Resistance Patterns & Stewardship

Resistance Patterns & Stewardship

Master antibiotic resistance patterns and stewardship principles with free flashcards and evidence-based practice tools. This lesson covers mechanisms of antimicrobial resistance, key resistance patterns in common pathogens, and comprehensive stewardship strategies—essential concepts for the NAPLEX and clinical pharmacy practice.

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Welcome 🎯

Antimicrobial resistance represents one of the greatest threats to modern medicine. As a pharmacist, you'll serve on the front lines of preserving antibiotic effectiveness through informed prescribing recommendations, patient counseling, and active participation in antimicrobial stewardship programs (ASPs). This lesson equips you with the knowledge to identify resistance patterns, understand their mechanisms, and implement evidence-based stewardship interventions.

💡 Why This Matters: The CDC estimates that antibiotic-resistant infections cause 2.8 million infections and 35,000 deaths annually in the U.S. alone. Your stewardship efforts directly impact patient outcomes and public health.

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Core Concepts: Mechanisms of Antimicrobial Resistance 🧬

Understanding Resistance Development

Bacteria develop resistance through several fundamental mechanisms. Understanding these pathways helps you predict which antibiotics will remain effective and which alternatives to recommend.

Four Primary Resistance Mechanisms:

Mechanism	Description	Examples	Clinical Impact
Enzymatic Degradation	Bacteria produce enzymes that destroy or modify antibiotics	β-lactamases (penicillinases, ESBLs, carbapenemases)	Renders entire antibiotic classes ineffective; requires β-lactamase inhibitors or alternative agents
Target Site Modification	Bacterial target proteins mutate, reducing antibiotic binding	MRSA (altered PBP2a), VRE (altered D-Ala-D-Lac)	Cross-resistance within antibiotic class; requires different mechanism agents
Efflux Pumps	Active transport systems pump antibiotics out of bacterial cells	Tetracycline resistance, fluoroquinolone resistance in Pseudomonas	Multi-drug resistance; may affect multiple antibiotic classes
Decreased Permeability	Changes in porin channels reduce antibiotic entry	Carbapenem resistance in Pseudomonas, Acinetobacter	Affects hydrophilic antibiotics; often combined with other mechanisms

β-Lactamase Classification 🔬

Ambler Classification System categorizes β-lactamases by molecular structure:

┌─────────────────────────────────────────────────┐
│        β-LACTAMASE CLASSIFICATION               │
├─────────────────────────────────────────────────┤
│                                                 │
│  Class A (Serine)          Class B (Metallo)   │
│  • ESBLs (CTX-M, TEM)      • NDM-1            │
│  • KPC carbapenemase       • VIM, IMP         │
│  ├─ Inhibited by:          ├─ Inhibited by:   │
│  └─ Clavulanate,           └─ EDTA (not       │
│     tazobactam,                clinically      │
│     avibactam                  available)      │
│                                                 │
│  Class C (AmpC)            Class D (Oxacillin) │
│  • Chromosomal AmpC        • OXA-type         │
│  • Cephalosporinases       • Carbapenemases   │
│  ├─ NOT inhibited by:      ├─ Weakly          │
│  └─ Traditional            └─ inhibited by    │
│     β-lactamase                clavulanate     │
│     inhibitors                                 │
│                                                 │
└─────────────────────────────────────────────────┘

🧠 Memory Device - "AMBLER'S SEAM":

• A = Aminoglycoside-modifying enzymes respond to standard inhibitors
• M = Metallo-β-lactamases (Class B) require metal ions
• B = Bad news - no clinically available inhibitors
• L = Look for avibactam for KPC (Class A)
• E = Extended-spectrum (ESBLs are Class A)
• R = Resistant AmpC (Class C) to standard inhibitors

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High-Yield Resistance Patterns 🎯

ESKAPE Pathogens

The ESKAPE acronym identifies the most concerning multidrug-resistant organisms:

MRSA: Methicillin-Resistant Staphylococcus aureus 🔴

Resistance Mechanism: Production of altered penicillin-binding protein (PBP2a) encoded by mecA gene

Key Clinical Distinctions:

Feature	HA-MRSA (Hospital-Acquired)	CA-MRSA (Community-Acquired)
Typical Patient	Healthcare exposure, chronic illness, invasive devices	Young, healthy, athletic populations
SCCmec Type	Types I, II, III (larger, more resistance genes)	Type IV, V (smaller, fewer resistance genes)
Common Presentations	Bacteremia, pneumonia, surgical site infections	Skin/soft tissue infections (abscesses, furuncles)
Additional Resistance	Often MDR (resistant to multiple classes)	Typically susceptible to more agents
Virulence Factors	Fewer toxins	PVL toxin (Panton-Valentine leukocidin)

💡 Clinical Pearl: CA-MRSA with PVL toxin can cause necrotizing pneumonia and severe skin infections. Always consider adding clindamycin (if susceptible) to inhibit toxin production, even if vancomycin/daptomycin is used for bactericidal activity.

