Antimicrobial Therapy

What are the three types of antimicrobial therapy?

1. Prophylactic Therapy: given to prevent an infection

• Consider in individuals at increased risk of developing infection

• Infection that has not occurred

2. Empiric Therapy: treatment given when an infection is suspected, before the organism(s) is identified

• Antimicrobial selection guided by patient’s presentation and history

3. Targeted Therapy: treatment selected to target a specific organism known to be causing an infection

• Antimicrobial selection guided by organism culture results and sensitivities

What are the 5 steps to antimicrobial therapy?

1. Assessment

2. Empiric therapy

3. Monitoring

4. Targeted therapy

5. Follow-up

Assessment step to microbial therapy

Information and Sample Collection

• Information: Is there an infection? Any infectious history?

• Sample: i.e. blood urine, sputum, for clinical or screening reasons.

  • Can conduct tests on them (gram staining, organism identification, and antibiotic susceptibility)

True or false: draw culture after administering antimicorbial agents.

False.

Especially for antibiotic susceptibility testing, collect sample first before antimicrobial therapy.

Drawing culture prior to administering any antimicrobial agents is important.

Collecting samples after a single dose of antimicrbials can refuce the likelihood of isolating an organism

What factors are involved with empiric therapy?

• Host/Patient factors

• Drug factors

• Infection fators

What are some examples of host/patient factors?

• Past medical history

• Age

• Allergies

• Prior infections or hospitalization

• Prior antimicrobial history

• Prior drug colonization

• History of resistance

What are the two main drug factors?

Pharmacokinetics (movement of drugs within the body)

• Absorption: route of administration (IV vs PO)

• Distribution: will the drug reach the site of infection?

• Metabolism:

  • How is the drug broken down?

  • Drug-drug interactions

• Excretion: how does the body get rid of the drug?

Pharmacodynamics (the action of the drug in the body)

• Drug spectrum of activity

• Mechanism of action

• Combination therapy

• Resistance

Drug Factors: What are the two antimicrobial spectrums?

• Broad Spectrum: active against a large variety of organisms

  • Pro: Increased likelihood of activity against an unknown organism

  • Con: Promote the development of drug resistance

    • Should also consider the empiric therapy prior to organism identification

• Narrow Spectrum: active against limited groups of organisms

  • Pro: Associated with reduced development of drug resistance

  • Con: Risk of poor activity / lack of effect against an unknown organism

    • Often used for targeted therapy after organism has been identified

Bacteriostatic vs Bactericidal

Bacteriostatic:

• Inhibits/slows bacterial growth

• Requires a functioning immune system to clear infection

• Used in less serious infections

Bactericidal:

• Causes bacterial death

• Preferred in serious infections or immunocompromised hosts

Drug factors: TIme vs Concentration dependent killing

TIme-dependent killing:

• Drug concentration must remain above minimum inhibitory concentration for effect

• The absolute amount of minimum inhibitory concentration does not impact activity

Concentration-dependent killing:

• The peak drug concentration determines effect

• Demonstrate a post-antibiotic effect where activity continues even when drug concentration is less than minimum inhibitory concentration

What are the types of combination therapy?

• Synergism (combining different antimicrobials to produce an effect that exceeds the sum of their individual effects)

• Broadens spectrum (combining antimicrobials with different spectrum to fill gaps in coverage)

• Double coverage (combining 2 different antimicrobials with activity against the same organism of interest which increases likelihood of success and reduces development of antimicrobial resistance)

Antimicrobial Resistance

• The ability of certain organisms to develop a tolerance to MDRO specific antimicrobials to which they were once susceptible

• This process occurs naturally over time, but is accelerated by misuse and overuse of antimicrobials

Risk factors for developing drug resistant organisms

• Prior antibiotic exposure

• Underlying disease (hemodialysis)

• Prior hospitalization

• Invasive procedures in healthcare settings

What are the two main mechanisms of resistance for drugs?

