Trimethoprim + Sulfamethoxazole

Pharmacokinetics

 - Well absorbed orally

 - High Urine Levels

 - Long Elimination T¹/₂: taken bid

 - Metabolites less soluble → crystalluria

Sulfamethoxazole + trimethoprim

Mechanism of Action

 - Synergistic combination

 - Inhibit folate synthesis

 - Bacteriacidal

 - Sulfamethoxazole: blocks dihydropteroate synthetase

 - Trimethoprim: block dihydrofolate reductase

Sulfamethoxazole + trimethoprim

Antimicrobial Spectrum

 - Gram-negative bacilli: E coli, K pneumoniae, Proteus spp

 - NOT P aeruginosa

 - MRSA action

Sulfamethoxazole + trimethoprim

Mechanism of Resistance

Trimethoprim: single aa substitution to DHFR promoter causing overproduction; resistance in gram-negative enteric bacteria, stphylococci, H influenzae, and Listeria monocytogenes

Sulfamethoxazole: sing aa mutation in E coli, S aureus, Staphylococcus haemolyticus, Campylobacter jejuni, and Helicobacter pylori; S pneumoniae and S pyogenes resistance base on 2 aa duplications in folP gene

Sulfamethoxazole + Trimethoprim

Indications

- UTI

- Skin infections

- MRSA

- Acute bacterial sinusitis if allergic to penicillin

Sulfamethoxazole + Trimethoprim

Adverse Effects

- Hypersensitivity→skin rashes, etc

- Leukopenia

- Hemolytic anemia with G-6-PD deficiency

- GI upset

Antibiotics Commonly used to treat bacterial

UTIs

1) Sulfamethoxazole + trimethoprim

2) Trimethoprim

3) Nitrofurantoin

4) Fluoroquinolones (ciprofloxacin, levofloxacin)

5) Aminoglycosides (gentamicin, tobramycin)

Nitrofurantoin

Pharmacokinetics

- Well absorbed orally

- Absorption enhanced with food

- Glomerular filtration & tubular secretion → high urine levels

Nitrofurantoin

Mechanism of Action

- Metabolite inhibit DNA, RNA, and protein synthesis

- Bactericidal

- Damages bacterial DNA in reduced form

- Reactive intermediates attack ribosomal proteins, respiration, pyruvate metabolism and other macromolecules

Nitrofurantoin

Antimicrobial spectrum

Nitrofurantoin

Mechanisms of Resistance

- May be chromosomal or plasmid mediated and involves inhibition of Nitrofuran reductase

 - Resistance rare

Nitrofurantoin

Indications

Nitrofurantoin

Adverse Effects

- Nausea/vomiting

- Ineffective when CrCl < 40ml/min

Fluoroquinolones

(Ciprofloxacin, levofloxacin, Moxifloxacin)

Pharmacokinetics

- Well absorbed orally

- High levels in kidney, prostate, and urine

- Long T¹/₂: taken bid to qd

- Metabolize and excreted in urine

- Moxifloxacin has less renal excretion

Fluoroquinolones

(Ciprofloxacin, Levofloxacin, Moxifloxacin)

Mechanism of Action

Fluoroquinolones

(Ciprofloxacin, Levofloxacin, Moxifloxacin)

Antimicrobial Spectrum

- Gram-negative spectrum, aerobic organisms (E coli → P aeruginosa)

- Variable resistance (low with E coli and K pneumonia, high with P aeruginosa)

- Resistance growing

- Repiratory fluoroquniolones have activity against  S pneumoniae, H influenzae, and atypical pathogens

- Low resistance rates in community respiratory infections but high rates with P aeruginosa

Fluoroquinolones

(Ciprofloxacin, Levofloxacin, Moxifloxacin)

Mechanism of Resistance

Three mechanisms known:

1. Some types of efflux pumps can act to decrease intracellular fluoroquinolone concentration

2. Plasmid-mediated resistance genes produce proteins that bind to DNA gyrase and protect it

3. Mutations at key sites in DNA gyrase and topoisomerase IV can decrease their binding affinity to fluoroquinolones

Fluoroquinolones

(Ciprofloxacin, Levofloxacin, Moxifloxacin)

Indications

- UTIs

- Respiratory Tract infections

Fluoroquinolones

(Ciprofloxacin, Levofloxacin)

Adverse Effects

- Nausea

- Insomnia

- Dizziness

- Drug interaction of Cipro and caffeine/theophylline

- Binds to bivalent metal cations

Aminoglycosides

(gentamicin, tobramycin)

Pharmacokinetics

- Not absorbed orally; IV or IM only

- Excreted in urine, not metabolized

- Dosing interval based upon CrCl

(↓CrCl → ↓dosage to avoid renal damage)

Aminoglycosides

(gentamycin, tobramycin)

Mechanism of Action

Aminoglycosides

(gentamicin, tobramycin)

