Microbiology Msii Temple Ashby

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Most important property of antibiotics

Back 1

Selective Toxicity (determined by mechanism of action...cell wall specificty is important here for instance)

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Mechanisms of antibiotic action

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1) ANTIMETABOLITES

2) INHIBITORS OF CELL WALL SYNTHESIS (most selective for bacteria)

3) AGENTS AFFECTING CELL MEMBRANES

4) INHIBITORS OF PROTEIN SYNTHESIS

5) INHIBITORS OF NUCLEIC ACID SYNTHESIS

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Antimetabolites

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Sulfonamides-
Competitive inhibitors of dihydropteroate synthetase (PABA + Pterin --> Pteroic Acid in THF Synthesis). Bacteriostatic


Trimethoprim-
Inhibits dihydrofolate reductase (Dihydrofolic acid --> THF in THF synthesis) Bacterioststic

NOTE they are rarely used alone today, but generally in concert.

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Inhibitors of cell wall synthesis

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Penicillins and cephalosporins Block transpeptidase reaction.

Vancomycin, Bacitracin Block early steps in cell wall synthesis.

Cycloserine blocks alanine racemase.

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Agents affecting cell membranes

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Polymyxins
Polypeptide antibiotics - form pores. Bind to phosphatidyl ethanolamine-rich areas of the membrane, and thus work more on gram - bacteria than gram +, and more on gram + than eukaryotic cells. This is often used topically as the skin will regenerate. It can also cause anaphylaxis.

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Inhibitors of Protein Synthesis

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Aminoglycosides (e.g. streptomycin & neomycin) bind to 30 S ribosomal subunit.

Tetracyclines Blocks binding of tRNA by binding to 30 S.

Chloramphenicol, erythromycin, clindamycin bind to 50S. Inhibit chain elongation.

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Inhibitors of Nucleic Acid Synthesis

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Rifampin Inhibits DNA dependent RNA polymerase & RNA synthesis.

Quinolones (e.g. ciprofloxacin). Block DNA gyrase.

Metronidazole Inhibits nucleic acid synthesis.

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Variables influencing the effectiveness of antimicrobial therapy

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1. Dx Vs. Choice of antibiotic (Regular pneumonia vs. legionaires etc)

2. Bactericidal vs. bacteriostatic (no bacteriostatics for dangerous infections [endocarditis, meningitis etc] or immune compromised pt's)

3. Specificity of Action (narrow vs. broad...narrow perferred as they are more potent, effective and less chance of superinfections)

4. Concentraiton of antibiotic at site of action (route and time of admin, chelation by food/drink, dose schedule/duration, Pt compliance, Body distribution and metabolism).

5. Host Factors
Host defenses (may be impaired by disease or drugs in which case antibiotic prophylaxis may be indicated)
AGE (effects rate of elimination, infants do not have a fully developed P450 system, elderly may have impaired renal fxn.
pregnancy (see flash card)
Susceptability to allergic reactions (Hx of allergy is greater risk, and severity is important)

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Antibioitc effect on pregnancy

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Streptomycin- may damage eighth cranial nerve and cause skeletal defects in the fetus

Tetracyclines- in last half of pregnancy cause hypoplasia of fetal teeth and bones and cataracts.

Sulfonamides and chloramphenicol- cross placenta and are contraindicated.

Some antibiotics are secreted in milk.

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Indications for Therapy with combination of antimicrobials

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To treat life-threatening infection

To treat a polymicrobial infection

To achieve synergy of the drugs (trimethoprim/sulfonamide combo...combinations of bactericidal or bacteriostatic drugs may be additive or synergistic, but one of each may be antagonistis as PCN and Tetracycline)

To prevent emergence of resistance

To allow use of a lower dose of one antibiotic (but combination side effects are an issue)

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Useful Antibiotic Combinatoins

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1. Isoniazid + Rifampin to treat TB.

2. Penicillin + aminoglycoside for mixed infections and prophylaxis. The mech of synergy is that Pcn kills some, and attenuates the cell wall of others allowing aminoglycosides to enter and kill them (the latter would not enter well through an intact cell wall).

3. Trimethoprim + Sulfamethoxazole to treat Pneumocystis carinii pneumonia.

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Adverse Effects of Antibiotics

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1. Gastrointestinal toxicity
Nausea and Vomiting
Superinfections caused by organisms resistant to the antibiotic and by fungi such as Candida.
pseudomembranous colitis (C. difficile) overgrowth. Severe and can be fatal, but not always 100% assoc with Ab use.

Hepatotoxicity
Most antibiotics are excreted unchanged through kidney. Some through liver.
Tetracyclines, amphotericin B and isoniazid can cause liver damage.
Chloramphenicol inhibits P450. (can lead to issues with maintanance meds etc)

Nephrotoxicity
May be direct or due to hypersensitivity reactions.
Include sulfonamides, aminoglycosides and outdated tetracyclines.

Neurotoxicity
Massive doses of penicillin G may cause neurotoxicity due to non-specific irritation.
Aminoglycosides and tetracyclines (in infants) can cause selective neurotoxicity.

