Drugs For Respiratory Tract Infection

DRUGS FOR RESPIRATORY TRACT INFECTION STUDENT DOC MARTINEZ

PENICILLAN TYPE

Piperacillin

MECHANISM OF ACTION

Inhibits transpeptidase  inhibiting cell wall synthesis.

Tazobactam Murein hydrolases degrade cell wall.

Bactericidal

Bacteria produce β-lactamase which inactivates the penicillin

ADMINISTRATION AND ELIMINATION

ADMINISTERED IV

Excreted predominantly by the kidney so dosage adjustment is necessary if renal function is markedly impaired

Spectrum of activity & uses

ADVERSE EFFECTS

Hypersensitivity reactions

CONTRAINDICATIONS

Patients exhibiting a hypersensitivity reaction to penicillins

Phlebitis

USES

DRUG OF CHOICE: P. aeruginosa Antipseudomonal penicillins+ β-lactamase inhibitor ± an aminoglycoside

Interstitial nephritis

**Cystic Fibrosis

Neurotoxicity

ALTERNATIVE: Serious infections caused by gram negative bacteria resistant To penicillin G and ampicillin

Tazobactam inhibits β-lactamase

CEPHALOSPORIN TYPE

Ceftriaxone (3RD Generation)

MECHANISM OF ACTION

Inhibits transpeptidase, a penicillin-binding protein, inhibiting cell wall synthesis. Murein hydrolases degrade cell wall. Bactericidal

NOTE: Cephalosporins are NOT effective against LAME (L. monocytogenes, atypicals [Chlamydia & mycoplasma], MRSA, and enterococcus)

GLYCOPEPTIDE

ADMINISTRATION AND ELIMINATION

ADVERSE EFFECTS

CONTRAINDICATIONS

Administered IM and IV

Hypersensitivity reactions

Patients exhibiting a hypersensitivity reaction to penicillins

Ceftriaxone is eliminated by the kidney

Local reactions at the site of administration

P450 metabolism and other routes. It is NOT necessary to adjust does in renal disease.

Nephropathy

USES

DRUG OF CHOICE: Gram-negative bacilli

TYPE

Vancomycin

MECHANISM OF ACTION

Vancomycin binds to Dalanyl-D-alanine at the free carboxyl end of modified disaccharide. This prevents elongation of the linear peptidoglycan polymer

ADMINISTRATION AND ELIMINATION

Administered by IV infusion

Eliminated by kidneys; adjust dose in patients with renal failure

D-Ala-D-Ala peptidoglycan termini are replaced with D-AlaD-lactate termini that are not recognized by vancomycin

ADVERSE EFFECTS

“Red-neck” or “red-man” syndrome

Ototoxicity

Nephrotoxicity

USES

Active against most gram positive cocci and bacilli (synergistic with aminoglycosides)

Used to treat serious infections due to staphylococci in patients who are intolerant to penicillins or when infection is caused by MRSA

MACROLIDE TYPE

MECHANISM OF ACTION

ADMINISTRATION AND ELIMINATION

ADVERSE EFFECTS

Azithromyc in

Binds to 50S subunit of ribosomes and inhibits translocation

Administered orally and intravenously

Gastrointestinal

Mechanisms of resistance i. Drug efflux by an active pump mechanism ii. Inducible or constitutive production of methylase enzymes which modify the ribosomal target and decrease drug binding iii. Hydrolysis of macrolides by esterases iv. Decreased penetration TRIMETHOPRIM AND SULFAMETHOXAZOLE

Azithromycin is eliminated by biliary excretion; very long half-life (40–70 hours) due to tissue binding

Nausea, vomiting, cramps, and diarrhea

USES

Bordetella pertussis (treat persons with the disease and prophylaxis for those who had close contact) Legionella spp Mycobacterium avium

Prolongs QT interval

complex (treatment and prophylaxis) Chlamydia trachomatis and Chlamydophila pneumoniae Mycoplasma

MECHANISM OF ACTION Comb of T-S: synergistic in affecting cell growth.

Sulfa:structural analog of PABA (inhibits incorporation into dihydropteroic acid interfere folate metabolism)

ADEM

Oral → Acetylated in Liver → Excreted in Urine (adjust).

DRUG INTERACTIONS:

Crystalluria

Potentiate effects of oral anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants by inhibiting metabolism or displacing drug from albumin binding sites. Adjust dose of other drugs if given with sulfonamide

Acute hemolytic anemia (if ↓ glucose-6-phos dehydrog) Allergic skin rx (maculopapular rashSteven Johnson Syndrome)

Trim: competitive inhibitor of dihydr reductase

MECHANISM OF RESISTANCE:

ADVERSE EFFECTS:

USE:

Kernicterusnewborns CONTRAINDICATIONS:

Concurrent use of azathioprine, 6mercaptopurine, methotrexate with trimethoprim may increase risk of bone marrow suppression

Neonates Sulfonamides ↓ Affinity of dihydr synthetase for sulfonamides

***Pneumocystis pneumonia (PCP)

OTHER: last month of pregnancy

↓ Uptake or active efflux ↑ Production of PABA or folate synth by enzs not inhibited by sulfonamides.