Antimicrobial spectrum

- Gram-negative bacilli

- Sometimes used against MRSA in combination

- Resistance, but low rates of resistance in gram-negative rods

Aminoglycosides

(gentamicin, tobramycin)

Mechanism of Resistance

Three mechanisms:

1. Reduced uptake due to transport defect or membrane impermeabilization

2. Altered ribosome binding sites due to mutation

3. Enzymatic modification for aminoglycoside modifying enzymes

Aminoglycosides

(gentamicin, tobramycin)

Indications

- UTIs

- Combination therapy for MRSA

Aminoglycosides

(gentamicin, tobramycin)

Adverse Effects

- Nephrotoxicity

- Ototoxicity (vesibular and cochlear) → dizziness, tinnitus, deafness (caused by accumulation of the drug)

Antibiotics commonly used to treat

respiratory tract infections

- Penicillins (Penicillin G, Amoxicillin/ampicillin alone or with β-lactamase inhibitor, piperacillin alone or with β-lactamase inhibitor)

- Cephalosporins (ceftriazone, ceftarolin, ceftazidime, cefepime)

- Macrolides (Erythromycin, clarithromycin, azithromycin)

- Tetracycline (tetracycline, doxycycline)

- Fluoroquinolones (Levofloxacin, Moxifloxacin,Ciprofloxacin)

Penicillin G

Pharmacokinetics

- Typically given parenterally because it is unstable in acidic stomach

- Excreted (filtered and secreted) in urine

- Short T¹/₂, but probenicid decreases rate of elimination

- Dosing interval increases with decreasing CrCl 

Penicillin G

Mechanism of Action

Penicillin G

Antimicrobial Spectrum

- Narrow spectrum

- Streptococcal pneumoniae is main use

Penicillin G

Mechanism of Resistance

- Change in PBP mediated by the mecA gene → reduced affinity to PBP2a (resistance)

- Occurs in Streptococcal pneumoniae and others

- Resistance also commonly due to β-lactamase enzymes that can be chromosomal or plasmid-mediated (H influenzae has 30% resistance rate for this reason)

- Use of β-lactamase inhibitor decreases resistance

Penicillin G

Indication

- Respiratory tract infections

- GAS pharyngitis and other GAS infections

- Nonresistant Streptococcal pneumoniae infections

- Gas Gangrene

- Treponema Palldum including during pregnancy

- Erysipelas

Penicillin G

Adverse Effects

- Hypersensitivity: rash → anaphylaxis

- High concetrations can cause seizures

- Diarrhea due to C. difficile due to normal flora clearnace

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Pharmacokinetics

- Augmentin absorbed orally

- Eunicin administered by IV

- Excreted (filtered and secreted) in urine

- Short T¹/₂, but probenicid decreases elimination

- Dosing interval increases with decreasing CrCl

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Mechanism of Action

- Amoxicillin/Ampicillin: bind to penicillin-binding proteins → lysis or alteration of bacterial cell

- Clavulanate/sulbactam: inhibit β-lactamase

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Antimicrobial spectrum

-Broad spectrum including S pneumoniae, H influenzae

- Aerobic (E coli) and anaerobic (B fragilis)

- NOT P aeruginosa

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Mechanisms of Resistance

- Use of Clavulanate/sulbactam decreases resistance due to β-lactamase enzymes

- Resistance also due to change in PBP mediate by mecA gene mutation → reduces affinity to PBP2a (occurs in Strep pnumoniae)

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Indication

- Streptococcal pyogenes infections

- Respiratory tract infections

- Mixed aerobic-anaerobic infections

Amoxicillin/Ampicillin

(Amoxicillin-clavulanate = Augmentin, Ampicillin-sulbactam = Eunicin)

Adverse Effects

- Hypersensitivity: rash → anaphylaxis

- High concentrations can cause seizures

- Diarrhea due to C difficile after clearance of normal flora

Piperacillin

(Piperaccilin-tazobactam = zocin)

Pharmacokinetics

- IV only

- Excreted (filtered and secreted) in urine

- Short T¹/₂, but probenicid decreases elimination rate

- Dosing interval increases with decreasing CrCl

Piperacillin

(Piperacillin-taxobactam = zocin)

Mechanism of Action

- Piperacillin: binds to penicillin-binding proteins → lysis or alteration of the bacterial cell

- Taxobactam: inhibits β-lactamase

Piperacillin

(Piperacillin-tazobactam = zocin)

Antimicrobial Spectrum

Piperalcillin

(Piperacillin-tazobactam = zocin)

Anitimirobial spectrum

Piperacillin

(Piperacillin-tazobactam = zocin)

Mechanism of resistance

Piperacillin

(Piperacillin-tazobactam = zocin)

Indications

- Respiratory tractinfections

- Anaerobic, mixed aerobic-anaerobic infection

- P aeruginosa infections

Piperacillin

(Piperacillin-tazobactam = zocin)

