6.3 Infectious Diseases and Antimicrobial Stewardship

Antimicrobial Stewardship and Pharmacodynamics

Antimicrobial Stewardship Programs (ASPs) optimize clinical outcomes, minimize toxicities, and reduce the selective pressure driving antimicrobial resistance. Key ASP interventions include prospective audit and feedback, formulary restriction, automatic IV-to-oral step-down protocols, dose optimization based on pharmacokinetic/pharmacodynamic (PK/PD) indices, and de-escalation based on microbiological culture and susceptibility testing.

PK/PD Classifications of Antimicrobials

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|                   ANTIMICROBIAL PK/PD CLASSIFICATION                    |
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|                                                                         |
|  1. TIME-DEPENDENT (T > MIC)                                            |
|     - Goal: Maximize time serum concentration exceeds MIC (%T > MIC)    |
|     - Strategy: Frequent intermittent dosing, extended or continuous IV |
|     - Drug Classes: Penicillins, Cephalosporins, Carbapenems, Aztreonam|
|                                                                         |
|  2. CONCENTRATION-DEPENDENT (Cmax / MIC)                                |
|     - Goal: Maximize peak serum concentration relative to MIC           |
|     - Strategy: High-dose, extended-interval (once-daily) dosing        |
|     - Drug Classes: Aminoglycosides (Gentamicin, Tobramycin), Daptomycin|
|                                                                         |
|  3. EXPOSURE-DEPENDENT (AUC / MIC)                                      |
|     - Goal: Maximize 24-hour total drug exposure relative to MIC        |
|     - Strategy: Optimize total daily dose (AUC24 / MIC ratio)           |
|     - Drug Classes: Vancomycin (target AUC 400-600), Fluoroquinolones,  |
|                     Macrolides, Tetracyclines                           |
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Community-Acquired Respiratory Infections

Community-Acquired Pneumonia (CAP)

Primary pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypical organisms (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila).

Pediatric Acute Otitis Media (AOM)

• First-Line: High-Dose Amoxicillin ($80-90\text{ mg/kg/day}$ divided BID or TID) for 5-10 days.
• Second-Line / Beta-Lactamase Coverage: High-Dose Amoxicillin/Clavulanate ($90\text{ mg/kg/day}$ amoxicillin component with $6.4\text{ mg/kg/day}$ clavulanate in a 14:1 ratio formulation to prevent clavulanate-induced diarrhea). Indicated if amoxicillin used within 30 days, concurrent purulent conjunctivitis, or clinical failure after 48-72 hours.

Group A Streptococcal Pharyngitis (S. pyogenes)

• First-Line: Penicillin V ($300\text{ mg}$ PO TID in children, $600\text{ mg}$ BID in adults) or Amoxicillin ($50\text{ mg/kg/day}$ once daily or divided BID) for a full 10-day course to prevent acute rheumatic fever.

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Urinary Tract Infections (UTIs)

Escherichia coli accounts for $> 75-85%$ of community UTIs, followed by Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus saprophyticus.

Uncomplicated Cystitis in Non-Pregnant Females

1. Nitrofurantoin Monohydrate / Macrocrystals (MacroBID): $100\text{ mg}$ PO BID with food for 5 days. Efficacy remains high with minimal resistance. Contraindication: Avoid if $\text{eGFR} < 30\text{ mL/min}$ (inadequate urinary concentrations and risk of peripheral neuropathy/pulmonary toxicity). Not indicated for pyelonephritis due to negligible tissue penetration.
2. Fosfomycin Tromethamine: $3\text{ g}$ PO single-dose dissolved in cold water. Inactivates MurA (peptidoglycan synthesis).
3. Trimethoprim-Sulfamethoxazole (TMP-SMX DS): $160/800\text{ mg}$ PO BID for 3 days. Use only if local E. coli resistance is $< 20%$ or guided by susceptibility.
4. Fluoroquinolones (Ciprofloxacin, Levofloxacin): Do not use for uncomplicated cystitis due to safety warnings (aortic aneurysm, tendinopathy, dysglycemia, peripheral neuropathy) and stewardship principles.

Complicated UTI and Acute Pyelonephritis

• Outpatient Pyelonephritis: Oral Ciprofloxacin ($500\text{ mg}$ PO BID x 7 days) or Levofloxacin ($750\text{ mg}$ PO daily x 5 days) if local FQ resistance $< 10%$; otherwise, administer initial IV dose of Ceftriaxone ($1\text{ g}$) prior to oral therapy. Total duration $7-14$ days.