Blood and Marrow
Chloramphenicol is toxic to marrow.
Hemolysis of red cells may occur with sulfonamides, chloramphenicol, or nitrofurantoin in patients deficient in glucose-6-phosphate dehydrogenase.

Allergic Reactions
Penicillins least toxic, most allergenic (all ='ly allergenic).
Antibiotics serve as haptens. Cross-sensitivity may occur. e.g. penicillins and cephalsporins.

Drug Interactions
Rifampin interferes with birth control pills and other drugs by enhancing breakdown (P450).
Chloramphenicol with phenytoin and coumadin by inhibiting breakdown.
Seldane and erythromycin (a sometimes fatal arrhythmia)

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Bacterial Resistance - Molecular Mechanisms

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1) Bacteria produce enzymes that destroy drug e.g. b-lactamases, chloramphenicol acetyl transferase.

2) Bacteria change their permeability to drug. (in or pumping out)

3) Bacteria develop altered target for drug. e.g. 30 S ribosomal protein.

4) Bacteria develop altered pathway to bypass reactions inhibited by drug. e.g. resistant bacteria may use preformed folic acid.

5) Bacteria develop altered enzyme less susceptible to drug. e.g. dihydropteroate synthetase.

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Bacterial Resistance - Molecular Mechanisms

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Natural resistance - not susceptible to a particular antibiotic. Gram negatives are not suceptable to Pcn’s..mycoplasma has no cell wall and thus PCN does not work.

Acquired resistance - antibiotic therapy & selection of resistant organisms.
1. Chromosomal resistance. Due to spontaneous mutation.
2. Infective drug resistance.
a. Conjugation Transfer of plasmid during mating.
b. Transformation Uptake of DNA liberated from ruptured cells.
c. Transduction Transfer of plasmid through bacteriophages.
d. Translocation or Transposition Incorporation of DNA as transposon

**note that plasmid resistances are often to multiple antibiotics and are particularly nasty (called R or resistance factors).

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Penicillins

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Chemistry:

Beta lactam ring connected to a 5 member thiol. In the original form (PCN G) it is acid labile (70% destroyed in the stomach). Amidase cleaves the lactam R and replaces it creating PCN V (totally acid stabile), or add a bulky R to make lactamase resistant PCN, another R helps the drugs get into gram -'ve, and we can change the thiol carboxylic acid salt from K or NA to Benzathine or Procaine making an insoluble form for IM use (repository/storage form)for prophylaxis and susceptable organisms.

Mechanism of Action:

Inhibit transpeptidases.
Activate autolysins.
Not effective against dormant bacteria.


Spectrum:

Pcn G and V…Narrow spectrum:
Gram positive aerobic & faculative, some anaerobes & spirochetes like syphylis
Broad spectrum analogs also kill gram negatives

Resistance:

b-lactamases (penicillinases).
Lack receptors or permeability so drug cannot reach receptors.
Autolytic enzymes not be activated: cells inhibited but not killed.
Some organisms not susceptible - Mycoplasma, Gram negatives.


Pharmacokietics:

Completely and rapidly absorbed when given parenterally.
Oral availability depends on penicillin.
1. Penicillin G All routes. Acid labile - only 30% of oral dose absorbed
2. Penicillin V ONLY given orally.
3. Repository forms : procaine & benzathine penicillin G. IM
Widely distributed.
Do not readily cross blood-brain barrier but may attain therapeutic levels when inflammation allows them to reach meninges. (not a covalent change, just a salt)

Eliminated by kidney as the intact molecule. Elimination time: 30-60 min in normal adults. Tubular secretion can be blocked by probenecid (Benemid).


Clinical Uses:

1) Penicillin G & Penicillin V- pneumococci, streptococci, meningococci, staphylococci & gonococci, spirochetes, Bacillis anthracis & Bacteroides (except B. fragilis).

2) Extended spectrum penicillins- More active against gram-ves.
Two groups:
Ampicillins- amoxicillin, cyclacillin, and hetacillin & bacampicillin
Carbenicillins- ticarcillin, azlocillin, mezlocillin & piperacillin.
Also effective against Pseudomonas and Proteus species and some strains of H. influenzae & E. coli resistant to ampicillin.

3) Penicillinase-resistant penicillins- Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin


Adverse Reactions:

Allergic reactions (2 to 8% of patients
Acute Within 30 min -anaphylactic shock Accelerated 30 min to 48 h.
Not life-threatening. Delayed More than 2 days. 90% are this type.

Note that you don’t have to have been prescribed PCN to be allergic, it is environmental, mold, food we eat, etc. Allergic to one = allergic to all.

Nonallergic responses
Huge doses of sodium salts may cause congestive heart failure, Potassium may cause cardiac toxicity in patients with renal impairment.
Superinfections.

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Penicillins

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Chemistry:

Beta lactam ring connected to a 5 member thiol. In the original form (PCN G) it is acid labile (70% destroyed in the stomach). Amidase cleaves the lactam R and replaces it creating PCN V (totally acid stabile), or add a bulky R to make lactamase resistant PCN, another R helps the drugs get into gram -'ve, and we can change the thiol carboxylic acid salt from K or NA to Benzathine or Procaine making an insoluble form for IM use (repository/storage form)for prophylaxis and susceptable organisms.

