Antimicrobial Regimen Selection

Objectives of Antimicrobial Regimen Selection

• Review general signs and symptoms of infection.
• Describe methods to identify pathogens.
• Identify and review factors to consider when selecting an antimicrobial agent, including facility, patient, and drug-specific factors.

Overview of Antimicrobial Use

• Antimicrobials are among the most widely used medications.
• The U.S. spends over $8 billion annually on antimicrobials.
• Antibiotics are not always the appropriate solution.
• Unnecessary or inappropriate antibiotic use occurs in:
  • 40-75% of nursing home antibiotic prescriptions
  • 20-50% of inpatient antibiotic prescriptions
  • 30% of outpatient antibiotic prescriptions
• Antibiotic overuse is the biggest driver of antimicrobial resistance.

Systematic Approach to Antimicrobial Selection

• Confirm: Presence of infection.
• Identify: The pathogen.
• Select: The appropriate antibiotic.
• Monitor: The patient's response to treatment.

Confirming Infection

• Fever, defined as a temperature exceeding 100.4°F, is often associated with infection.
  • Other causes of fever include malignancy, autoimmune disorders, and drug-induced fever.
  • Consider the impact of antipyretic therapy.
• Local signs of infection include swelling, redness, pain, and purulent drainage.
• A normal white blood cell (WBC) count ranges from 4,000 to 10,000 cells/mm³.
  • Infections often correlate with elevated WBC counts.
  • Systemic steroids can also increase WBC levels.
• Imaging techniques utilized are X-rays, ultrasounds, CT scans, and MRIs.

Drug-Induced Fever

• Drug-induced fever may result from a hypersensitivity reaction or the development of an antigen-antibody complex.
• Drug-induced fever is not common, accounting for about 5% of drug reactions.
• Almost any drug, including antibiotics, can cause a drug fever.
• More common medications associated with drug-induced fever include:
  • Antibiotics like β-lactams, nitrofurantoin, and sulfonamides
  • Anticonvulsants
  • Allopurinol
  • Hydralazine
  • Phenothiazines
  • Methyldopa

Identifying the Pathogen

• Cultures should be obtained before administering antibiotics when feasible to avoid sterilizing cultures, which delays pathogen identification.
• Blood cultures should be performed on all acutely ill febrile patients.
  • Adult blood cultures involve drawing two sets from two different sites at separate times, with each set containing anaerobic and aerobic bottles, totaling four blood cultures.
• The culture process usually takes several days: Gram stain → Culture → Identification of organism → Antibiotic susceptibility.
• The location of the culture is important, examples include:
  • Sterile sites: Blood, cerebrospinal fluid (CSF), peritoneal fluid, and synovial fluid.
  • Non-sterile sites: Sputum, stool, skin, and wound cultures.
• Bacterial growth is not always indicative of a pathogen; contamination or colonization can occur.
  • Contamination: such as skin flora or sputum
  • Colonization, such as asymptomatic bacteriuria

Rapid Diagnostics

• Nucleic Acid Amplification Tests (NAAT) / Polymerase Chain Reaction (PCR) rapidly identify multiple pathogens and resistance mechanisms within hours, with panels varying by site (blood, CSF, nasal, stool, etc.).
• Serologic testing involves antibody and antigen testing for infections like syphilis, Coxiella, Bartonella spp.

Antibiotic Selection Factors

• Facility-specific factors
• Patient-specific factors
• Drug-specific factors
• Stages of Antibiotic Selection:
• Empirical antibiotic therapy
• Definitive antibiotic therapy

Facility Specific Factors

• Local resistance rates are determined via antibiogram.
• Hospital or insurance formulary determines which antibiotics area available

Patient Specific Factors

• Patient History: factors to consider include:
  • Past infections with their organisms and susceptibilities
  • Previous antibiotic exposure
• It is critical to differentiate between Community-acquired vs healthcare-acquired infections
• Site of infection
• Social history, considering:
  • Pets
  • Occupation
  • Travel
• Host Factors such as:
  • Drug allergies
  • Age
  • Comorbidities
  • Pregnancy
  • Organ dysfunction (renal/hepatic impairment)
• Concomitant medications and potential drug-drug interactions

Drug Specific Factors: ADME

• Absorption is the systemic uptake of the drug, examples include:
  • Oral vancomycin is not absorbed outside the GI tract.
  • Cefdinir has only ~20% bioavailability.
• Distribution affects:
  • Tissue penetration
  • Volume of distribution
  • Distribution in critical illness
• Drug Metabolism considers:
  • Triazole antifungals:
  • Voriconazole is a substrate and an inhibitor of CYP2C9, CYP3A4, and CYP2C19.
  • Itraconazole has an active metabolite.
  • Rifampin interacts with several medications based on CYP450.
• Excretion: most antibiotics are renally excreted and require renal dose adjustments.

Drug Specific Factors: Pharmacokinetics and Pharmacodynamics

• Drug concentrations are also important

  • Minimum inhibitory concentration (MIC) indicates AUC:MIC; peak:MIC ratio; T > MIC

• It's important to differentiate:

  • Bacteriostatic vs. bactericidal antibiotic effects

• Bactericidal effects can be either:

  • Concentration-dependent (e.g., aminoglycosides)
  • Time-dependent (e.g., β-lactams)

Minimum Inhibitory Concentration (MIC)

• MIC defines in vitro levels of susceptibility or resistance of specific bacterial strains to a specific antibiotic.
• The lowest concentration of an antimicrobial agent inhibits visible in-vitro growth of microorganisms.
• MICs are specific to each antibiotic and organism.

Drug Specific Factors: Tissue Penetration

• Treatment failure occurs when the right drug for the bug cannot reach the infection site.
• Nitrofurantoin has excellent E. coli susceptibility, but can only be used for cystitis.
• Echinocandins have broad-spectrum antifungal activity but do not concentrate in the urine or CNS.
• Deep-seated infections require parenteral therapy (e.g., meningitis, endocarditis, osteomyelitis).
• Dose also matters for tissue penetration
  • Ceftriaxone standard dosing: 1-2gm Q24h
  • Ceftriaxone CNS dosing: 2gm Q12h

Drug Toxicity

• Approximately 20% of medication-related visits to the ED are caused by antibiotics, the most common cause of medication-related ED visits.
  • Nephrotoxicity (e.g., aminoglycosides, vancomycin)
  • Hepatotoxicity (e.g., rifampin, daptomycin)
  • Neurotoxicity (e.g., cefepime, carbapenems, fluoroquinolones)
  • Hematologic toxicities (e.g., linezolid, SMX-TMP)
  • Almost all antibiotics can cause C. difficile infections.

Stages of Antibiotic Selection

• With Empiric Therapy:

  • Antibiotic therapy is initiated without finalized culture and sensitivity results
  • This relies on known epidemiologic data on what to target
  • Use includes: Disease-specific Guidelines, Local Antibiogram, and Understanding of organisms of concern based on the site of infection

• Definitive Therapy:

  • Antibiotic therapy is tailored to the narrowest spectrum of effective activity based on cultures and sensitivities.