Interfere with ergosterol synthesis via fungal P450

Fluconazole - highest bioavailability

CNS penetration (cryptococcal meningitis)

Itraconazole - dimorphic fungi

Oral only, does not get to CNS

Voriconazole - invasive aspergillosis

Visual disturbances

Ketoconazole - first azole, high level P450 inhibition (topical use)

Liver toxicitiy

Beta (1-3) Glucan Synthesis Inhibitor 

(Anti-fungal)

Caspofungin

Inhibits glucan (for cell wall maintenance)

Invasive aspergillosis that is unresponsive to Amp B and Voriconazole

Do not give with cyclosporine

Polygenes

(Anti-fungals)

Binds to ergosterol creating pores in membrane

Amphotericin B - systemic mycosis (broad spectrum)

Safe in pregnancy

Nystatin - cream, suppository for localized candida

Too toxic for parenteral admin

Lanosterol Inhibitor

(Anti-fungal)

Terbinafine 

Accumulates squalene to toxic levels

Keratophilic and fungicidal for onchyomycosis

Microtubule Inhibitor

(Anti-fungals)

Griseofulvin

Mitotic inhibitor interferes with microtubule assembly

Keratophilic, not fungicidal

Prevents infection in new nail growth for onychomycoses

Do not used with Warfarin or Phenytoin

DNA/RNA Synthesis Inhibitors

(Anti-fungals)

Flucytosine

Anti-metabolites that block DNA/RNA synthesis

Narrow spectrum, only used in combinations where synergy is seen for cryptococcus

Pancytopenia (adverse effect)

Penicillins

(Beta lactams)

Analog of D-ala D-ala to inhibit cell wall synthesis

Leads to bacterial cell lysis

Penicillin G - Gram +, anaerobes

Causes pseudomembranous colitis

Nafcillin - not susceptible to beta-lactamases

Amoxicillin - Gram + and Gram - (broader spectrum)

Better GI absorption

Delayed hypersensitivity more common

Amoxicillin + Clavulanic Acid (Augmentin) - Contains beta-lactamase inhibitor 

Pipercillin - pseudomonas

Cephalosporins

(Beta-lactams)

Structurally related to penicillins

Mechanism of action identical to penicillin

Not readily inactivated by Beta-lactamases

Cefazolin (first gen) - Gram + skin and soft tissue infections, surgery prophylaxis

Parenteral administration

Cefoxitin (second gen) - Gram + and Gram -

Especially resistant to Beta-lactamses

PID, lung abscess (mixed aerobic, anaerobic)

IV administration

Cefriaxone (third gen) - gonorrhea, Lyme disease

Use with aminoglycosides

CNS penetration

Carbapenem

(Beta-lactam)

Imipenem + Cilastatin

Resistant to inactivation by Beta-lactmases

Broadest activity of all antibiotics

Seizures

Monobactam

(Beta-lactam)

Aztreonam

Resistant to Beta-lactamase inactivation

Aerobic Gram - bacilli

Enterobacteriaeceae

Pseudomonas

No cross allergenicitiy

Little cross allergenicity with other pens or cephs

Vancomycin

Peptidoglycan synthetase inhibitor

Gram + (IV)

Used for Pseudomembranous colitis (oral)

Flushing due to rapid infusion histamine release

Macrolides

Promotes dissociation of tRNA from ribosome

Cytostatic drugs

Erythromycin - Gram + cocci and bacilli

Liver toxicity, Long QT, Hypersensitivity

Do not used with Warfarn, Theophylline, Cyclosporine

Induced + Constitutive resistance

GI effects big reason for discontinuation

Salt formulation better tolerated but increased risk of liver toxicity

Clarithromycin - Gram + and Gram -, M. avium

Reversible hearing loss

Reduce dose with liver and kidney disease

Do not use in pregnancy

Azithromycin - Once day dosing and shorter treatment duration

No P450 interactions

Good penetration, but not to CNS

Half life: 3 days

Clindamycin - Gram + and Gram - anaerobes, Gram + aerobes

Causes Pseudomembranous colitis (C. diff resistant) - Tx with metronidazole, vancomycin

Structurally distinct from erythromycin

Only constitutive resistance

Macrolide

Forms covalent bonds with bacterial DNA

Metronidazole

Anaerobes

Used for Pseudomembranous colitis

Yeast infections

Systemic amebiasis (kills trophozoites, not cysts)

Metallic taste, Dark urine

CNS effects

Do not use with EtOH

Macrolide

Protein synthesis inhibitor at 23S RNA 

(Inhibits protein synthesis)

Linezolid

Used as last resort for vancomycin resistant infections, MRSA

Do not need to dosage adjust with renal dysfunction

Rarely cross resistant with other protein synthesis inhibitors

Cannot use in PKU

Tyramine foods interaction

Interactions with pseudoephedrine, SSRIs

Macrolide

Membrane depolarizer that causes bacteria to lose ions

Daptomycin

Rapid bacterial death (hours)