Mechanism of Action:

Inhibit transpeptidases.
Activate autolysins.
Not effective against dormant bacteria.


Spectrum:

Pcn G and V…Narrow spectrum:
Gram positive aerobic & faculative, some anaerobes & spirochetes like syphylis
Broad spectrum analogs also kill gram negatives

Resistance:

b-lactamases (penicillinases).
Lack receptors or permeability so drug cannot reach receptors.
Autolytic enzymes not be activated: cells inhibited but not killed.
Some organisms not susceptible - Mycoplasma, Gram negatives.


Pharmacokietics:

Completely and rapidly absorbed when given parenterally.
Oral availability depends on penicillin.
1. Penicillin G All routes. Acid labile - only 30% of oral dose absorbed
2. Penicillin V ONLY given orally.
3. Repository forms : procaine & benzathine penicillin G. IM
Widely distributed.
Do not readily cross blood-brain barrier but may attain therapeutic levels when inflammation allows them to reach meninges. (not a covalent change, just a salt)

Eliminated by kidney as the intact molecule. Elimination time: 30-60 min in normal adults. Tubular secretion can be blocked by probenecid (Benemid).


Clinical Uses:

1) Penicillin G & Penicillin V- pneumococci, streptococci, meningococci, staphylococci & gonococci, spirochetes, Bacillis anthracis & Bacteroides (except B. fragilis).

2) Extended spectrum penicillins- More active against gram-ves.
Two groups:
Ampicillins- amoxicillin, cyclacillin, and hetacillin & bacampicillin
Carbenicillins- ticarcillin, azlocillin, mezlocillin & piperacillin.
Also effective against Pseudomonas and Proteus species and some strains of H. influenzae & E. coli resistant to ampicillin.

3) Penicillinase-resistant penicillins- Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin


Adverse Reactions:

Allergic reactions (2 to 8% of patients
Acute Within 30 min -anaphylactic shock Accelerated 30 min to 48 h.
Not life-threatening. Delayed More than 2 days. 90% are this type.

Note that you don’t have to have been prescribed PCN to be allergic, it is environmental, mold, food we eat, etc. Allergic to one = allergic to all.

Nonallergic responses
Huge doses of sodium salts may cause congestive heart failure, Potassium may cause cardiac toxicity in patients with renal impairment.
Superinfections.

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Penicillins

Back 17

Chemistry:

Beta lactam ring connected to a 5 member thiol. In the original form (PCN G) it is acid labile (70% destroyed in the stomach). Amidase cleaves the lactam R and replaces it creating PCN V (totally acid stabile), or add a bulky R to make lactamase resistant PCN, another R helps the drugs get into gram -'ve, and we can change the thiol carboxylic acid salt from K or NA to Benzathine or Procaine making an insoluble form for IM use (repository/storage form)for prophylaxis and susceptable organisms.

Mechanism of Action:

Inhibit transpeptidases.
Activate autolysins.
Not effective against dormant bacteria.


Spectrum:

Pcn G and V…Narrow spectrum:
Gram positive aerobic & faculative, some anaerobes & spirochetes like syphylis
Broad spectrum analogs also kill gram negatives

Resistance:

b-lactamases (penicillinases).
Lack receptors or permeability so drug cannot reach receptors.
Autolytic enzymes not be activated: cells inhibited but not killed.
Some organisms not susceptible - Mycoplasma, Gram negatives.


Pharmacokietics:

Completely and rapidly absorbed when given parenterally.
Oral availability depends on penicillin.
1. Penicillin G All routes. Acid labile - only 30% of oral dose absorbed
2. Penicillin V ONLY given orally.
3. Repository forms : procaine & benzathine penicillin G. IM
Widely distributed.
Do not readily cross blood-brain barrier but may attain therapeutic levels when inflammation allows them to reach meninges. (not a covalent change, just a salt)

Eliminated by kidney as the intact molecule. Elimination time: 30-60 min in normal adults. Tubular secretion can be blocked by probenecid (Benemid).


Clinical Uses:

1) Penicillin G & Penicillin V- pneumococci, streptococci, meningococci, staphylococci & gonococci, spirochetes, Bacillis anthracis & Bacteroides (except B. fragilis).

2) Extended spectrum penicillins- More active against gram-ves.
Two groups:
Ampicillins- amoxicillin, cyclacillin, and hetacillin & bacampicillin
Carbenicillins- ticarcillin, azlocillin, mezlocillin & piperacillin.
Also effective against Pseudomonas and Proteus species and some strains of H. influenzae & E. coli resistant to ampicillin.

3) Penicillinase-resistant penicillins- Methicillin, Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin


Adverse Reactions:

Allergic reactions (2 to 8% of patients
Acute Within 30 min -anaphylactic shock Accelerated 30 min to 48 h.
Not life-threatening. Delayed More than 2 days. 90% are this type.

Note that you don’t have to have been prescribed PCN to be allergic, it is environmental, mold, food we eat, etc. Allergic to one = allergic to all.

Nonallergic responses
Huge doses of sodium salts may cause congestive heart failure, Potassium may cause cardiac toxicity in patients with renal impairment.
Superinfections.