1. Preventing the antimicrobial from reaching its target at sufficient concentrations

   1. decreasing uptake into the organism

   2. inactivating enzymes (i.e. beta-lactamases)

   3. increased efflux

2. Modifying the target of the antimicrobial

   1. altering the target

   2. alternative enzymes

Different antimicrobials require levels to be drawn at various time points: Trough level

lowest serum concentration; draw blood 30 mins prior to next dose

Different antimicrobials require levels to be drawn at various time points: Peak level

highest serum concentration: draw blood immediately after the dose has been administered

Are broad or narrow spectrum agents associated with a higher risk of resistance?

broad

Goal of targeted therapy

Choose an antimicrobial that has demonstrated activity against the organism but has the narrowest spectrum and the least toxicity

Antimicrobial Principles: Summary

What are some targets of antibiotics?

• Cell wall

• DNA / RNA synthesis

• Plasma membrane

• Ribosomes

• Metabolic pathways

• Create free radicals

What are bacterial cell walls made up of? What is transpeptidation?

• Peptidoglycan: major component

• Transpeptidation: the last step of cell wall synthesis

  • Penicillin binding proteins (PBPs) form cross links in the cell wall

What are the three main types of Beta-Lactams?

Penicillins, Cephalosporins, and Carbapenems

What is the mechanism of action for beta-lactams?

Beta-lactams interrupt cell wall synthesis by:

• Binding to PBPs

• Inhibits transpeptidation

• Results in:

  • Improper cell wall formation → inability to withstand osmotic pressure → cell ruptures → cell death

• Bactericidal, time-dependent killing

Beta-lactam penicillins: Spectra, Uses, Adverse effects

Spectra: Narrow, covers Gram-positives > Gram-negatives

Commonly used for: Otitis media, skin infections, strep throat

Adverse effects:

• Common: GI upset, rash

• Uncommon: Anaphylaxis, seizures, hemolytic anemia, neutropenia, thrombocytopenia

What are the mechanisms of resistance for beta-lactams?

1. Bacterial cell production of beta-lactamases

2. Modification PBP binding site (e.g., Methicillin-resistant Staphylococcus aureus [MRSA])

3. Changes to porin channels

4. Drug efflux pumps

What is Beta-lactamase?

an enzyme that cleaves the beta-lactam ring through hydrolysis

• Inactivates beta-lactam antibiotics

• breaks the bond between penicillin and the lactam ring

When are beta-lactams paired with beta-lactamase inhibitors? What may be some issues? What’s an example?

to overcome resistance

• Inactive beta-lactamases to extend spectrum of activity → MSSA, gram negatives, anaerobes

Increase risk of nausea, vomiting and diarrhea (including C. difficile infections)

Examples: Amoxicillin-clavulanic acid (IV, PO), Piperacillin-tazobactam (IV)

Beta-lactam cephalosporins: Spectra, Uses, Adverse effects

Spectra: Mid-to-broad, covers Gram-positives and increasing Gram-negatives coverage with higher generations

Used for: Skin and soft tissue infections, pneumonia, intra-abdominal infections, pyelonephritis

Adverse effects: GI upset, rash, seizures. With higher generations there is an increased risk of C. difficile infection and resistance

What are the generations of cephalosporins?

• First-fifth generations

• Increasing generation → increasing gram negative coverage

Beta-lactam carbapenems: Spectra, Uses, Adverse effects

Spectra: Broad, covers Gram-positives, Gram-negatives, oral andgut anaerobes

Used for: Only for severe, infections caused by ESBL or Amp-C producing bacteria. Note: Infectious Disease team should be involved

Adverse effects: GI upset (nausea, diarrhea), eosinophilia, seizures, resistance, increased risk of C. difficile infections

Up to 10% of patients have a reported penicillin allergy, but < 1% are a true allergy. What is a true allergy?

Type I IgE-mediated: anaphylaxis, hypotension, angioedema

• Avoid all penicillins and cephalosporins with similar side chain

Low cross-reactivity between beta-lactams, but stay away from all beta-lactams if you’ve ever had a reaction to one of them

What is an example of a severe non-IgE-mediated hypersensitivity reaction?

Type IV non-IgE-mediated: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS)

• Avoid all beta-lactams (penicillins, cephalosporins and carbapenems)

What antibiotics target the cell wall?

• Beta lactams (penicillins, cephalosporins, monobactams, and carbapenems)

• Glycopeptides (vancomycin)

• Bacitracin

• Fosfomycin

What is the mechanism of action for vancomycin?