Adverse Effects

- Hypersensitivity: rash → anaphylaxis

- High concentrations can cause seizures

- Diarrhea due to C difficiles after clearance of normal flora

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Pharmacokinetics

- Ceftiaxone and Ceftaroline IV only; Ceftazidime and Cefepime IV or IM

- CSF penetration varies, ceftriaxone preferred for meningitis

 - Ceftaroline excreted (filtered and secreted) into urine; ceftriaxone excreted into bile

 - Often longer T¹/₂ than penicillin

- Dosing dependent on CrCl

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Mechanism of Action

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Antimicrobial Spectrum

- 3rd generation active against gram-negative

- Cefepime activite against gram-positive and gram-negative organisms particularly against Enterobacteriaceae

- Action against H influenzae

- Ceftaroline has activity against MRSA

- Ceftaxidime and Cefepime active against Pseudomonas aeruginosa

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Mechanism of Resistance

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Indications

- Respiratory tract infections

- Skin and soft-tissue infections (1st generation mostly, unless infection by MRSA)

- Anaerobic or mixeda aerobic-anaerobic

- GAS pharyngitis

- Streptococcal pneumoniae infections

- Streptococcal pneumoniae infections

- Neisseria gonorrhea urethritis (ceftriaxone)

- MRSA infections (ceftaroline only)

- Psuedomonas aeruginosa infections (cefepime and ceftazidime)

3rd-generation Cephalosporins

(Ceftriaxone, Ceftaroline, Ceftazidime)

4th-generation Cephalosporin

(Cefepime)

Adverse Effects

- Hypersensitivity

- High concentration can cause seizures

- Can lead to overgrowth of other bacteria (Enterococci, C difficile)

Macrolides

(Erthromycin, Clarithromycin, Azithromycin)

Pharmacokinetics

- Orally absorbed

- Newer agents have longer T¹/₂

- Metabolized by the liver; CYP 450 drug interactions can occur, but not with azithromycin

Macrolides

(Erythromycin, Clarithromycin, Azithromycin)

Mechanism of Action

Macrolides

(Erythromycin, Clarithromycin, Azithromycin)

Antimicrobial Spectrum

- Broad spectrum against respiratory pathogens (S pneumoniae, H influenzae, mycoplasma)

- Clarithromycin and azithromycinhave improved activity against H influenzae compared to erythromycin

Macrolides

(Erithromycin, Clarithromycin, Azithromycin)

Mechanism of Resistance

- Resistance i sprimariy due to active efflux and change in the binding site in the ribosome

- High rates of resistance in S pneumoniae

Macrolides

(Erythromycin, Clarithromycin, Azithromycin)

Indications

Macrolides

(Erythromycin, Clarithromycin, Azithromycin)

Adverse Effects

- GI upset; nausea, vominitin, diarrhea

- Drug interactions; for example clarithromycin + statin may lead to myositis or rhabdmyolysis

- Use with caution in patients with arrythmias because macrolides ↑ QT interval

- Use with caution in patients receiving CYP-3A inhibitors

- Heptatotoxicity

Tetracyclines

(Tetracyclin, Doxycycline)

Pharmacokinetics

- Absorbed orally

- Doxycycline has a long T¹/₂

- Excreted in urine and feces

- Binding by multivalent cations; should not take with milk or drugs with cations

Tetracyclines

(Tetracyclin, Doxycycline)

Mechanism of Action

Tetracyclines

(Tetracycline, Doxycicline)

Antimicrobial Spectrum

- Broad spectrum against respiratory pathogens (S pneumoniae, H influenzae, mycoplasma)

- High rates of resistance in S pneumoniae to tetracycline; doxycycline resistance is lower

Tetracyclines

(Tetracycline, Doxycycline)

Mechanism of Resistance

Tetracyclines

(Tetracyclin, Doxycycline)

Indications

Tetracyclines

(Tetracycline, Doxycycline)

Adverse Effects

- Nausea

- Dizziness

- Photosensitivity

- Teeth discoloration in children

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Pharmacokinetics

- Cefazolin usually administered IV or IM; Cephalexin well absorbed orally; Ceftriaxone administered IV or IM

- CSF penetration varies; Ceftriaxone drug of choice for meningitis

- Cefazolin and Cephalexin excreted (filtered and secreted) into urine; Ceftriaxone excreted into bile

- Often longer T¹/₂ than penicillins

- Dosing dependent upon CrCl

- Cefazolin is highly protein bound

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Mechanism of Action

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Antimicrobial Spectrum

- 1st-generation cephalosporins have good activity against gram-positive organisms (S aureus, Streptococci)

- 3rd generation active against gram-negative including H influenzae

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Mechanism of Resistance

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Indications

- Skin and Soft tissue infections

- Group A streptococcal pharyngitis, other streptococcal infections

- Staph aureus infections

1st-generation Cephalosporins

(Cefazolin, Cephalexin)