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Cephalosporins

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Chemistry:

2 available R groups for modification. No repository form in spite of the COOH


Mechanisms and Spectrum:

Same mechanism as penicillin - inhibits transpeptidase reaction

3 generations based on spectrum of action
and sequence of development
• all Active against gram+ve cocci, gram -ve bacilli.
• Wider spectrum includes Klebsiella
• Includes H. influenzae and B. fragilis.


Resistance:

Similar mechanisms of resistance to penicillins but different enzymes - Cephalosporinases.

Little cross-resistance so that cephalosporins can be used against penicillin-resistant bacteria.


Pharmacokinetics:

1st Generation - Cefadroxil (Oral), Cefazolin (IV)...Good for gram +ve, modest for gram -ve. Cannot be used to treat meningitis. Rarely drug of choice, except or surgical prophylaxis - then only 1st generation as others are too expensive.

2nd Generation - Cefaclor (oral), Cefoxitin (IV)...Cefaclor is for sinusitis in penicillin allergy or resistance (as long as we do not have anaphylaxis)

3rd Generation - Cefotaxime (IV) excreted primarily in urine, All have expanded activity against gram -ve, less for +ve
All Enter CNS and are drugs of choice for gram -ve meningitis.


Clinical Uses:

Indicated for Klebsiella (4 % of dental infections) infections.

Surgical prophylaxis - Use low cost, long half-life drugs e.g.cefazolin.

Mixed infections, anaerobes eg Bacteroides, of chest, abdomen, pelvis.

Penicillinase producing N gonorrhoeae.

Gram-negative rod bacterial meningitis by those that reach CNS (generally third generation).


Adverse Effects:

Allergic reactions. Increased risk of susceptibility if allergic to penicillins (esp dangerous if the person had anaphylaxis). Can be used in patients who show non-acute reactions to penicillin but not in patients with immediate-onset allergy to penicillin.

GI upset.

Pain when given IM. (Lots of it!)

IV may result in thrombophlebitis.

Some cause bleeding disorders that can be reversed with vitamin K (interfere with gamma glutamyl rxn that is vitamin K dependant, so K suppliments will help).

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Monicyclic B-lactams (monobactams)

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Produced by certain gram-negative bacteria.
Modified to produce aztreonam which is active against gram-negatives eg. Pseudomonas, Serratia, and E.coli. Not active against gram positives. Works on cell wall synthesis.

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Carbapenems

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Isolated from certain streptomyces. Semisynthetic is imipenem. High resistance for b-lactamases. Effective on dormant bacteria.

Major problem - metabolized in renal tubule. Thus-Used in conjunction with cilastatin, an inhibitor of renal dehydropeptidase - combination is known as Primaxin™.

Major toxicity is seizures.

If the R group is substituted for imipenem then you get high penicillinase resistance.

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Clavulanic Acid

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Clavulanic acid. Isolated from Strep. clavuligerus.

Not an antibiotic. Inhibits b-lactamases

Used to potentiate other antibiotics. Used in combination with amoxicillin and ticarcillin i.e. Augmentin™ (oral)& Timentin™(parenteral).

Other b-lactamases inhibitors are sulbactam and tazobactam used in combination with ampicillin and piperacillin.

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Chloramphenicol

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Mechanism and Spectrum:

Binds to 50 S and inhibits peptide bond formation. Usually bacteriostatic.

May be bactericidal against H.influenzae and N. meningitidis. (both can cause menengitis)

Broad spectrum against gram-negatives. Most anaerobes. (a little gram + too)


Resistance:

Drug destroyed by chloramphenicol acetyl transferase. Coded 4 by a plamid.


Pharmacokinetics:

Oral or parenteral; rapidly absorbed from GI tract. Well-distributed, including CSF, and placenta. Inactivated to glucuronic acid derivative in liver (not excreted unchainged in urine)


Clinical Uses:

Typhoid fever and other Salmonella infections.

Refractory cases of meningitis and brain abscesses.

Topically, for eye infections (not against chlamidia).


Adverse Effects:

Red cell anemia - inhibits marrow mitochondrial protein synthesis.

Aplasia of bone marrow - allergic phenomenon (not concentration related. The 1:40,000 fatality rate due to aplastic anemis is why the drug is rarely used today).

Gray syndrome - in infants due to accumulation of drug since they lack glucuronic acid conjugation detoxification mechanism. (p450)

Drug interactions - with phenytoin & coumadin due to inhibition of P450.

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Tetracyclines

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Chemistry:

Solutions rapidly decompose at elevated temperature or pH.

Natural Tetracyclines have rapid renal clearance ( T1/2= 6-10 hrs, Tetracycline-65ml/min, Chlortetracycline-35ml/min) however the semi-synthetics/lipid soluble forms clear more slowly (t1/2= 16-20hrs, doxycycline-16ml/min, Minocycline-10ml/min).


Mechanism of action:

Bacteriostatic - binds reversibly to 30 S ribosomal subunit.

Very broad spectrum includes Chlamydia, Rickettsia, Mycoplasma, some protozoa.

Resistance:

Results from decreased uptake or active extrusion. Also decreased 30S affinity (mutation etc...).


Pharmacokinetics:

Oral. Uptake impaired by divalent cations (do not take with antacids, Ca++, high end suppliments, milk etc…or it gets chelated).

