Nucleic Acid Synthesis/Folic Acid Synthesis Inhibitors Pharmacology - GRAVATT

• 1. Identify which antibiotics are in the cell wall synthesis or cell membrane inhibitor drug class. 

• 2. Describe how the antimicrobial kills it’s intended target. 

• 3. Choose which antibiotic kills which microbe. 

• 4. Differentiate antibiotics based on potential adverse reactions, drug/drug or drug/food interactions.

• 5. Design a treatment regimen based on available dosage forms.

Learning Objectives

• 1. Drug Classes and associated antibiotics

• 2. How does the antibiotic kill the microbe? 

• 3. Bug/Drug coverage

• 4. Adverse reactions of antibiotics

• 5. Notable notes- differences in ADME

• 6. Drug/drug or drug/food interactions

• 7. Dosage forms (NOT DOSES)

What should I know?

Fluoroquinolones, Rifamycins, Metronidazole, Nitrofurantoin

What ABX target DNA/RNA synthesis?

Linezolid, Tedizolid, Tetracyclines, Macrolides, Aminoglycosides, Clindamycin

What ABX target Folate Synthesis?

• Mechanism of Action- Affecting DNA/RNA synthesis OR Folic Acid Synthesis (Sulfonamides), which leads to the halting of bacterial cell replication, causing cell death

• Fluoroquinolones

• Rifamycins

• Metronidazole

• Nitrofurantoins

• Sulfonamides

Nucleic Acid/Folic Acid Synthesis Inhibitor Points

• NVD

• Risk of C. DIff

• Hypersensitivity Reactions

Common Side effects of Nuclec Acid Synthesis Inhibitors

• Agents: Ciprofloxacin, Levofloxacin, Delafloxacin, Moxifloxacin

• Mechanism of Action

  • Inhibit DNA topoisomerases, specifically topoisomerase II and IV which leads to breaks within the DNA and cellular death 

• Metabolism

  • All are metabolized by the liver

  • All EXCEPT moxifloxacin are eliminated renally; therefore, DO NOT use moxifloxacin for UTIs

• Administration

  • High Bioavailability (> 90% for most, less for Ciprofloxacin or Delafloxacin) 

    • Ciprofloxacin 200mg IV = 250mg PO 

Spectrum of Activity: Varies by Agent, but broad spectrum (Gram +, Gram -, Atypicals)

• Respiratory FQ: Levofloxacin, delafloxacin, moxifloxacin

• Pseudomonas: Ciprofloxacin, levofloxacin, delafloxacin

• Anaerobes: Moxifloxacin

• MRSA: Delafloxacin

Respiratory (LDM)

Pseudomonas (CLD)

Anaerobes (M)

MRSA (D)

Fluoroquinolones Points (“-Floxacins”)

• Suppresses CYP 450 - ↓metabolism of warfarin, carbamazepine, barbituates

• Cannot give with milk, antacids, sucralfate or iron products AND tube feeds; separate by 2 hours

• Avoid with drugs that can also cause QTc prolongation

• Avoid use in Children and Pregnancy

  • Inhibition of long bone growth

• Avoid use in those with myasthenia gravis

Fluoroquinolones DDI’s/Food

• CNS effects: HA, dizziness, agitation, hallucinations and confusion (elderly)

• Phototoxicity, rash (< 2%)

• QTc prolongation

• Seizures

• Achilles tendon rupture

  • RF: > 60YO, h/o solid organ transplant, use of steroids, strenuous physical activity, h/o tendon disorders, renal failure

• Hypo/Hyperglycemia

• Peripheral neuropathy

• Aortic aneurysm/dissection

• Delafloxacin- avoid IV use due to cyclodextrin in renal dysfunction

Fluoroquinolones Adverse reactions

Spectrum:

• Mostly Gram (-) Organisms

  • Including Pseudomonas

• Some Gram (+)

  • Not as good as other agents

• Atypical Organisms

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Clinical Uses:

• UTI’s

• GNR bacteremias, bone/joint infections. Nosocomial infections

• Alternative for G(-)Rod infections in those with Beta-lactam allergies

  
  

Comments:

• Available generic, so very inexpensive

• Increasing resistance with E.coli

• BA: 70%

Fluoroquinolones (Ciprofloxacin) Spectrum, clinical uses, and comments

Spectrum:

• Mostly Gram (-) Organisms

  • Also covers Pseudomonas

• Some Gram (+)

  • BETTER STREPTOCOCCUS and STAPH coverage

• Atypical Organisms

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Clinical Uses:

• UTI’s

• GNR bacteremias, bone/joint infections. Nosocomial infections

• Alternative for G(-)Rod infections in those with Beta-lactam allergies

• PLUS

  • CAP

  • Sinusitis

  • SSTI’s

  • Alternative for Mycobacterial infections

Comments:

• Available generic, however still expensive

• BA > 95%

Fluoroquinolones (Levofloxacin) Spectrum, clinical uses, and comments

Spectrum:

• Gram (-) Organisms

  • Not as good Gram Negative Rod coverage

  • DOES NOT COVER Pseudomonas

• Some Gram (+)

  • BETTER STREPTOCOCCUS and STAPH coverage

• Atypical Organisms

• Also Anaerobic Coverage

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Clinical Uses:

• CAP

• Sinusitis

• SSTI’s

Comments:

• Cannot be used for UTI’s

• BA: 86%

Fluoroquinolones (Moxifloxacin) Spectrum, clinical uses, and comments

Spectrum:

• Some Gram (-) Organisms

  • Also covers Pseudomonas

• GOOD Gram (+)

  • BETTER STREPTOCOCCUS and STAPH coverage (Including MRSA)

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Clinical Uses:

• SSTI’s

Comments:

• BA: 59%

Fluoroquinolones (Delafloxacin) Spectrum, clinical uses, and comments

• Gene Mutation

  • Altered Target sites

  • Efflux pumps

• Plasmid Mediated

  • QNR proteins

  • FQ modifying enzymes

  • Efflux pumps

Mechanisms of Resistance for Fluoroquinolones

• Agents: rifampin, rifabutin, rifapentine, rifaximin

• Mechanism of Action

  • Inhibits RNA polymerase, which stop transcription by blocking messenger RNA

• Metabolism

  • Hepatic; highly lipophilic and crosses BBB

• Administration

  • Rifampin- typically 1:1 IV:PO

  • Rifaximin: nonabsorbed antimicrobial that only acts within the GI tract (think of how PO Vancomycin works)

  • Rifapentine- given once weekly 

• Spectrum of Activity

  • Rifampin, rifabutin, rifapentine: Mycobacterium species

  • Rifampin: Gram +, including MRSA; never use a a solo agent

  • Rifaximin: Gram +, Gram – such as enterobacteriacae; only active in the GI tract

Bacteriostatic

Rifamycins Points

DDI/Food interactions:

•  Take on an empty stomach

• TONS of DDIs as it is a POTENT INDUCER of CYP450

  • Rifabutin has les DDIs and the preferred drug to use when patients on antiretrovirals 

• ALWAYS check for DDIs

Adverse Reactions:

• Red/orange discoloration of bodily fluids- urine, tears, saliva

  • May stain contact lenses

• Liver dysfunction- monitor LFTs

• Rash

• Fever

• Rifabutin- optic neuritis and leukopenia

Rifamycins DDI’s and Adverse reactions

• Mechanism of Action

  • Production of free radicals that damages DNA and causes cellular death

• Metabolism

  • Hepatic metabolism

  • Great penetration into the CSF as well as other tissues

• Spectrum of Activity

  • Gram – and + anaerobes and protozoa

• Administration

  • Available IV and PO (equivalent doses)

Bacteriocidal

Metronidazole Points

DDI’s/Food interactions":

• Avoid use with warfarin (increases INR)

Adverse Reactions:

• Metallic taste

• Disulfuram like reaction (intolerance to alcohol)

• Rare: hepatotoxicity and pancreatitis

Metronidazole DDI’s/Food Interactions + Adverse Reactions

Spectrum:

• Anaerobes

  • B. Frag

  • Other Clostridium sp.

• Protozoa

  • Giardia lamblia

  • Trichomonas vaginalis

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Clinical Uses:

• In combination with other agents to cover anaerobes

• Bacterial vaginosis

• H. pylori treatment

• Crohn’s disase

• Giardia infections

Comments:

• Available Generic, so very inexpensive

• TASTES BAD!!