• Inhibits cell wall synthesis

• Binds to the terminal end of peptidoglycan precursor → prevents polymerization → weakens the cell wall → cell death

• Bactericidal, time- dependent killing

Vancomycin: Spectra, Uses, Adverse effects

Spectra: Gram-positives only, including MRSA

Uses: IV: MRSA infections, endocarditis, meningitis PO: C. difficile infections

Adverse effects: Ototoxicity, nephrotoxicity, infusion reactions, irritation and injection site reactions

Oral formulation used exclusively for C diff infections

Vancomycin can give an infusion reaction called Flushing Syndrome. What is it?

• Characterized by pruritus, flushing, and erythema of the face and upper torso → NOT life-threatening

• Due to rapid infusion of the drug leading to histamine release

  • Related to infusion rate

  • Managed by slowing the infusion rate

What makes a vancomycin allergy different than an infusion reaction?

Vancomycin allergy:

• Anaphylaxis, hypersensitivity, hives, angioedema, bronchoconstriction → can be life-threatening

• Managed by stopping infusion and administering epinephrine

What to monitor when on vancomycin?

• Nephrotoxicity (increasing serum creatinine (SCr) and decreasing urine

  output)

• Serum trough levels once at steady state (pre-fourth dose)

  • Low trough (< 10 mg/L) → subtherapeutic, inadequate dose for treatment

  • High trough (> 20 mg/L) → supratherapeutic, increased risk of nephrotoxicity

  • If trough is out of range, let the pharmacist know for dose adjustment

What is the mechanism of action for fosfomycin?

• Inactivates MurA enzyme involved in peptidoglycan synthesis → weakens cell wall → cell lysis

• inhibits adherence of bacteria to epithelium

• Bactericidal, concentration dependent killing

Fosfomycin: Spectra, Uses, Adverse effects

Spectra: broad, gram positives and gram negatives

Uses: Uncomplicated UTI (PO), meningitis, intra-abdominal infections, skin and soft tissue infections

Adverse effects: GI upset, electrolyte disturbances, C. difficile infection, hypersensitivity reactions

What antibiotics target the plasma membrane?

• Polymyxins (polymyxin B and colistin)

• Lipopeptides (daptomycin)

What is the mechanism of action of daptomycin?

• Binds to the cell membrane leading to depolarization, efflux of potassium, and inhibition of DNA, RNA and protein synthesis

• Bactericidal, concentration dependent killing

Daptomycin: Spectra, Uses, Adverse effects

Spectra: Gram-positives only, including MRSA

Uses: Complicated skin and soft tissue infections, S. aureus bacteremia, infective endocarditis

Adverse effects: Myopathy/rhabdomyolysis, eosinophilic pneumonia

Avoid with pneumonia

What to monitor for when patient is on daptomycin?

Rhabdomyolysis: rapid breakdown of skeletal muscle

• Can be life-threatening

• Monitor: patient reported muscle pain, creatine kinase (CK) and dark urine

Eosinophilic pneumonia

• Monitor: eosinophils, new-onset fevers and dyspnea

What antibiotics target DNA synthesis?

• Fluoroquinolones

  • Ciprofloxacin

  • Levofloxacin

  • Moxifloxacin

What antibiotics target RNA synthesis?

• Rifamycins

  • Rifampin

What is the mechanism of action for Fluoroquinolones?

• Inhibition of DNA synthesis by inhibiting bacterial DNA gyrase and topoisomerase IV → promotes the breakage of DNA

• Bactericidal, concentration dependent killing

Fluroquinolones: Spectra, Uses, Adverse effects

Spectra: Broad, Gram-positives, Gram-negatives, and atypicals

Uses: Ciprofloxacin - UTIs, bacteremia, Levofloxacin, moxifloxacin - pneumonia

Adverse effects: GI symptoms, photosensitivity, C. difficile infections, QTc prolongation, tendonitis (most commonly Achilles tendon), seizures, CNS effects

Avoid if pregnant or breastfeeding

Fluoroquinolones and metal cations

Fluoroquinolones bind bivalent or trivalent metal cations → decrease absorption

Avoid administering oral fluoroquinolones with bivalent or trivalent metal cations by 2 hours

• This includes supplements such as: zinc, magnesium, iron, calcium (e.g., TUMS and other antacids, multivitamins, iron supplements)

What antibiotics create free radicals?