Well-distributed. High concentrations found in skin. (good for acne but can cause photosensitivity). It crosses the placenta and fetal levels can be high.

Forms complexes with calcium - deposited in bone & teeth.

Urinary excretion major route of elimination
(Thus, usable for UTI's except doxycycline which is excreted in feces)


Clinical Uses:

First choice in few infections:

Mycoplasma, chlamydiae & rickettsia.

Plague, brucellosis & leptospirosis. Sometimes + aminoglycoside.

Used to treat severe acne.


Adverse Reactions

Toxicity rare. Most common is GI irritation. BUT also may cause:

Liver Damage

Depress development of bone and teeth, thus should not be given during pregnancy and up to 8 years old.

Outdated tetracyclines can give transient renal dysfunction.

High concentrations can inhibit host protein synthesis.

Phototoxic reaction: photosensitization & severe sunburn.

Superinfections because of broad spectrum (more so with doxycycline, but others as well).

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Aminoglycosides

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Chemistry:

Polar amino base attached by glycosidic linkage to one or more sugars


Mechanism of Action:

Bind to one or more proteins in 30 S ribosome subunit.

Bacteriostatic at low, bactericidal at high concentration (possibly as a result of time spent blocking ribosome?)

Entry into cell greatly enhanced via cell-wall active drug combination (with PCN for instance)

Broad spectrum against gram positive & negative bacteria. Main action against aerobic gram negative rods


Resistance:

Metabolized by membrane bound enzymes. Amikacin resistant to these enzymes hence broadest spectrum.


Pharmacokinetics:

Negligible GI absorption. Given parenterally.

Distributes in extracellular space. Poor absorption into eye, CSF, respiratory secretions. (Require intrathecal or intraventricular injection to get high CSF levels for menengitis tx due to polarity [rarely done]). Good bone penetration: can be used for osteomyelitis.

Mainly excreted as active drug through glomerular filtration. (UTI effective)


Clinical Uses:

STREPTOMYCIN- TB & other mycobacterial infections + isoniazid or other drugs. Non TB Systemic infections eg. plague, tularemia (rabbit fever)

Combination + Penicillin for endocarditis, tetracyclines for plague.

KANAMYCIN & NEOMYCIN- Topical. Some ointments also contain polymyxin & bacitracin.

Oral. Preoperative reduction of gut flora (being used topically in the gut, not for systemic effect).

Parenteral. Kanamycin IM against bacteremia by gram-negatives. + clindamycin for penetrating abdominal wounds.

AMIKACIN
Semisynthetic derivative of kanamycin. Resistant to enzymes that destroy gentamicin & tobramycin.


Clinical Uses:

GENTAMICIN
IM- Severe infections by gram -ves resistant to less toxic drugs.

Topical-For infected burns or skin lesions.

Intrathecal- Gram negative meningitis (if 3rd gen cephalosprins fail). Requires intrathecal injection. No good in neonates.

TOBRAMYCIN
Similar to gentamicin.

NETILMICIN
Similar to gentamicin; stable to enzyme degradation.

SPECTINOMYCIN
Aminocyclitol antibiotic related to aminoglycosides. Given IM. Alternative for gonorrhea in penicillin allergic patients and for resistant gonococci.


Adverse Effects:

Auditory, vestibular & renal toxicity with prolonged therapy.

Reversible renal impairment (nephrotoxicity) in 5-25% of pt's on Aminoglycosides >3days. Damaged brush border lets enzymes/contents leak, lysosomes fill with drug. Streptomycin is least neprhotoxic, Neomycin is most.

Ototoxicity- Auditory toxicity results from destruction of hair cells in the organ of Corti and retrograde damage to auditory nerves. Vestibular toxicity results from damage to hair cells of the ampullar cristae, giving vestibular dysfunction and vertigo. Streptomycin during pregnancy can give deafness in the newborn.

Generally monitor blood levels because of toxicity. Acute symptoms: nausea, vomiting, vertigo.

May get allergic skin rash in 5%.

Superinfections.

Few side-effects likely from prophylaxis (as when used to clean out bowel pre-operatively. Used to be prevalant in dental work).

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Polymixins

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Chemistry

Basic polypeptides MW 1400. Contain Methyloctanoic acid.


Mechanism of action:

Strongly bactericidal. Disrupt cell membranes rich in Phosphotidylethanolamine.

Active against gram-negative bacilli, esp. Pseudomonas & coli


Resistance:

Proteus & nesseriae highly resistant, due to impermeability of outer membranes. In susceptible bacteria, resistance is rare.


Pharmacokinetics

Not absorbed from GI tract.
When used parenterally mainly excreted in urine.


Clinical uses:

Topical- + bacitracin or neomycin. Wounds, burns, sinuses (P. aeruginosa). Skin regeneration is helpful in this case.

Intramuscular- Urinary tract infections with Pseudomonas & coliforms.

Oral- Not absorbed from gut, used to suppress aerobic gram-negatives of gut in immunosuppressed persons for prophylaxis.


Adverse reactions:

Toxicity limits dose and duration of therapy. Neurotoxic & nephrotoxic. High blood levels can cause respiratory arrest.