Asymptomatic Bacteriuria (ASB)

ASB is defined as $\ge 10^5\text{ CFU/mL}$ of bacteria in urine without urinary symptoms. Treat ONLY in:

1. Pregnant individuals: (increases risk of pyelonephritis, low birth weight, preterm delivery). Screen at 12-16 weeks; treat with cephalexin, nitrofurantoin (avoid in 1st trimester and near term at 36-42 weeks due to neonatal hemolytic anemia), or amoxicillin/clavulanate for 3-7 days.
2. Patients undergoing invasive urological procedures with suspected mucosal trauma. Do NOT screen or treat ASB in catheterized patients, elderly nursing home residents, non-pregnant premenopausal women, or diabetic patients.

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Skin and Soft Tissue Infections (SSTIs)

• Non-Purulent Cellulitis: (Spreading erythema, warmth, edema; predominantly Streptococcus pyogenes and methicillin-sensitive Staphylococcus aureus [MSSA]). Treat with Cephalexin ($500\text{ mg}$ PO QID), Cefadroxil ($500\text{ mg}$ PO BID), or Cloxacillin ($500\text{ mg}$ PO QID) for 5-7 days.
• Purulent Cellulitis / Cutaneous Abscess: (Predominantly community-acquired MRSA [CA-MRSA]). Incision and drainage (I&D) is the primary definitive treatment. If systemic signs or extensive surrounding cellulitis present, add oral antibiotics with MRSA activity: TMP-SMX ($1-2\text{ DS tabs}$ PO BID), Doxycycline ($100\text{ mg}$ PO BID), or Clindamycin ($300-450\text{ mg}$ PO TID) for 5-10 days.
• Severe Inpatient MRSA Infections: IV Vancomycin (target AUC/MIC ratio $400-600$), Daptomycin ($6-10\text{ mg/kg}$ IV daily; inactivated by pulmonary surfactant, do not use in pneumonia), or Linezolid ($600\text{ mg}$ PO/IV BID; weak MAO inhibitor, monitor for serotonin syndrome and myelosuppression with prolonged use $> 14\text{ days}$).

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Sexually Transmitted Infections (Canadian Public Health Guidelines)

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Clostridioides difficile Infection (CDI)

C. difficile is a toxin-producing, spore-forming anaerobic bacterium triggered by broad-spectrum antibiotic exposure (clindamycin, fluoroquinolones, cephalosporins, carbapenems).

• Initial Episode (Non-Severe or Severe):
  • Oral Vancomycin: $125\text{ mg}$ PO QID for 10 days.
  • Oral Fidaxomicin: $200\text{ mg}$ PO BID for 10 days (narrow-spectrum, lower recurrence rates, preserves gut microbiome).
  • Practice Change: Oral metronidazole is no longer recommended for initial CDI due to inferior clinical cure rates.
• Fulminant CDI (Hypotension, Shock, Ileus, Toxic Megacolon):
  • High-dose Oral Vancomycin ($500\text{ mg}$ PO/NG tube QID) PLUS IV Metronidazole ($500\text{ mg}$ IV q8h) PLUS Vancomycin retention enema if ileus present.
• Recurrent CDI:
  • First Recurrence: Fidaxomicin $200\text{ mg}$ BID x 10d (if vancomycin used initially) or tapered/pulsed oral vancomycin regimen.
  • Multiple Recurrences ($\ge 2$ recurrences): Fecal Microbiota Transplantation (FMT) or Bezlotoxumab (monoclonal antibody targeting C. difficile Toxin B).

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Beta-Lactam Allergy Assessment and Cross-Reactivity

Up to $10%$ of patients report a penicillin allergy, but $> 90-95%$ are found to be tolerant upon formal evaluation.

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|                   BETA-LACTAM ALLERGY EVALUATION                        |
+-------------------------------------------------------------------------+
|                                                                         |
|  Type I IgE-Mediated (Immediate < 1 hr):                                |
|  - Anaphylaxis, bronchospasm, laryngeal edema, acute urticaria/hives   |
|  - Mechanism: Specific IgE against core beta-lactam ring / side chains |
|                                                                         |
|  Non-IgE / T-Cell Mediated (Delayed > 72 hrs):                          |
|  - Mild, flat, non-pruritic maculopapular exanthem (low risk)          |
|  - Severe Cutaneous Adverse Reactions (SCARs): SJS, TEN, DRESS, AGEP   |
|    --> ABSOLUTE CONTRAINDICATION to re-exposure with ANY beta-lactam    |
|                                                                         |
|  Cross-Reactivity Truths:                                               |
|  - Cross-reactivity between penicillins and 3rd/4th gen cephalosporins  |
|    (ceftriaxone, cefepime) or carbapenems (meropenem) is < 1-2%.        |
|  - Cross-reactivity is driven by IDENTICAL R1 SIDE CHAINS (e.g.,        |
|    Amoxicillin shares identical side chain with Ampicillin, Cefadroxil, |
|    and Cefprozil; Ampicillin shares side chain with Cephalexin).       |
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