeomycin (Streptomyces)
3.3 Glycopeptide o Streptomycin
- Vancomycin o Tobramycin
 Streptococcus orientalis; g(+) o Kanamycin
 DOC: MRSA (VRSA  Daptomycin) o Neomycin
 MOA: alter RNA synthesis (sim. to rifampicin) - SNAGmicin (Micromonospora)
 A/E: Redman/ Redneck syndrome o Sisomicin
 If rapid infusion o Netilmicin
- BACITRACIN o Amikacin
- Bacillus subtilis, g(+) act. o Gentamicin
- Topical use since nephrotoxic
- Special precautions
B. PROTEIN SYNTHESIS INHIBITORS o Narrow TI
- Buy AT 30, CEL at 50 o No significant level in CSF, eyes
1. Tetracycline - A/E
- Absorption impaired by food except DOXYCYCLINE, MINOCYCLINE o Nephrotoxicity
- Interacts w/ milk, Al3+, Ca2+, Mg2+, Fe2+ (chelation)  Neomycin
- Lipid solubility: high for Doxycycline & minocycline  Gentamicin
o *LUNA (lipophilic, unionized, non-polar  Absorbed)  Tobramycin
- G(+), (-), anaerobe, atypical organism (mycoplasma, chlamydia, o Vestibular toxicity
legionella, pneumophila)  Streptomycin
- I: cholera, malignant pleural effusion  gentamicin
- Warnings o Ototoxicity
o Photosensitivity : demeclocycline  Neomycin
o Hepatotoxicity  Amikacin
o nephrotoxicity  Kanamycin
- Doxycycline - Interactions
 Choice for px w/ preexisting renal conditions since it is not o (+) cephalosporins  nephrotoxicity
excreted renally o (+) neuromuscular blockers(eg Tubocurarine)  paralysis
 Prophylaxis for leptospirosis, lyme disease, anthrax 2. Macrolides
- Minocycline - G(+), (-), anaerobes
 Penetrate saliva - Penetrate pleural fluid, CSF if meninges are inflamed
- Most common A/E: GIT upset
 Theoretically used for meningococcemia but used for
- Erythromycin
pimple tx nowadays
- Tigecycline  Aka Ilotycin; from Streptomyces erythreus
 G (+)  Prototype, natural macrolide
 For skin & intraabdominal infection  Best prep: erythromycin estolate
- Demeclocycline  DOC: chlamydia, corynebacterium, CAP (Streptococcus
 Syndrome of inappropriate ADH secretion (SIADH) pneumoniae)
2. Aminoglycosides  1% used as prophylaxis for ophthalmia neonatorum

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Module 6.2 Antibiotics
 A/E: cholestatic hepatitis
- Clarithromycin C. NUCLEIC ACID SYNTHESIS INHIBITORS
 More active vs. mycobacterium & toxoplasma 1. Sulfonamides
 I: erythromycin-resistant Streptococcus & staphylococci - Structural analogs of P-ABA
- Roxithromycin - G (+), (-)
 Respi. Tract infection - Bacteriostatic
- Azithromycin - MOA: inh dihyropteroate synthase
 Penetrates tissue rapidly but slowly released  used for 3 - I: Pneumocystis carinii pneumonia, toxoplasmosis, nocardiosis
days only - Classes/ forms
 Less active vs. staphylococcus & streptococcus o Oral absorbable
3. Chloramphenicol  sulfisoxazole
- G (+), (-), anaerobes o Oral non-absorbable
- x act. vs Chlamydia (erythromycin)  sulfasalazine
- Chloramphenicol palmitate (oral), succinate (parenteral) o Topical
- DOC: typhoid fever  Silver sulfadiazine (Flamazine®)
- A/E: cross-allergenic w/ diuretics & sulfonylurea; SJS; crystalluria
2. Trimethoprim
- A/E - inh. dihydrofolic acid reductase
o Gray baby syndrome: impaired glucuronidation process - x act. vs. Pseudomonas
(phase II) - A/E: megaloblastic anemia
o Aplastic anemia 3. Co-trimoxazole (Bactrim®)
o Glu-6-Phospate Dehydrogenase deficiency (*included in - Sulfamethoxazole + trimethoprim
Newborn screening) hemolysis - Bactericidal
4. Lincosamides - I: UTI, shigellosis, Pneumocystis carinii pneumonia
- G (+), anaerobe (vaginal infections) - C/I:
- Lincomycin o Pregnancy: folate deficiency  neural tube defect
 Streptomyces lincolnensis o Streptococcal pharyngitis
 Structurally distinct from macrolide but has sim. activity 4. Quinolones
- Clindamycin - inh. DNA replication by interfering w/ DNA gyrase (TOPO II)
 Intraabdominal & pelvic infections - g (+), (-)
- 1st gen: Nalidixic acid
 x penetrate meninges
- 2nd gen: for g(+) & anaerobes
 A/E: fatal colitis
 Ciprofloxacin: best g (-) act., also for anthrax, gonorrhea,
 Interaction: enhance neuromuscular effect of some drugs
mycobacterium
(sim. to tetracycline)
 Ofloxacin
2. Linezolid
- G (+)  Norfloxacin
- Act on 23s & 50s - 3rd gen:
- Bacteriostatic vs: enterococcie, staphylococci  Levofloxacin: best g (+) act.; enhanced g(+),(-), anaerobe
- Bactericidal vs: streptococcus - 4th gen:
- I: Vancomycin-resistant enterococcus faecium (VREF)  Trovafloxacin
3. Streptogramins  Moxifloxacin: atypical (chlamydia, mycoplasma, legionella)
- Synercid®: Quinupristin (Strep B) & dalfopristin (Strep A) - Kinetics:
- I: life-threatening infections, VREF, MRSA o Penetrates tissue well (sim. to Azithromycin)