3rd-generation Cephalosporin

(Ceftriaxone)

Adverse Effects

- Hypersensitivity

- High concentrations can cause seizures

- Can lead to overgrowth of other bacteria causing diarrhea (Enterococci, C difficile)

- First-generation cephalosporins

- Anitstaphylococcal penicillins

- Ceftriaxone

- Vancomycin

- Clindamycin

- Linezolid

- Daptomycin

Antistaphylococcal penicillins

(Nafcillin)

Pharmacokinetcis

- Usally administered by IV or IM

- Short T¹/₂, but probenicid decreases elimination rate

- Nafcillin is excreted in bile

- Highly protein bound

Antistaphylcoccal penicillins

(Nafcillin)

Mechanism of Action

Antistaphylococcal Peniccilins

(Nafcillin)

Antimicrobial spectrum

- Activity against gram-positive organsims (S aureus and  Streptococci)

- NOT active against MRSA (PBP2a)

Antistaphylococcal Penicillins

(Nafcillin)

Mechanism of Resistance

- Inactivation by β-lactamases

 - Alterations in PBP

Antistaphylococcal Penicillins

(Nafcillin)

Indications

- Skin and soft tissue infection

- Coagulase-negative Staphylococci

- S aureus infections

Antistaphylococcal Penicillins

(Nafcillin)

Adverse Effects

- Hypersensitivity (rash → anaphalaxis)

- High concentrations can cause seizures

- Diarrhea caused by C difficile

- Hepatitis

Vancomycin

Pharmacokinetics

- Poorly absorbed, used orally only for treatment of C difficile; IV administration

- Tissue distribution is limited

- Long T¹/₂ and is extended in renal failure

- Renally excreted by glomerular filtration

Vancomycin

Mechanism of Action

Vancomycin

Pharmacokinetics

- Poorly absorbed, used orally only for treatment of C difficile; IV administration

- Tissue distribution is limited

- Long T¹/₂ and is extended in renal failure

- Renally excreted by glomerular filtration

Vancomycin

Mechanism of Action

Vancomycin

Antimicrobial spectrum

- Active against gram-positive cocci (S aureus, Enterococcus, Streptococci) including MRSA and PRSP (Penicillin-resistant S pneumoniae)

- Active against C difficile

Vancomycin

Mechanism of Resistance

Vancomycin

Indications

- Skin and soft tissue infections

- Coagulase-negative Staphylococci infections

- MRSA infections

- Streptoccocus pneumoniae infections

Vancomycin

Adverse Effects

- Rash caused by histamine release

- Nephrotoxic especially with other nephrotoxic drugs such as aminoglycosides

- High concentrations can be ototoxic

- Hematologic Effects such as thrombocytopenia and neutropenia

Clindamycin

Pharmacokinetics

- Absorbed orally

- Well distributed

- Hepatic metabolism

- Biliary and fecal excretion

Clindamycin

Mechanism of Action

- Inhibits proteinsynthesisby inhibiting tRNA binding

- Can inhibit toxin formation

Clindamycin

Antimicrobial spectrum

- Active against gram-positive cocci and anaerobes

- Active against some strains of MRSA; resistance in S aureus is variable

Clindamycin

Mechanism of Resistance

Clindamycin

Indications

- Skin and soft tissue infections

- Anaerobic or Mixed aerobic-anaerobic infections

- Acute bacterial sinusitis

- GAS pharyngitis

- MRSA infections

- Gas gangrene

- Pelvic Inflammatory Disease caused by Neisseria gonorrhoeae

- Impetigo

Clindamycin

Adverse Effects

Linezolid

Pharmacokinetics

- Oral or IV, 100% bioavailability

- Good tissue distribution including SF

- Metabolized in liver

- Few drug interactions

- Weak MAO inhibitor, can ↑ serotonin levels

Linezolid

Mechanism of Action

Linezolid

Antimicrobial spectrum

- Acitve against gram-positive cocci (Staphylococcus, Enterococcus) including MRSA and VRE

- Very active against atypical respiratory pathogens

Linezolid

Mechanism of Resistance

- Resistance is uncommon

- Intrinsic resistance of gram-negtive due to efflux pumps, which actively pump linezolid

- Resistance of gram-positive due to point mutations in 23S ribosomal RNA

Linezolid

Indications

- Skin and soft tissue infections

- Alternative for coagulase negative Staphylococci infections

- MRSA infections

Linezolid

Adverse Effects

- Diarrhea

- Headache

- Nausea

- Thrombocytopenia; should monitor platelets

Peripheral neuropathy with long-term use (>3 mos) as used in osteomyelitis

- Serotonin Sydrome (clonus, seizuers, altered mental status, even death) if givenwith and SSRI