Used for Vancomycin resistant MRSA, S. aureas, and Gram +, skin infections

Causes muscle weakness - do not use with statins

Not useful for pneumonia

Anti-Malarials

Clinical Cure

Allows accumulation of heme moiety by inhibiting heme polymerase

Chloroquine - Falciparum, Vivax, Ovale merozoites

Will not kill Falciparum gametocytes

Will not kill dormant sporozoites of Vivax or Ovale

Quinine - Chloroquine-resistant Falciparum, Vivax, severe malaria

Cinchonism, hemolytic anemia

Mefloquine - Falciparum, Vivax, severe malaria

Nightmares, Teratogenic

Also for prophylaxis

Once per week dosing

Also Artemether and Pyrimethamine/Sulfadoxine 
(see their individual flashcards)

Anti-Malaria

Radical Cure

Primaquine

Kills hypnozoites, falciparum gameocytes, prevents relapse

Vivax, Ovale in liver

Given with chloroquine

Hemolytic anemia in G6PD 

Anti-Malarial

Combination Drug

Long acting sulfonamide

Anti-malarial

Combination drug

Produces reactive oxygen species with iron

Artemether-Lumefantrine

(Coartem)

Chloroquine-resistant Falciparum

Well tolerated

Diloxanide

Asymptomatic infections

Flatulence, itchiness, dry mouth

Pentamidine - interferes with DNA/RNA synthesis

Toxic to pancreatic Beta cells

Aerosol and IM

Atovaquone - interferes with mitochondrial eletron transfer

Rash

Should take with food

Isoniazid - mycolic acid inhibitor

Glossitis

Rapid/slow acetylators

Rifampin - interfere with RNA polymerase

orange-red feces

Enterohepatic cycling

Pyrazinamide - unknown mechanism

exacerbates gout

Ethambutol - inhibits well wall synthesis

Enhances action of Rifampin

optic neuritis, red-green vision loss

Streptomycin - inhibits protein synthesis

Vestibular and hearing impairment

Administered IM

Dapsone - PABA antagonist (folate inhibitor)

Hemolytic anemia in G6PD

Clofazimine - produces cytotoxic oxygen radicals

Red discoloration of urine, skin, sweat

Bacteriostatic protein synthesis inhibitors

Prevents addition of amino acids to polypeptide chain

Fanconi syndrome

Tooth discoloration

Gram + and Gram - 

Tetracycline - no food, cross resistance

Doxycycline - take with food, longer 1/2 life and wider activity

Minocycline - vestibular dysfunction

reaches CSF

Tigecycline - IV only, less resistant

Irreversible inhibitors of protein synthesis

Exhibits concentration dependent killing

Aerobic Gram - enteric

Synergystic with Beta-lactama, Vancomycin

Ototoxicity, Nephrotoxicity

Streptomycin - once daily dosing

Does not reach CNS

Gentamicin - pre-operative bowel sterilant

Neomycin - high ototoxicity

Amikacin - not susceptible to enzymatic inactivation, ototoxocity esp high

Aminoglycoside

Inhibits peptidyltransferase

Chloramphenicol

Aerobic and Anaerobic Gram + and Gram -

Meningococcal meningitis

Gray Baby Syndrome

Aplastic anemia

Mimic PABA to prevent folic acid utilization

Synergystic with pyrimethamine

Requires hydration

Gram + and Gram - 

Hematopoietic toxicity

Hypersensitivity

Sulfisoxazole - oral, frequent resistance

Sulfamethoxazole - oral for UTI with trimethorphan

Cotrimazole (Bactrim) - Sulfameth + Trimeth

Dapsone - Leprosy with Rifampin

Ciproflaxin

Inhibits Topoisomerase II - blocks bacterial DNA synthesis

Concentration dependent killing

Gram + and Gram - 

Respiratory, skin, urinary, GI, prostate, bone, kidney, ear, STDs, Antrax, Tularemia