Metronidazole Spectrum, Clinical Uses, and comments

Mechanism of Action

• It’s byproducts cause DNA damage

Metabolism

• Liver metabolism; renal excretion

Spectrum of Activity

• Staphylococcus, Enterococcus (including VRE) and GNRs (not pseudomonas)

Administration

•  Only PO

• 2 formulations

  • Macrodantin - crystalline form- 4 times daily

  • Macrobid- macrocystalline/monohydrate form- BID 

• ONLY can be used of lower UTIs; does not get adequate concentrations for Upper UTIs

• Cannot be used in those with CrCL< 30 ml/min

  • Will not be enough drug to kill the bacteria when renal function is below this threshold

• Bacteriocidal in the URINE only

Nitrofurantoin (macrobid) Points

DDI/Food:

• Take with meals

Adverse reactions

• Rare

  • Liver toxicity

  • Pulmonary toxicity

• Avoid use in those pregnant and at term (38+ weeks)

  • Risk of hemolytic anemia

Nitrofurantoin DDI/Food/ Adverse reactions

Mechanism of Action

• Inhibits bacterial cell wall synthesis which inhibitors pyruvyl transferase which is needed for bacterial cell wall synthesis 

Metabolism

• Renal metabolism and excretion

Spectrum of Activity

• Staphylococcus, Enterococcus (including VRE) and GNRs including many resistant one such as ESBL

• Administration

•  Only PO in the US (IV in Europe)

• Mix powder with water and administer

• ONLY can be used of lower UTIs; does not get adequate concentrations for Upper UTIs

• Bacteriocidal in the URINE only

Fosfomycin Points

DDI’s/Food:

• NONE!!!

Adverse Reactions:

• Headache

• Vaginitis/Dysmenorrhea

Fosfomycin DDI’s/Adverse reactions

Sulfamethoxazole/trimethoprim, Sulfadiazine

Mechanism of Action

• Inhibition of folic acid synthesis through inhibition of dihydrofolic acid formation from para-aminobenzoic acid; trimethoprim inhibits dihydrofolic acid reduction to tetrahydrofolate which leads to inhibition of enzymes of the folic acid pathway

Metabolism

• Renal and liver metabolism 

Spectrum of Activity

• Gram (+) including MRSA, Gram (-) such as E. coli, Pneumocystis and protozoa

Administration

• Available as PO, IV, Ophthalmic and Topical

• Sulfamethoxazole/trimethoprim – combination product

  • SS: Sulfamethoxazole 400mg/Trimethoprim 80mg

  • DS: Sulfamethoxazole 800mg/Trimethoprim 160 mg

  • Dosed based on the TRIMETHOPRIM component

• Bacteriocidal 

Sulfonamides Points

DDI’s/Food:

• Avoid use with warfarin as it can raise INR

• Use with caution with potassium supplements due to risk of hyperkalemia

• Contraindicated in pregnancy, breastfeed or newborns < 2 months old

Sulfonamides DDI’s/Food Interactions

• Nephrotoxicity

  • Renal crystal formation

  • Acute interstitial nephritis

• Trimethoprim- Hyperkalemia

• Allergies – can be severe as w/ Stevens Johnson Syndrome

• Bone Marrow Suppression – usually with high doses for prolonged periods of time

• Hemolytic anemia (G6PD deficiency)

• Kernicturus

• Rare – liver failure

• Contraindicated in pregnancy, breastfeed or newborns < 2 months

Sulfonamides Adverse Reactions

Spectrum:

• Some Streptococcus species

• Staphylococcus species (including MRSA)

• Enterobacteraciae

• Listeria

• Nocardia

• Pneumocystis jiroveci

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Clinical Uses:

• UTIs

• Skin/soft tissue infections (including MRSA)

• Treatment of Prevention of infections in immunocompromised

• Nocardia

• Pneumocystis jiroveci

Comments:

• generic, inexpensive

• Increasing resistance with E. Coli

• Needs dose reduction with renal filaure

• WATCH FOR DRUG RASH

Sulfonamides (Bactrim) Spectrum, Clinical Uses, and comments

• Decreased Permeability

  • Dihydropteroate synthase gene mutation= resistance to PJP

  • Dihydrofolate reductase gene mutation= resistance E. faecalis and Campylobacter

• Plasmids

  • Resistant genes= E. coli resistance

• Efflux Pumps

Sulfonamide Resistance mechanisms

• Skin testing not well validated

• Oral dose challenge recommended

Notes:

• Highest rate of BENIGN rashes of any antibiotic

• Higher in the HIV population, esp. those with low CD4 counts

• Dapsone does not cross react

• Low cross reactivity with non-abx sulfa drugs

Sulfa Allergies recommended method of testing for allergy

Spectrum of activity:

• Clostridium species, Staph aureus, Enterococcal species

Approved Indications:

• C. Diff associated diarrhea

Dose:

• 200 mg PO every 12 hours

PK/PD considerations:

• Bacteriocidal for intestinal flora

• Metabolism: Intestinal hydrolysis

• Excreted via feces

  • Not systemically absorbed

Adverse Effects:

• Nausea

Dificid (Fidaxomicin) Points