• Metronidazole

• Nitrofurantoin

What is the mechanism of action for metronidazole?

• Becomes reduced by anaerobic organisms → becomes cytotoxic free radical that breaks DNA, inhibits nucleic acid synthesis and results in loss of DNA integrity → cell death

• Bactericidal, concentration dependent killing

Metronidazole: Spectra, Uses, and Adverse Effects

Spectra: Anaerobes

Uses: C. difficile infection, intra-abdominal infections

Adverse effects: Nausea/vomiting, metallic taste, peripheral neuropathy, disulfiram-like reaction with alcohol use

Avoid alcohol use.

What antibiotics affect metabolic pathways?

• Folic acid synthesis

  • sulfonamides

  • sulfones

  • trimethoprim

• mycolic acid synthesis

  • izoniazid

What is the mechanism of action for Sulfamethoxazole/Trimethoprim?

• Sulfamethoxazole (SMX) and trimethoprim (TMP) work together synergistically

• Inhibits folic acid synthesis which is necessary for DNA synthesis

• Bactericidal; time dependent killing

Sulfamethoxazole/Trimethoprim: Spectra, Uses, and Adverse Effects

Spectra: Gram-positives (including MRSA) and Gram-negatives

Uses: UTI, Pneumocystis jiroveci prophylaxis

Adverse effects: Skin rash (SJS, TENS; uncommon), hyperkalemia, thrombocytopenia (rare), nephrotoxicity

Avoid for the following:

• History of severe reaction to sulfonamides, pregnant (1st and 3rd trimester) and breastfeeding, neonates, glucose 6-phosphate dehydrogenase deficiency

What antibiotics affect the 30S subunit ribosome?

• Aminoglycosides

• Tetracyclines

What antibiotics affect the 50S subunit ribosome?

• macrolides

• lincosamides

• chloramphenicol

• oxazolidnones

What is the mechanism of action for Linezolids (oxazolidinones)?

• Binds to the P-site of the 50S ribosomal unit → prevents formation of the 70S complex

• Bactericidal against streptococci

• bacteriostatic against staphylococci and enterococci

• Time dependent killing

Linezolids: Spectra, Uses, and Adverse Effects

Spectra: Gram-positives (including MRSA)

Uses: Pneumonia, bloodstream infections, endocarditis, hospital-acquired meningitis

Adverse effects: Myelosuppression (> 2 weeks use), peripheral/optic neuropathy (> 4 weeks use), C. difficile infection, lactic acidosis, serotonin syndrome

Avoid if on MAOIs.

What is the mechanism of action for macrolides?

• Reversibly binds to the 50S ribosomal subunit → prevents transpeptidation → protein synthesis inhibited

• Bacteriostatic, time dependent killing

• Ex. azithromycin, clarithromycin, erythromycin

Macrolides: Spectra, Uses, Adverse effects

Spectra: Gram positives, atypical bacteria and some Gram negatives

Uses: Community acquired pneumonia, sexually transmitted infections

Adverse effects: GI upset, QTc prolongation, hepatotoxicity, hypersensitivity reaction

What is the mechanism of action for clindamycin (lincosamide)?

• Similar mechanism to macrolides: reversibly binds to 50S ribosomal subunit → inhibits transpeptidation → protein synthesis inhibited

• Bacteriostatic, time dependent killing

Clindamycin: Spectra, Uses, Adverse effects

Spectra: Gram-positives, anaerobes

Uses: Skin and soft tissue infections, dental infections

Adverse effects: C. difficile infection, GI symptoms, rash

What is the mechanism of action for aminoglycosides?