Tourette's, Achilles rupture

Do not give with caffeine

Anti-Herpes 

Acyclic guanosine derivative

Acyclovir

HSV-1, HSV-2

VZV, EBV, CMV, HHV-6

Requires 3 phosphorylations to become active

IV admin reaches CSF

Renal and neurotoxicity

Anti-CMV 

Pyrophosphate analog

Inhibits viral DNA polymerase

Foscarnet

CMV retinitis

CMV colitis

CMV esophagitis

Acyclovir-resistant HSV or VZV

Seizures

IV only

Nucleoside analogs

Competitively inhibits reverse transcriptase

Incorporates into viral DNA

Mitochondrial toxicity

Abacavir - guanosine analog

Slow development of resistance

Genetic disposition to hypersensitivity

Tenovir - adenosine analog

Only requires 2 phosphorylations to activate

Given with emtricitabine

Lamivudine - cytosine analog

Synergystic with NRTIs for HIV-1

Emtricitabine - fluorolated analog of Lamivudine

Once daily dosing

Cannot give with Lami, give with Tenovir

Do not resemble nucleosides

Binds directly to HIV-1 reverse transcriptase

Inhibits polymerase activity

Only works on HIV-1

Very fast resistance

Stevens-Johnson Syndrome

Inhibits proteolytic cleavage of Gag and Gag-Pol

Prevents budding and maturation of virus

Used in combination due to resistance

Redistribution of body fat

Insulin resistance

Atazanvir - once daily dosing

Give with Ritonavir

Do not give with PPI

Ritonavir - increases lipids and liver enzymes

Drug interactions

Low doses with other PIs increase serum levels and allows for less frequent dosing and more tolerability

Lopinavir - only co-admin with Ritonavir to increased Lopinavir blood levels

Can be used in pregnancy

Maraviroc - binds to CCR5 receptor necessary for entrance into CD4 (prevents entry)

Only HIV-1 that is very resistant

Oral

Hepatotoxicity

Raltegravir

Binds to integrase to prevent replication

Inhibits viral DNA strand integration in host genome

Resistant HIV (in combination)

Changes in lipid levels

Inhibits penetration, translocation, transcription, protein processing, maturation, and release

Interferons - HBV, HCV 

Causes flu-like symptoms

Contraindicated in arrhythmias

Ribavirin - guanosine analog inhibits viral mRNA polymerase

Flu A, Flu B, Paraflu, RSV, HCV, HIV-1

Hemolytic anemia

Teratogenic

Inhibits progency of flu

Flu A, Flu B

Amantidine - M2 proton ion channel inhibitor

Oral

Resistance is common

Osteltamivir - Sialic acid analog

Oral

Hepatic activation

Zanamivir - Sialic acid analog

Inhaled

Most common and widely distributed species

Subtropical and temperate areas

"Relapsing malaria"

Tropical regions only

Causes most severe and fatal disease

Medical emergency especially in children and pregnant females

Subtropical areas only

Less common

The least common species

Africa

"Relapsing malaria"

Newly discovered species in humans

Monkey malaria

Malaysia

Sporozoites: infective form

Transmitted during blood-meal feeding of female mosquito

Invade and reside within hepatocytes

Merozoites: produced several days after initial infection

Some sporozoite progeny in liver enter the blood stream and infect erythrocytes (ring-cell stage)

Erthrocyte stages: merozoites infect the RBCs

Parasites attach to RBC receptors and are endocytosed

Asexual reproduction (schizogony) results in rupture of RBC and release of up to 25 parasites (merozoites)

Dormant hypnozoites

After immune response has terminated the erythrocytic cycle, P. vivax and P. ovale sporozoites can remain dormant in the liver and cause a relapse months to years later

P. vivax

P. ovale

Fever every 48 hours (every 3rd day)

P. malariae

Fever every 72 hours (every 4th day)

P. falciparum

No clear differentiation between cold and fever stages

No wet stage

More dangerous due to complications caused by capillary blockage

Uncomplicated Malaria

1. Chloroquine sensitive

   P. falciparum: Chloroquine 

   P. vivax or P. ovale: Chloroquine + Primaquine

2. Chloroquine resistant

  P. vivax: Quinine + Doxycycline + Primaquine

               Mefloquine + Primaquine

  P. falciparum: Artemether-Lumafrantrine

                      Quinine + Mefloquine

Severe Malaria

1. All Types, All Regions

   Quinine + Doxycycline + Clindamycin

Adverse Effect of Quinine

Tinnitus

Headache

Nausea

Abdominal pain

Visual disturbances

Immediate: 0-30 min

Acute anaphyllactic reaction

Most serious form of penicillin allergic reactions

Sx: urticaria, angioedema, asthma, laryngeal edema

Accelerated: 1-72 hours

Sx similar to immediate although severe anaphylaxis, hypotension, and death are rare

Delayed: 3-30 days

Usually self-limiting

Usually involves skin reactions

Less often: serum sickness, hemolytic anemia, thrombocytopenia, nephropathies, and Stevens-Johnson syndrome may occur

Cross hypersensitivity with all penicillins (unless otherwise specified)

Mechanisms of Resistance

Penicillins

1. Beta-lactamases

Bacterial enzymes hydrolyze the functional Beta-lactam ring

Overcome this with less susceptible drug or co-admin with a Beta-lactamase inhibitor

2. Decreased permeability (decreased porins)

3. Alterations in transpeptidases so that the drug does not kind efficiently

1. Decreased uptake

2. Altered transpeptidases

3. Super Beta-lactamase inactivation

Erythromycin Mechanism of Resistance

1. Methylation of 23S RNA - disrupts drug binding

Inducible and constitutive

2. Enterobacteriacae hydrolyze drug

3. Efflux by active pump

4. Chromosomal mutation of 50S