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Module 6.2 Antibiotics
o Interactions - 2nd choice for MRSA (1st choice is Vancomycin)
 (+)Probenecid or acidification of urine: ↑ t2/2 - Enhance effect of Amphotericin B (#1 antifungal)
quinolones - (+) doxycycline: 1st line for Brucellosis/ undulant fever
- A/E c. Pyrazinamide
o Arthropathy in growing cartilage  CI in children <18yrs - Weakly tuberculocidal
5. Anaerobic DNA inhibitors  Intracellular bacilli
- Metronidazole (Flagyl®): 7 d, metallic aftertaste  Effective for 1st 2 mos of therapy (during w/c there
- Secnidazole (Flagentyl®): 4 tab is increased inflammation)
- Clindamycin - MOA: unknown; converted to active pyrazinoic acid in an
acidic environment
D. ANTI-TB & LEPROSY DRUGS - Ptics: good penetration in meninges (TB meningitis)
1. Anti-TB (Mycobacterium tuberculosis) - A/E: hepatotoxicity, gout (inh. of uric acid excretion)
- Multi-drug therapy d. Ethambutol
- *sidenote: DOC for cholera (Doxycycline, Tetracycline) - Tuberculostatic
- Isoniazid (>12mos)  rifampicin (9 mos)  pyrazinamide (6 mos)  Fast multiplying bacilli
- First-line agents  Prevent development of resistance
a. Isoniazid - MOA: inh. incorporation of mycolic acid, & RNA synthesis
- Tuberculocidal - A/E: optic neuritis (RED-GREEN color blindness)
 Fast-multiplying agents are killed - Ende pwede for meningitis (x cross meninges)
 Dormant are inhibited e. Streptomycin
 intra- & extracellular bacilli - Active against extracellular bacilli
- Cheapest anti-TB - Penetrate meninges
- MOA: inh. mycolic acid synthesis - A/E: vestibular toxicity (w/ gentamicin)
- Ptics: penetrate tissue rapidly - Second-line agents
- Metabolism o Fluoroquinolones
 acetylation (SLOWest, FASTeast) o Aminoglycosides (Amikacin, Kanamycin)
 competes w/ pyridoxine (Iso a Pyri) o Cycloserine
- A/E: peripheral neuropathy, hepatotoxicity o Ethionamide
- *sidenote: Vitamin B (TRNPaPyFC) o Linezolid
 B1: Thiamine o Rifabutin
 B2: Riboflavin o P-aminosalicylic acid
 B3: Niacin/ nicotinamide - Tx regiment (Directly Observed Tx, Short Course)
 B5: pantothenic acid - 6 mos. therapy
 B6: pyridoxine, pyridoxal, pyridoxamine o Intensive initial phase: 2-3 mos
 B7: biotin o Continuation phase: 4-6 mos
 B9: folic acid - 9 mos. min. for Extrapulmonary TB
 B12: cyanocobalamin o Intensive: 2 mos
b. Rifampicin o Maintenance: 7 mos
- Tuberculocida - Tx failure: remains (+) ≥ 5mos after tx
- TB relapse: (+) after 1 full course of therapy
 Slow multiplying organism atypical cells
- Tx default: (+) after interruption of Tx for ≥ 2mos
 Good sterilizing & resistance-preventing action
- Drug interactions: Isoniazid inh., rifampicin inducer, pyrazinamide +
 MOA: inh. RNA synthesis (sim w/ Vancomycin)
allopurinol
 A/E: red orange discoloration of body fluids

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Module 6.2 Antibiotics
2. Anti-Leprosy (Mycobacterium leprae)
- Multi-drug approach: ↓relapse & resistant cases
-
Tuberculoid Lepromatous
Rifampicin + dapsone Rifampicin + dapsone
for 6 mos + clofazimine for 24
mos.

a. Dapsone
- Structural analog of sulfonamides
- MOA: inh folate synthesis
- Other ind: Pneumocystis carinii pneumonia (HIV px)
- A/E
 Hemolysis in G6PD px
 “Sulfone syndrome”: exfoliative dermatitis
 Exfoliation also present in S. aureus
scalded skin syndrome
b. Rifampicin
c. Clofazimine
- Sulfone-resistant
- A/E: skin discoloration

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