Daptomycin

Pharmacokinetics

- Not absorbed orally; only IV

- High protein binding

- Excreted primarily by the kidneys, 60% unchanged

- T¹/_{2 increases with renal failure- Bound and inactivated by pumonary surfactant in the epithelial lining fluid of the lungs; not good for pneumonia}

Daptomycin

Mechanism of Action

Daptomycin

Antimicrobial Spectrum

Daptomycin

Mechanism of Resistance

Daptomycin

Indications

- Skin and soft tissue infections

- Coagulase-negative Staphylococci

- MRSA infection

Daptomycin

Adverse Effects

- Hypersensitivity (fever, rash, etc)

- Effects on the skeletal muscle causing muscle pain or weakness; increases in CPK

- Penicillins

- Cefoxitin

- Carbapenems

- Metroidazole

- Clindamycin

- Tigecycline

Cefoxitin

Pharmacokinetics

- IV administation

- Excreted in urine

- Short T¹/₂

Cefoxitin

Mechanism of Action

Cefoxitin

Antimicrobial spectrum

- Active against a broad range of gram-negative and gram-positive bacteria including anaerobes

- Inactive against most P aeruginosa and enterococci

- Inactive against MRSA

Cefoxitin

Mechanism of Resistance

Cefoxitin

Indications

- Anaerobic or mixed aerobic-anaerobic infections

- Used with Doxycycline for Pelvic Inflammatory Disease 

Cefoxitin

Adverse Effects

Carbapenems

(Imipenem, Meropenem)

Pharmacokinetics

- Not absorbed orally, must be given by IV

- Distributed in the body like penecillin

- Renally eliminated by tubular secretion

- Cilastatin, a DHP II inhibito, prevents inactivation of imipenem in the kidneys

- Doses should be decreased with renal insufficiency

Carbapenems

(Imipenem, Meropenem)

Mechanism of Action

- High affinity for PBP's

- Binds and causes bacteria cell alteration or lysis

Carbapenems

(Imipenem, Meropenem)

Antimicrobial spectrum

- Broad-spectrum activity against aerobic and anaerobic organisms

- Good activity against P aeruginosa

- Resistant to many β-lactamase enzymes

Carbapenem

(Imipenem, Meropenem)

Mechanism of Resistance

Carbapenems

(Imipenem, Meropenem)

Indications

- Anaerobic or mixed aerobic-anaerobic infections

- Gas gangrene

Carbapenems

(Imipenem, Meropenem)

Adverse Effects

- Hypersensitivity reactions; can exhibit cross allergy with other β-lactams

- Nausea

- Seizures with high doses of imipenem/cilastatin

Metronidazole

Phamacokinetics

- Well absorbed; can be given orally or by IV

- Widely distributed into tissues, including CSF

- Long T¹/₂

- Extensively metabolized into oxidative products

Metronidazole

Mechanism of Action

Metronidazole

Antimicrobial Spectrum

- Active against anaerobic bacteria and protozoa

- Anaerobes only

Metronidazole

Antimicrobial Spectrum

- Active against anaerobic bacteria and protozoa

- Anaerobes only

Metronidazole

Mechanism of Resistance

- Low rates of resistance in anaerobic organisms

- Resistance is due to decreased oxidoreductase activity → reduced activation

- Resistant strains have increased levels of LDH

Metronidazole

Indications

- Anaerobic or mixed aerobic-anaerobic infection

- Gas gangrene

- Second line treatment of Pelvic Inflammatory Disease in combination with Azithromycin

Metronidazole

Adverse Effects

- GI symptoms (nausea, anorexia)

- Metallic taste

- Pancreatitis

- Drug interactions when taken with alcohol, warfarin, and phenytoin due to disulfiram reaction

Tigecycline

Pharmacokinetics

- Only IV (not absorbed orally)

- Long T¹/₂ requiring only twice-daily dosing

- Low serum levels; high tissue concentrations

- Eliminated in feces via biliary excretion; 10% renal clearance so don't need to worry about renal insufficiency

Tigecycline

Mechanism of Action

- A minocycline derivative

- Blocks binding of tRNA to the 30S subunit of ribosome

Tigecycline

Antimicrobial Spectrum

- Broad-spectrum activity against aerobes and anaerobes

- Not active against P aeruginosa

Tigecycline

Mechanism of Resistance

Tigecycline

Indications

- Anaerobic and mixed aerobic-anaerobic infections

- MRSA infections

Tigecycline

Adverse Effects

- High rate of nausea and vomitin

-Low rates of C difficile diarrhea

- Rare pancreatitis

- Isoniazid

- Rifampin, Rifabutin

- Ethambutol

- Pyrazinamide

Isoniazid

Pharmacokinetics

- Can be administered orally, IV, IM

- Very low protein binding

- Metabolized in the liver by CYP 450, 2C19 and 3A4

- Excreted primarily by the urine, but secondarily in feces

- Inhibits CYP 450 system

Isoniazid

Mechanism of Action

- Bactericidal to rapidly dividing mycobacteria and bacteriostatic if bacteria is slow growing