• Binds irreversibly to the 30S ribosomal subunit → prevents transpeptidation → protein synthesis inhibited

• Bactericidal, concentration dependent killing

Aminoglycosides: Spectra, Uses, Adverse effects

Spectra: Gram negatives, synergy with beta-lactams for Gram positives

Uses: Sepsis caused by Gram-negatives, UTIs, intra-abdominal infections, endocarditis (with beta-lactams)

Adverse effects: Reversible nephrotoxicity (can monitor drug levels), irreversible oto- and vestibular toxicity

Aminoglycosides: Dosing types

• Extended-interval dosing: single, large dose once daily

  • More rapid bactericidal activity and less toxic

  • Recommended for most infections in most patients

• Traditional dosing: Smaller doses given multiple times a day

  • Used when can’t use extended-interval dosing and for synergy

What is the mechanism of action of tetracyclines?

• Bind to the 30S ribosomal subunit → blocks the attachment of tRNA to mRNA-ribosome complex → protein synthesis inhibited

• Bacteriostatic, time dependent killing

• Examples: tetracycline, doxycycline, minocycline

Tetracyclines: Spectra, Uses, Adverse effects

Spectra: Broad, Gram-positives, Gram-negatives, certain anaerobes

Uses: Acne, skin and soft tissue infection, Lyme disease

Adverse effects: Damage growing bones and teeth, GI upset, dizziness/vertigo, photosensitivity

Avoid in pregnancy and children. Separate from metal cations.

What are the three types of fungi?

• Yeast

  • Single celled, budding reproduction E.g., Candida species

• Mold

  • Multi cellular, branching filaments E.g., Aspergillus species

• Dimorphic fungi

  • Yeast at higher temps (37°C)

  • Mold at lower temps (25°C) E.g., Histoplasma

What is the cell membrane of fungi made up of?

Ergosterol → fungal version of cholesterol

• Azoles and terbinafine target ergosterol synthesis

Chitin → like cellulose and beta-glucan → similar to fibre

• two most important substances

• Polyoxins inhibit chitin synthase

• Echinocandins inhibit Beta-glucans synthesis

What is the mechanism of action for polyenes?

• Binds to ergosterol in the fungal membrane → form a pore through the membrane → electrolyte leakage → cell death

• Resistance: rare, due to decrease or change in structure of ergosterol

• Fungicidal

Polyenes - Nystatin: Spectra, Uses, Adverse effects

Spectra: Candida

Uses: Superficial oral candidiasis (Thrush)

Adverse effects: Generally well-tolerated, gastrointestinal upset

Avoid with systemic infections (Poorly absorbed, cannot be used for systemic infections)

Polyenes - Amphotericin B: Spectra, Uses, Adverse Effects

Spectra: Most broad spectrum; most activity against infections

Uses: Systemic mycoses

Adverse effects: Nephrotoxicity, hepatotoxicity, infusion-related reactions (fever, chills, headache, arrhythmia, cramps, weakness), electrolyte abnormalities

Echinocandins - Mechanism of Action

• Inhibits the synthesis of Beta (1,3)-D-glucan (component of the cell wall) by inhibiting Beta (1,3)-D-glucan synthase

• Impaired cell wall synthesis→ cell rupture and death

• Fungicidal (Candida) or Fungistatic (Aspergillus)

Echinocandins - Caspofungin, Anidulafungin, Micafungin: Spectra, Uses, Adverse Effects

Spectra: Most Candida Species, all Aspergillus species

Uses: Candidiasis, aspergillosis

Adverse effects: Typically well tolerated, infusion related reactions (rash, facial swelling, respiratory spasms, gastrointestinal distress), hepatotoxicity

Avoid with CNS, urinary or ocular infection

What to monitor for echinocandins?

• Monitor for potential infusion reactions (e.g., facial swelling, flushing, rash)

• Monitor liver function (caspofungin requires dose adjustment in hepatic impairment)

Echinocandins - What method of administration?

• IV ONLY; if oral therapy is clinically warranted and the infection is susceptible, a switch to an alternate antifungal would be required

• Poor penetration to CNS, vitreal fluid and urine

• Very few drug interactions

Azoles - Mechanism of Action

• Inhibits cytochrome P450 14-alpha lanosterol demethylase → inhibits conversion of lanosterol to ergosterol → increases permeability and accumulation of toxic sterols → cell death

• Resistance: altered drug binding site

• Fungicidal or fungistatic (depending on species)

Azoles: Spectra, Uses, and Adverse Effects

Spectra: Broad spectrum depending on agent

Uses: Topical Agents: Tinea infections, superficial candidiasis, Oral/IV agents: Systemic Mycoses (Candidiasis)

Adverse Effects: Headache, nausea and vomiting, diarrhea, rash, hepatotoxicity, QTc prolongation, hallucinations (voriconazole)

Clinical Pearls of Azoles

• Intravenous to oral Step Down: bioavailability is typically high and oral may be used even for deep seated infections

• Many drug interactions!