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Bacitracin

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Chemistry:

Mixture of water soluble polypeptides. Stable when dry.


Mechanism of Action:

Inhibits cell-wall formation of gram-positives.

Interferes with final transfer of mucopeptide to cell wall.


Pharmacokinetics:

Little absorbed from gut, skin, wounds, mucous membranes, hence little toxicity when used topically. IM injection is fairly well absorbed and widely distributed to be excreted by kidney.


Clinical uses:

Topical. Ointment with polymyxin or neomycin.

Used in antibiotic colitis (C-Diff growth as a result of antibiotic use) as less expensive alternative to vancomycin but potentially toxic.


Adverse reactions:

Nephrotoxic. Virtually abandoned for systemic use.

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Vancomycin

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Chemistry:

Glycoprotein (thus must be parenteral) antibiotic MW1500 from Streptomyces orientalis.


Mechanism of Action:

2 sites of action; cell wall & cell membrane. Bactericidal.

Narrow spectrum; Streptococci, pneumococci, staphylococci, some anaerobes(similar to PCN’s).


Resistance:

Vancomycin Resistant Enterococci (VREs) MRSA with vanco resistance would be very bad news!!).

To limit resistance, SYNERCID -mixture of two Streptogramins which are macrolide-like antibiotics. Parenteral.

LINEZOLID (Zyvox) inhibits protein synthesis. Orally available


Pharmacokinetics:

Not absorbed in GI tract therefore given parenterally (except for for C. difficle enterocolitis).

IM injection gives tissue necrosis and IV bolus injection gives thrombophlebitis; therefore infused IV.

Well-distributed including bone & CSF during meningeal inflammation.

80% excreted in urine in active form. Reduce dose in cases of renal dysfunction (elderly pt’s for instance).


Clinical uses:

Toxic. Reserved for serious infections due to resistant gram +ves. Methicillin-resistant Staph. aureus (MRSAs).

Also used clostridial enterocolitis when it is given orally - poor absorption minimises risk of side effects.

Note that it is reserved more for use in hospitals to reserve it effectiveness on bugs that are resistant to other drugs, but resistance is developing.


Adverse reactions:

Ototoxicity & nephrotoxicity.

Causes flushing due to histamine release (Red man or Red neck syndrome).

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Metronidazole (Flagyl)

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Chemistry:

Synthetic drug. Developed as an Anti-parasitic. (nitroimidazole).

The nitro moiety has to be reduced to an amine, so that it has to be modified/metabolized to become active, (it is a prodrug)


Mechanism of Action:

Active only against obligate anaerobes. Penetrates all bacteria but in anaerobes the nitro moiety is reduced to the active form.

Inhibits DNA replication - generally bactericidal.
Few reports of acquired resistance.


Pharmacokinetics:

Oral. Long half life (8 hours). Well distributed even in bone and CSF. Metabolized in liver and mainly excreted in urine.


Clinical Uses:

B. fragilis particularly for endocarditis & CNS abscesses.

First choice for C.difficile colitis. (others are bacitracin and vancomycin)

Used for preoperative preparation of the colon.


Adverse Reactions:

Generally well tolerated. Common side effects nausea, anorexia, epigastric pain. Disulfiram-type reactions (anabuse to increase hangover after alcohol). Possibly carcinogenic if overused?

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Erythromycin (Macrolide Family)

Back 29

Chemistry:

Erythromycin is Bacteriostatic, and not well absorbed so we have the semi-synthetics Clarithromycin and Azithromycin.

The chemical modifications improve acid stability, tissue permeability, and Broaden the spectrum


Mechanism:

Binds to 23S RNA of 50 S subunit. Spectrum similar but not identical to penicillin G. Also effective against Mycoplasma, Rickettsia, and Chlamydia.


Resistance:

Major disadvantage. Ribosomes no longer bind erythromycin.

Never use as sole drug to treat severe staphylococcal infections.

Can be used with rifampin to treat legionaires disease.


Pharmacokinetics:

Given orally as capsules or tablets with acid-insoluble films or as water insoluble salts. Well-distributed. Does not cross blood brain barrier except when meninges are inflamed. Penetrates well into abscesses (important as abcesses are not well vascularized).

Concentrated in liver & secreted in the bile. Little renal excretion.


Clinical Uses:

Excellent alternative to penicillin G. Drug of first choice for cell-wall deficient microorganisms (Mycoplasma).

Indicated against Corynebacterium & Legionnaire's disease in combination with Rifampin. Also in prophylaxis for endocarditis in penicillin allergic patients.


Adverse Reactions:

Not very toxic. Few side effects.

Drug reactions have been reported. The antihistamine Seldane was withdrawn because of an interaction with erythromycin leading to sometimes fatal arrythmias.

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Clindamycin (Lincosamides)

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Chemistry:

Clindamycin derived from Lincomycin by substitution of Cl for OH, and is the only variety that is used today.


Mechanism of action:

Binds to 50 S ribosomal subunit. Bacteriostatic and bactericidal.

Similar but narrower range than erythromycin.


Resistance:

Similar mechanism to erythromycin.


Pharmacokinetics:

Lincomycin was used parenterally.