- Must be activated by KatG

- Acts by blocking fatty acid synthase which inhibits mycolic acid synthesis which is required for the mycobacterial cell wall

Isoniazid

Antimicrobial Spectrum

Isoniazid

Mechanism of Resistance

- Most commonly due to mutation of the catalase-peroxidase (KatG) that reduces its activity, preventing prodrug conversion to the active form

- Another mechansim involves missense mutation of the bacterial genes inhA and KasA, involved in mycolic acid synthesis

- NADH dehydrogenase mutations cause resistance as well

Isoniazid

Adverse Effects

- Rash

- Hepatitis

- Sideroblastic anemia

- Peripheral neuropathy

- Mild CNS effects

- Drug interactions when taken with phenytoin, disulfiram, theophylline

Rifampin

Pharmacokinetics

- Administered orally or by IV

- 90-95% bioavailability

- Metabolized by the intestinal cell wall and liver

- Excreted most in feces, but partially in urine

Rifampin

Mechanism of Action

Rifampin

Antimicrobial Spectrum

 - Active against most gram-positive bacteria (Staphylococci) as well as many gram-negative (E coli, Pseudomonas, Klebsiella)

- Active against Neisseria meningitidis and H influenzae

- Active against Mycobacterium tuberculosis

Rifampin

Mechanism of Resistance

Rifampin

Indications

- Mycobacterium tuberculosis infections

- MRSA infections in combination therapy

Rifampin

Adverse Effects

- Generally well tolerated

- Nausea, vomiting

- Fever

- Rarely hepatitis

- Hypersensitivity

Ethambutol

Pharmacokinetics

- Administered orally, bioavailability is ~80%

- 10-40% of the drug is bound to plasma protein

- Majority is not metabolized and is renally excreted

Ethambutol

Mechanism of Action

Ethambutol

Antimicrobial Spectrum

Ethambutol

Mechansim of Resistance

Ethambutol

Indications

- TB

- Other mycobacterial infections

Ethambutol

Adverse Effects

- Very few serious adverse effects

- Diminished visual acuity

- Rash

- Fever

Pyrazinamide

Pharmacokinetics

- Well absorbed orally; biovailability is >90%

- Metabolized then excreted by kidney

- Excretion is reduced in renal failure

Pyrazinamide

Mechnism of Action

- Activated by acidic conditions

- Actual mechanism still unknown

Pyrazinamide

Antimicrobial Spectrum

- Active only at acidic pH

- M tuberculosis infections

Pyrazinamide

Mechanism of Resistance

- Resistance due to reduced affinity of pyrazinamidase with reduced affinity for pyrazinamide

- Reduced affinity decreases the conversion of pyrazinamide

Pyrazinamide

Indications

- M tuberculosis infection

- Co-administration with isoniazid or rifampin has let to a 1/3 reduction in teh duration of anti-TB therapy

Pyrazinamide

Adverse Effects

- Injury to the liver is most serious side effect

- Hyperurecemia in nearly all patients

- Athralgia, anorexia, nausea, vomiting, dysuria, malaise, and fever

Amphotericin B

(Liposomal preparations)

Pharmacokinetics

- Only IV (not well absorbed)

- Higher doses usedfor treatment than deoxycholate

- Widely distributed, but CSF levels are minimal

- Extensively metabolized by the liver

- Initial T¹/₂ ~ 24, terminal T¹/₂~15 days

- Achieve lower renal tissue concentration than deoxycholate; concentrated in reticuloendothelial tissues (livere and spleen)

Amphotericin B

(Liposomal preparations)

Mechanism of Action

Amphotericin B

(Liposomal preparations)

Antimicrobial Spectrum

- Broad-spectrum of activity against most pathogenic fungi, including invasive Aspergillosis

- Resistance is uncommon

Amphoberiticin B

(Liposomal preparations)

Mechanism of Resistance

Amphotericin B

(Liposomal preparations)

Indications

- Candida infections

- Aspergillus infections

Amphotericin B

(Liposomal preparations)

Adverse Effects

- Infusion reactions (fever, chills, nausea, hypotension, tachycardia, rigors); pretreatment meds often given; least reaction with liposomal preparation

- Nephrotoxicity, the dose-limiting toxicity; sodium loading can help; less nephrotoxicity than with deoxycholate

- Other drugs can add to nephrotoxicity including aminoglycosides, cyclosporine, foscarnet, cisplatin

- Hypokalemia and hypomagnesemia; amelioride can help

- Liver toxicity

Itraconazole

Pharmacokinetics

- Only oral formulation (lipid soluble)

- Variable absorption (improved with food, decreased with drugs that raise stomach pH)

- Poor CSF penetration

- Highly protein bound

- Metabolized in GI tract and liver

- Low urine recovery

- Significant drug-drug interactions: it is a potent inhibitor of CYP 3A4 (antiarrythmics, antiepileptics, antiretrovirals, psychotropics, statins, immunosuppressants, etc.)