Maintain adequate fluid intakeacetylated compounds less soluble than parent → crystallize in acidic urine causing obstruction Pts with hx of allergy have greater risk of having allergic rx to sulfonamid NONantibiotic drug.

Trim:

↓ affinity of dihydr reduct for trim VANCOMYCIN - GLYCOPEPTIDE Indications

Most Gram-Positive Cocci and Bacilli (synergistic with aminoglycosides)

Used to treat serious infections due to

ADME Very poorly absorbed from the GI tract and is usually give by IV infusion

Adverse Effects “Red-neck” or “red-man” syndrome caused by release of histamine from cutaneous mast cells; related to dose and rapidity of infusion

staphylococci in patients who are intolerant to penicillins or when infection is caused by MRSA

Widely distributed; good penetration except for CNS unless meninges are inflamed

Eliminated by kidneys; adjust dose in patients with renal failure

Ototoxicity; hearing loss is first observed in the high frequency range

Nephrotoxicity; Increased risk in patients with underlying renal disease or who are taking potentially nephrotoxic drugs (e.g., aminoglycosides)

FLUOROQUINOLONE TYPE

MECHANISM OF ACTION

Levofloxaci n

Inhibition of enzymes:

Bactericidal*

DNA gyrase & Topoisomerase IV

MECHANISM OF RESISTANCE

Mutations in bacterial genes encoding DNA gyrase or topoisomerase IV

ADMINISTRATION AND ELIMINATION

Administered oral and IV

Excreted in the urine; ↓ dose in renal impairment

Increased efflux out of the cell

ADVERSE EFFECTS

GI: nausea, vomiting, abdominal discomfort

CNS: headache, dizziness

USES

Patients who received recent antibiotic therapy; patients with comorbidities (e.g., COPD, diabetes). Legionella spp

Musculoskeletal: increased risk of tendonitis and tendon rupture usually involving the Achilles tendon

Chlamydophila pneumoniae Mycoplasma

**community acquired pneumonia TETRACYCLINE TYPE

Doxycycl ine

MECHANISM OF ACTION

Passive diffusion through outer membrane

Transport across the cytoplasmic membrane via an energy-dependent process in both gramnegative and gram-positive organisms.

Inside the cell they bind to

MECHANISM OF RESISTANCE

Decreased accumulation of drug inside bacterial cells

Decreased influx

Acquisition of energydependent efflux pathway

ADMINISTRATION AND ELIMINATION

Administered orally

Doxycycline is eliminated through the digestive tract

ADVERSE EFFECTS

GI Distress (N & V, pseudomembranous colitis) Photosensitivity rxn

Teeth (discoloration) Teratogenic

USES

Drug of first choice: Mycoplasma pneumoniae and Chlamydophilia

**Community acquired pneumonia

the 30S ribosome blocking binding of

Plasmid-mediated and Inducible

aminoacyl-tRNA to the A site ANTIVIRALS Amantadin Inhibits uncoating: The e influenza A virus contains a membrane protein M2 which forms a proton channel. Amantidine blocks the channel so reducing H+ flow. This affects the acidity of the endosomal compartment such that viral uncoating does not occur.

Resistance occurs due to mutations in the M2 protein

Oral administration

Excreted renally (reduce dose in renal disease)

Over the last 2–3 years resistance has developed to Amantadine such that the CDC has recommended that it not be used for prophylaxis or treatment of respiratory infections caused by the

Gastrointestinal: Anorexia nausea

CNS: Nervousness, insomnia, difficulty concentrating, ataxia

Treatment of influenza A (treatment within the first 48 hours after the exposure reduces the duration of symptoms and speeds functional recovery)

Teratogenic Prevention of influenza A when started before exposure

The drug is NOT active against Influenza B virus

influenza A virus.

NEURAMINIDASE INHIBITORS TYPE

MECH OF ACTION AND RESISTANCE

ADMINISTRATION/METABOLISM

ADVERSE RXN / C.I.

USE

Oseltamivir Zanamivir

Blocks neuraminidase → inhibits virus release (virus stays attached)

ORAL (prodrug) → liver; active metabolite → excrete urine (Decrease dose in Renal Failure)

Mutations in neuraminidase (prevent rearrangement). Significant resistance worldwide.

Ribavirin

Synthetic purine nucleoside analog. Inhibits RNA/DNA virus replication

1. N/V (better w/food) 2. Headache 3. Neuropsych events (suicide in kids)

Prophylaxis and tx of Influenza A and B Bird flu

Careful if child, adolescent INHALED → urine excretion

1. Cough 2. Nasal, throat discomfort 3. Rare bronchospasm, ↓ lung function

Aerosol only

Conjuctival irritation, wheezing, occasional ↓in PFTs.