Clindamycin is orally available. Well-distributed except in CSF. Excellent penetration into bone to near plasma levels.

Excreted in bile, active drug appears in feces.


Clinical Uses:

Primarilly gram +ve

Susceptible strep. staph. or Bacteriodes

Anaerobic pneumonias (esp in elderly who lay constantly and aspirate a lot).

***Gram +ve Bone infections.

Combined + aminoglycoside for penetrating wounds of abdomen.


Adverse Reactions:

Severe diarrhea & potentially fatal pseudo- membranous colitis due to C. difficile. Occurs in 3% to 5% of patients (the most freq ex of C-Diff cause, but there are others)

Treat with metronidazole (or oral vancomycin or bacitracin).

Note: C. difficile colitis is becoming more prominent even in the absence of antibiotic use.

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Urinary Antiseptics

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Antibacterial in urine but little or no systemic effect.

Acidifying agents suppress bacteria (Bactericidal below pH 5.5. e.g. ketogenic diets, ammonium chloride, ascorbic acid, mandelic acid, methionine and hippuric acid (cranberry juice).

Nitrofurantoin

Methenamine mandelate & hippurate- Methenamine releases formaldehyde which is antibacterial. Do not use with sulfonamides which form insoluble compounds with formaldehyde.

Nalidixic acids & Oxolinic acids- Synthetic. Indicated only for coliform urinary tract infections.

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Quinolones (Fluoroquinolones HIS FAVORITE)

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Chemistry;

Includes Nalidixic Acid (derivations of which are urinary antiseptics) and Ciprofloxacin.


Mechanism of Action:

Block DNA synthesis by inhibiting DNA gyrase.

Gram-negative rods Enterobacteria, Pseudomonas, and Neisseria.

Gram-positive and intracellular pathogens (eg. Legionella).


Resistance:

Apparent in some Pseudomonads.


Pharmacokinetics:

Oral - well absorbed and widely distributed.

Mostly excreted through kidney, 20% metabolized in liver.


Clinical Uses:

Urinary tract infections including Ps. aeruginosa.

Enteritis (Salmonella, Campylobacter & E.coli traveler's diarrhea).

Gonococcal urethritis or pharyngitis.

***Gram -ve Bone Infections (eg. Pseudomonas).

Respiratory, gynecological, soft tissue infections.


Adverse Effects:

Nausea, vomiting, diarrhea are most common.

Headache, dizziness, insomnia, abnormal liver function test, rash. Psychosis (rare).

May elevate theophylline to toxic levels, giving seizures.

Permanent cartilage damage in immature animals.

Rupture of the Achilles tendon (rare).

Superinfections.

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Sulfonamides

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Chemistry:

Derivatives of p-aminobenzenesulfonamide.


Mechanism of Action:

Competitive inhibitors of dihydropteroate synthetase.
Block folic acid synthesis. Reversible. Bacteriostatic.

Broad spectrum - (Not effective against Enterobacter, Proteus or Pseudomonas.)


Resistance:

Through overproduction of PABA or change in enzyme to bind drug less tightly. Plasmid mediated resistance.


Pharmacokinetics:

Oral. Adequately absorbed by GI tract.

Some acetylated but enough appears unchanged in urine to treat urinary tract infections.

Use sodium salts for IV because of increased solubility.


Clinical Uses:

Topical-
Sodium sulfacetamide on conjunctiva. Skin infections on burns.

Insoluble sulfonamides for bowel surgery.

Sulfasalazine used for ulcerative colitis and other bowel diseases. (the salacilic group delivers it to the bowel where it is cleaved off…a delivery system).

Oral-
Urinary tract infections due to gram positive cocci or E.coli.

Chlamydial infections of genital tract, eye or respiratory tract

Bacterial infections. Treatment of choice on nocardiosis. (a bug, nothing to do with the heart)

IV-
For comatose patients with meningitis.


Adverse Reactions:

Older ones poorly soluble - crystalluria, damaging kidney and bladder.

Newer ones more soluble but must maintain urine flow or keep urine alkali.

Other effects: nausea, vomiting, headache etc. Also allergic reactions.

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Trimethoprim

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Mechanism of Action:

Binds to dihydrofolate reductase, 50,000 more effective in bacteria than on same enzyme in mammalian cells.


Pharmacokinetics:

Oral or IV with sulfamethoxazole (Cotrim or Bactrim)synergistic & may be bactericidal. (Act on 2 different enzymes of THF production system)


Clinical Uses:

Urinary tract infections, otitis media, chronic bronchitis, shigellosis & Pneumocystis carinii pneumonia

Trimethoprim alone for gram-negative urinary tract infections. Trimethoprim is a weak base. It concentrates in prostatic fluids and in vaginal fluid, which are weak acids.

Erythromycin-sulfisoxacole for otitis media.