Itraconazole

Mechanism of Action

Itraconazole

Antimicrobial Spectrum

Itraconazole

Mechanism of Resistance

- Primary mechanism of resistance in Candida is accumulation of mutation in ERG11, which protect heme in the enzyme pocket from biding to the azole

- Increased azole efflux adds to resistance

- Primary mechanism of resistance in Aspergillus causes increased azole transport and decreased ergosterol content

Itraconazole

Indications

- Candida and Aspergillus infections outside of the CNS

- Chronic Granulomatous Disease as an antifungal

Itraconazole

Adverse Effects

- Nausea, abdominal pain

- Rash

- Hepatitis

- Hypokalemia, edema and hypertension; should be used with caution in CHF patients

Fluconazole

Pharmacokinetics

- IV and PO (100% bioavailability)

- Water soluble → penetrates many tissues

- CSF concentrations are half those in serum

- High urine concentration

- Long T¹/₂

- Mostly renal excretion; doses decreased in patients with renal failure

- Can inhibit the metabolism of other drugs via CYP 3A4 and CYP2C9

Fluconazole

Mechanism of Action

Fluconazole

Antimicrobial Spectrum

Fluconazole

Mechanism of Resistance

- Primary mechanism of resistance in Candida is accumulation of mutation in ERG11, which protect heme in the enzyme pocket from biding to the azole

- Increased azole efflux adds to resistance

- Primary mechanism of resistance in Aspergillus causes increased azole transport and decreased ergosterol content

Fluconazole

Indications

Fluconazole

Adverse Effects

- GI upset (nausea, vomiting)

- Skin rash

- Hepatitis

Voriconazole

Pharmacokinetics

-IV and PO; 95% bioavailable

- Good tissue penetration, including CSF

- Metabolized by the liver; renal insufficiency doesn't effect dosing

- Multiple drug interaction; inhibits CYP2C9 (warfarin, phenytoin) and CYP3A4 (tacrolimus, cyclosprine)

Voriconazole

Mechanism of Action

Voriconazole

Antimicrobial Spectrum

Voriconazole

Mechanism of Resistance

- Primary mechanism of resistance in Candida is accumulation of mutation in ERG11, which protect heme in the enzyme pocket from biding to the azole

- Increased azole efflux adds to resistance

- Primary mechanism of resistance in Aspergillus causes increased azole transport and decreased ergosterol content

Voriconazole

Indications

- Aspergillus infection

- (Candida Infection)

Voriconazole

Adverse Effects

- Abnormal vision (blurred, photophobia) occurs in 1/3 of patients and lasts for about 30 minutes

- Nausea, fever, chills

- Rash

- Hepatitis

Caspofungin

Pharmacokinetics

- Only IV

- Widely distributed with a half-life of 10 hours

- Brain and CSF penetration is limited due to high protein binding

- Undergoes hydrolysis and N-acetylation in the liver

- Urine exretion is minimal

- Drugs such as rifampin, phenytoin, and efavirenz can reduce caspofungin levels by increasing its metabolism

Caspofungin

Mechanism of Action

- Inhibits β-glucan synthesis via inhibition of glucan synthetase; this leads to increased cell wall permeability and lysis of the cells

- Fungicidal

Caspofungin

Antimicrobial Spectrum

- Active against Candida species and Aspergillus species

- Maintains activity against fluconazole-resistant Cadida albicans

Caspofungin

Indications

- Candida infections

- Coverage of Aspergillus but not primary treatment of Aspergillus infections

Caspofungin

Adverse Effects

- Phlebitis

- Skin rash, fever, headache, nausea

- Hepatits

5-Fluorocytosine

Pharmacokinetics

- Well absorbed with oral administration

- Widely distributed in the body

- Most excreted unchanged in urine

5-Fluorocytosine

Mechanism of Action

5-Fluorocytosine

Antimicrobial Spectrum

5-Fluorocytosine

Mechanism of Resistance

5-Fluorocytosine

Indications

5-Fluorocytosine

Adverse Effects

- May depress the bone marrow and lead to leukopenia and thrombocytopenia

-Rash, nausea, vomitin, diarrhea

- Severe entercolitis

- Elevated hepatic enzymes

- Amphotericin B

- Itraconazole

- Fluconazole

- Voriconazole

- Caspofungin

- 5-fluorocytosine

Acyclovir and Valacyclovir

Pharmacokinetics

- Oral acyclovir is poorly absorbed (10%) whereas Valacyclovir, a prodrug, has bioavailability of 55%

- Can also be given by IV

- Widely distributed in the body including brain and CSF

- Eliminated in the Urine

Acyclovir and Valacyclovir

Mechanism of Action

- Active Metabolites inhibit viral replicationby acting as substrates fo and inhibiting viral DNA polymerase (chain termination)