Resistance has not be documented for most viruses

RSV, especially if severe underlying respiratory or cardio disease or immunocompromised

TERATOGENIC and EMBRYOTOXIC

Patients exposed to the drug should not conceive children during treatment or for 6 months after stopping the drug. ANTIMYCOBACTERIALS  ANTI-TUBERCULOSIS DRUGS TYPE

MECH OF ACTION & RESISTANCE

ADEM

ADVERSE EFFECTS

USE

Ethambutol

Bacteriostatic: Inhibits arabinosyl transferases (myco cell wall synth)

Oral: → Renal elimination (adjust dose in R.F.)

Optic neuritis (∆ in color, visual acuity) - Monitor vision often!!

TB

Isoniazid

Prodrug Needs cat-perox to activate

Oral or IV/IM, rapidly penetrates tissues →

1. ↑ liver enzs 2. Hepatoxicitymay be fatal

Latent TB infection.

Inhibits enzymes needed for synthesis of mycolic acid (specific - cell wall) Bacteriostatic® resting cells but Bactericidal ® rapidly dividing cells.

acetylated liver. ↑ dose if rapid acetylators (japan/inuit ppl).

(esp older) 3. Periph neuropathy numb, tingling prevented by pyridoxine (Vit B6 - helps neurons)

Active TB: Ison + Rifam.

GI disturbances

TB

↓ dose slow (white) & liver disease

Pyrazinami de

Bactericidal: inhibits mycolic acid synth -

** Inhibits cell wall synth **

Oral → Liver metabolism → Kidney excretion (adjust dose for both R.F & L.F)

Hepatotoxicity

Arthralgias

Resistance develops rapidly  inactivation of mycobacterial enzyme

Rifampin RifampinInhibits RNA

that converts pyrazinamide to an active compound Bactericidal: Inhibits RNA synth by binding to DNAdependent RNA polymerase **only one of the antimyco NOT attacking cell wall **

ANTIFUNGALS Amphoteric Binds ergosterol in fungal in B cell membranes forming

Oral (well-absorbed), IV → Liver metabolism (adjust dose in LIVER FAILURE)

Common: rash, fever, nausea, vomit

Latent TB: Active TB: Ison + Rifam.

↑ liver enzs

CLASSIC: Potent inducer of P450 enzs, May enhance elimin of others (digoxin, oral anticoags & contracept). Advise to use another method of BC.

Hepatotox (esp chronic liver, EtOH, old)

Insoluble H2O - is a huge molecule

Infusion rxn** (fever, chill) prevented w/ NSAIDS or

** Good ORAL MRSA Drug per Dr. Thomson **

Urine, other secretions orange-red (stain contacts)

Aspergillus

pores or channels → ↑ permeability of cell, loss of constituents. **Makes membrane leaky & N the fungus**

meperidine Complex w/bile salt deoxycholate or lipid prep (expensive but less adverse rxs). IV or intrathecal (for CNS) ** NO GI absorb

AZOLES - ANTIFUNGALS Fluconazol Blocks the enzyme e lanosterol 14-α-demethylase  inhibiting the conversion of lanosterol Itraconazol to ergosterol. e Advantage over imidazole: do not inhibit human sterol synth.

Ketoconazo le (prototypical imidazole)

**NOT USED AS MUCH

There is an accumulation of 14-α-methylsterols which disrupt cell membranes or inhibit cell functions.

Nephrotoxicity (reversible) Normochromic, normocytic Anemia (↓ erythropoietin, is reversible, tied to nephro tox)

Oral, topical → Absorb GI tract

Nausea, vomiting

Metabolized in LIVER → Renally excreted

Rash

Oral, IV: ↑ gastric pH→ ↓ bioavailability

Hepatitis (rare but fatal), ↑liver enzymes

Slow metabolized.

RESISTANCE:

Oral (req acidic env for dissolution), topical.

Mutation in ERG11  Drug can’t bind mutant enzyme

↑ Gastric pH → ↓ bioav

other drugs metabolized by CYP3A4 (e.g., phenytoin, warfarin, many

Cryptococcus neoformans Dimorphic pathogens (Histoplasma capsulatum, Blastomyces derm, Paracoccidioides brasilensis, Coccidioides immitis)

Alternative to AmpB but also hits Dermatophytes**

Aspergillus

Endocrinologic abnormalities, e.g., women, menstrual irregularities; men, gynecomastia; due to inhibition of steroid biosynthesis; more important for ketoconazole

Drug Interactions: these drugs inhibit P450 enzymes thus ↑plasma concentrations of

Candida

**Ketoconazole causes SEVERE Endocrinologic Abnormalities  MAY inhibit Human steroidogenesis (GONADAL AND ADRENOCORTICAL)

Candida

Cryptococcus neoformans Dimorphic pathogens (Histoplasma capsulatum, Blastomyces derm, Paracoccidioides brasilensis, Coccidioides immitis)

Dermatophytes Very cheap. Use when lower cost important. Replaced by Itraconazole.

others).