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Penicillin List

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Narrow spectrum:
Penicillin G
Penicillin V
Benzathine penicillin G

Extended spectrum:
Ampicillin
Carbenicillin

Penicillinase-resistant:
Methicillin

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Cephalosporins List

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First-generation:
Cefadroxil (oral)
Cefazolin

Second-generation:
Cefaclor (oral)
Cefoxitin

Third-generation:
Cefotaxime

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Monobatams List

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Imipenem
Aztreonam
Clavulanic acid

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Chloramphenicol List

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Chloramphenicol

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Aminoglycosides

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Streptomycin
Amikacin
Gentamicin
Netilmicin
Tobramycin

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Peptides

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Polymyxin
Bacitracin
Vancomycin

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Drugs Used with Vancomycin Resistant Organisms

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Synercid
Linezolid (Zyvox)

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Metronizadole List

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Metronizadole

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Macrolides

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Erythromycin
Clarithromycin
Azithromycin

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Clindamycin List

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Clindamycin

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Quinolones List

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Nalidixic acid
Ciprofloxacin
Norfloxacin

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Sulfonamides

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Sulfamethoxazole (combined
with trimethoprim)
Sulfacetamide (Opthalmic)
Sulfadiaziane (Topical)

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Trimethoprim List

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Trimethoprim

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Tuberculosis Drugs

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First-line drugs:
Isoniazid
Rifampin
Ethambutol
Pyrazinamide
Streptomycin

Second-line drugs
Aminosalicylic acid
Capreomycin
Cycloserine
Ethionamide

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Leprosy Drugs

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Dapsone (Acedapsone)
Rifampin
Clofazimine

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Tb control Drugs

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First Line-
isoniazid
rifampin
ethambutol
pyrazinamide
streptomycin

They are always used in combinations as resistance develops so rapidly

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Isoniazid

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Chemistry: Isonicotinic acid hydrazide (INH). Similar to pyridoxine. Prodrug activated by peroxidase.

Spectrum/Mechanism: Limited to M. Tuberculasis amd M. Kansasii. Reaches similar concentration intracellylarly and extracellylarly. Inhibits synthesis of mycolic acids unique to Mycobacterium cell wall.

Pharmacokinetics: Oral, good bioavailability. Metabolized in the liver, exreted in urie. Some people are slow inactivators, and some rapid. Inactivation is via acetylation which takes 1hr in rapid folks, and 3hrs in slow. It is genetically controlled by an autosomal recessive trait (in USA 50% whites and blacks are slow, 15% US asians).

Adverse Effects: CNS and PNS effects may result from pyridoxine deficiency (prevent/reverse with pyridoxine suppliment). Prolonges use may damage liver.

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Rifampin

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Chemistry: Semisynthetic rifamycin.

Spectrum/Mechanism: Inhibits DNA dependant RNA polymerase. Used with INH, Ethambutol, or other TB drug. When used with INH it is generally bactericidal. Good oral bioavailability with CSF levels reaching 10-40% of serum. Excreted through liver/bile. Can be used for Leprosy @ 600mg/dy or as a single monthly dose in combination therapy (with dapsone)

Pharmacokinetics:

Adverse Effects: Harmlessly turns bodily secretions red (may stain contact lenses). Induces P450 enzymes reducing the half life of many drugs.

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Ethambutol

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Chemistry: Synthetic agent.

Spectrum/Mechanism: Inhibits polymerization of arabinoglycan (essential for mycobacterial cell wall). Active only against M. Tuberculosis, M Kanasii, and Other Mycobacteria. (first line).

Pharmacokinetics: Well absorbed orally, but resistance develops rapidly hence use in combination.


Adverse Effects: Rare hypersensitivy. More common are visual disturbances.

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Pyrazinamide

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Chemistry: related to Nicotinamide

Spectrum/Mechanism: Converts to the active form (pyranazoic acid), Futher mechanism is unknown. well absorbed orally.

Pharmacokinetics:

Adverse Effects: Hepatotoxicity in 1-5% of patients.

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Streptomycin

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Chemistry: Aminoglycoside that inhibits protein synthesis. Is very polar and can't enter cells, mainly acting on extracellular organisms. Combined Tx to delay resistance.

Spectrum/Mechanism: No oral admin, IV only. Used mostly for life threatening TB, or when it is on the move.

Pharmacokinetics:

Adverse Effects:

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Second Line TB Drugs.

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Ethionamide- related to isoniazid. Can cause GI upset and neurological symptoms

Aminosalicylic acid (PAS)- Similar to PABA & sulfonamides

Capreomycin- Peptide. Toxic to kidney and 8th nerve.

Cycloserine- analong of D-Ala. Psychotic rxn (tx with phenytoin)

Ciprofloxacin and Levofloxacin- act on DNA gyrase

Ansamycin- derived from rifamycin, atypical mycobacteria indluce M. Avium-intracellulare complex which causes serious disseminated pulmonary disease in AIDS.

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Dapsone

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Diamnophenylsulfone, related to sulfonamides (folic acid inhibitor). Used for leprosy. Resistance can emerge with low doses. Side effects include GI problems, Hemolysis, and methemoglobinemia. Acedapsone is a repository form given IM to maintain level for 3 months. Also used to Tx PCP in aids pt's.

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Clofazimine

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Phenazine dye that may be used instead of dapsone in sulfone resistant of intolerant cases of leprosy. Unknown mechanism, possible DNA binding. Stored as crystals in skin and RES tissues and released slowly (serum half-lift of up to 2 months). Side effect is skin to turn red-brown or nearly black.