- Phosporylated by viral thymidine kinase to become active

Acyclovir and Valacyclovir

Antimicrobial Spectrum

Acyclovir and Valacyclovir

Mechanism of Resistance

-Occurs when thymidine kinase (TK) is absent or altered

- Resistance is uncommon in immunocompetent patients

Acyclovir and Valacyclovir

Indications

- Herpes Infection; when taking during pregnancy acyclovir decreases clinical HSV recurrence at the time of delivery and asymptomatic viral shedding at deliver

- Herpes-zoster infection

Acyclovir and Valacyclovir

Adverse Effects

- GI upset and headache

- Renal insufficiency

Amantadine

Pharmacokinetics

- Absorbed orally

- Cleared by both glomerular filtration and tubular secretion

- Half-life is increased in renal insufficiency

Amantadine

Mechanism of Action

Amantadine

Antimicrobial Spectrum

- Acitve against influenza A

- Not active against influenza B

Amantadine

Mechanism of Resistance

Amantadine

Indications

Amantadine

Adverse Effects

- CNS events (nervousness, lightheadedness, insomnia, confusion); these can be enhance by other drugs such as antihistamines and phenyl propanolamine)

- GI upset (nausea, loss of apetits)

- Teratogenic

Oseltamivir

Pharmacokinetics

- Absorbed orally (prodrug)

- Active compound (carboxylate) is excreted by glomerular filtration and tubular secreation

Oseltamivir

Mechanism of Action

Oseltamivir

Antimicrobial Spectrum

- Active against influenza A and B viruses

- Resistance is now common in H1N1 strains

Oseltamivir

Mechanism of Resistance

Oseltamivir

Indications

Oseltamivir

Adverse Effects

- Nausea, vomiting; these effects are decreased with food

- Headache

- Can be harmful during pregnancy

- Lamivudine (3TC)

- Zidovudine (ZDV, AZT)

- Emtricitabine

- Abacavir

NRTI

Mechanism of Action

- Must first undego intracellular phosphrylation to be active

-Mimic other nucleosides and are incorporated into the DNA strand

- Inhibit the viral reverse transcriptase enzyme thus inhibit transcription of viral RNA into dsDNA

- Halts production of new virions

NRTIs

Adverse Effects

- Lactic Acidosis

- Abacavir = severe hypersensitivity reactons; having a positive HLA-B5701 allele increases the risk of hypersensitivity reactions

- Zidovudine = headache,anemia, neutropenia

- Efavirenz

- Rilpivirine

NNRTI

Mechanism of Action

NNRTI

Adverse Effects

- Efavirenz = hepatitis

- Rilpivirine = depressive disorder, not approved if the viral load is > 100,000 copies, taken with a meal

- Nelfinavir

- Atazanavir

- Ritonavir

- Darunavir

PI

Mechanism of Action

- Stop the protease enzyme from forming mature virions

- When the PIs bind to the enzyme, HIV is still being produced, but they are considered inactive

- Low dose Ritonavir is used to boost serum levels of the PIs

PIs

Adverse Effects

- Poor absorption

- Drug interactions (P450)

- Lipid abnormalities; should check patient's TGs and cholesterol routinely

- Lipodystrophy, redistribution of fat

- Cause or worsen diabetes

- GI symptoms

- Enfurviritide

- Maraviroc

Fusion Inhibitors

Mechanism of Action

- Enfuviritide = blocks HIV CD4 cell fusion through co-receptors

- Maraviroc = CCR5 antagonists; not effective in cells with CXCR4 receptors

Fusion Inhibitors

Pharmacokinetics

- Enfuviritide = administered SC bid

- Maraviroc = Oral administration

Fusion Inhibitors

Adverse Effects

- Raltegravir

- Elvitegravir

Integrase Inhibitors

Mechanism of Action

Raltegravir

Adverse Effects

- Diarrhea

- Rash

- Increased CPK

Elvitegravir

Administration

- Only available in a comination drug called Stribild (elvitegravir+cobicistat+emtricitabine+tenofovir)

- Cobicistat isnot active against HIV; it inhibits CYP3A4 and enhances other HIV drugs

- Quinine

- Malarone

- Chloroquine

Quinine

Pharmacokinetics

- May be administered orally or IM

- Metabolized by the liver

- Excretedin the urine

Quinine

Mechanism of Action

- Gametocidal

- Active against blood schizonts but not liver stage parasites

- Mechanism is unknown

Quinine

Antimicrobial spectrum

Quinine

Indications

- P vivax and P ovale infections

- Parental or Oral treatment of Severe Falciparum

Quinine

Adverse Effects

- Tinnitus

- Headache,nausea, dizziness

- Flushing

- Visual distrubances

- Together known as Cinchonism