• Renal and hepatic function must be monitored on oral/IV therapy; QTc prolongation can occur with any systemic azole

What azole has the best safety profile?

• If susceptible, use fluconazole as it has the best safety profile + excellent oral bioavailability + excellent penetration into CNS/vitreal fluid

What is the mechanism of action for Terbinafine?

• Interferes with squalene epoxidase → inhibit ergosterol biosynthesis → alter cell membrane permeability and accumulation of toxic sterols → cell death

• Resistance: mutation in squalene epoxidase

• Fungicidal

Terbinafine - Spectra, Uses, Adverse Effects

Spectra: Dermatophytes, Candida

Uses: Superficial Mycoses

Adverse Effects: Headache, nausea/vomiting, diarrhea, rash, skin reactions, hepatotoxicity

Avoid with breastfeeding

What are viruses?

• Consist of DNA or RNA within a protein outer shell

• Require the use of host cell machinery to replicate; cannot replicate on their own

• Infect host cells and “re-program” to replicate and the virus

What are the two types of antivirals?

Neuraminidase Inhibitors and Polymerase Inhibitors

Neuraminidase Inhibitors – Mechanism of Action

• Neuraminidase is an influenza viral enzyme that facilitates the release of new viruses

• These drugs inhibit this process - preventing the virus’ ability to spread and replicate further

What allows for resistance to neuraminidase inhibitors?

Mutations in the neuraminidase enzyme prevent the antivirals from binding

Neuraminidase Inhibitors - Oseltamivir (PO), Zanamivir (inhaled) - Spectra, Uses, and Adverse Effects

Spectra: Activity against Influenza A & B

Uses: Prophylaxis or treatment of Influenza A or B

Adverse Effects: Oseltamivir: Nausea/vomiting, headache, confusion/delirium (rare), Zanamivir: bronchospasms (avoid in Asthma or COPD)

When should you take oseltamivir for maximum benefit?

Take oseltamivir with food (to improve tolerability), start treatment within 48 h for maximum benefit

Polymerase Inhibitors – Mechanism of Action

• DNA polymerase is responsible for viral DNA synthesis

• Polymerase inhibitors incorporate into viral DNA by competing for DNA polymerase → inhibits DNA synthesis

What causes resistance in Polymerase Inhibitors?

Mutations in viral DNA polymerase or thymidine kinase

Polymerase Inhibitors: Narrow Spectrum: Acyclovir (IV/PO), Valacyclovir (PO), Famciclovir (PO) - Spectra, Uses, Adverse Effects

Spectra: Narrow, activity against HSV, VZV

Uses: Treatment of oral herpes (HSV1), anogenital herpes

(HSV2) and shingles (VZV)

IV acyclovir often used HSV encephalitis

Adverse effects: Nephrotoxicity, headaches, anorexia, vomiting

IV acyclovir

infuse slowly and maintain hydration to reduce risks of nephrotoxicity

Polymerase Inhibitors: Broad Spectrum: Ganciclovir (IV/PO), Valganciclovir (PO) - Spectra, Uses, Adverse Effects

Spectra: Activity against HSV, VZV, CMV (only additional virus!)

Uses: Treatment or prophylaxis of CMV, VZV only

Adverse Effects: Neutropenia (20-40%), thrombocytopenia (10-20%), nephrotoxicity, diaphoresis, diarrhea, anorexia, vomiting

Oral ganciclovir

very poor bioavailability (5%) and rarely used, reduce risk of nephrotoxicity by slow infusion and maintaining hydration

The choice of empiric antibiotic therapy is influenced by what?

patient-specific factors, characteristics of the infection and pathogen, drug properties, and supporting clinical evidence

What is targeted antibiotic therapy?

tailored to a specific pathogen