ESBL-Producing Enterobacteriaceae 🧫

Extended-Spectrum β-Lactamases hydrolyze penicillins, cephalosporins (including 3rd generation), and aztreonam—but NOT carbapenems or cephamycins.

Treatment Approach Decision Tree:

┌────────────────────────────────┐
│  ESBL-Producing Organism       │
│  Detected in Culture           │
└──────────────┬─────────────────┘
               │
               ▼
┌──────────────────────────────────────┐
│  What is the infection severity?     │
└──────────────┬───────────────────────┘
               │
    ┌──────────┴──────────┐
    ▼                     ▼
┌─────────────┐    ┌─────────────┐
│  Severe     │    │  Mild/Mod   │
│  (sepsis,   │    │  (cystitis, │
│  pneumonia) │    │  simple     │
│             │    │  infection) │
└──────┬──────┘    └──────┬──────┘
       │                  │
       ▼                  ▼
┌──────────────┐    ┌──────────────────┐
│ Carbapenem   │    │ Consider oral:   │
│ (preferred)  │    │ • Nitrofurantoin │
│              │    │   (UTI only)     │
│ • Ertapenem  │    │ • Fosfomycin     │
│ • Meropenem  │    │   (uncomplicated │
│ • Imipenem   │    │   cystitis)      │
└──────────────┘    │ • Amox-clav*     │
                    │ • TMP-SMX*       │
                    │ • Fluoroquinolone*│
                    │   (*if susceptible)│
                    └──────────────────┘

⚠️ Critical Stewardship Point: Even if an ESBL-producing organism shows in vitro susceptibility to 3rd-generation cephalosporins, DO NOT use them. Clinical failures are common due to inoculum effect and inducible resistance.

Carbapenem-Resistant Enterobacteriaceae (CRE) ⚠️

Definition: Enterobacteriaceae resistant to ≥1 carbapenem OR producing a carbapenemase enzyme

Most Common Carbapenemases:

• KPC (Klebsiella pneumoniae carbapenemase) - Class A, most common in U.S.
• NDM (New Delhi metallo-β-lactamase) - Class B
• OXA-48 - Class D, common in Middle East/Europe

Treatment Options for CRE:

Agent	Mechanism	Spectrum	Clinical Considerations
Ceftazidime-Avibactam	Avibactam inhibits Class A, C, some D β-lactamases	Excellent for KPC, ESBL, AmpC	❌ NOT active against NDM (metallo-β-lactamases). Preferred for KPC-producing CRE
Meropenem-Vaborbactam	Vaborbactam inhibits Class A, C β-lactamases	KPC, ESBL, some AmpC	❌ NOT active against metallo-β-lactamases or OXA-48. Good penetration
Imipenem-Relebactam	Relebactam inhibits Class A, C β-lactamases	Similar to meropenem-vaborbactam	Newer option, growing clinical experience
Cefiderocol	Siderophore cephalosporin (trojan horse mechanism)	Broad: KPC, NDM, OXA-48, Pseudomonas, Acinetobacter	✅ Active against metallo-β-lactamases. Reserve for salvage therapy
Colistin	Disrupts bacterial membrane	Gram-negative (not Serratia, Proteus, Burkholderia)	Nephrotoxicity concern. Consider combination therapy. Requires loading dose
Tigecycline	Glycylcycline (inhibits protein synthesis)	Many CRE strains	❌ NOT for bacteremia (low serum levels), UTI. FDA black box warning for mortality

🧠 Memory Device - "VIPER for CRE":

• Vaborbactam - KPC killer
• Imipenem-relebactam - similar spectrum
• Polymyxins (colistin) - last resort
• Elude metallo-β-lactamases (most agents can't)
• Reserve cefiderocol (broadest, save for tough cases)

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Antimicrobial Stewardship Principles 🛡️

Core Elements of ASPs

The CDC Core Elements provide a framework for hospital antimicrobial stewardship programs:

┌──────────────────────────────────────────────┐
│    CDC CORE ELEMENTS OF STEWARDSHIP          │
├──────────────────────────────────────────────┤
│                                              │
│  1️⃣ LEADERSHIP COMMITMENT                    │
│     ├─ Dedicate necessary resources          │
│     └─ Support accountability                │
│                                              │
│  2️⃣ ACCOUNTABILITY                           │
│     ├─ Single leader responsible             │
│     └─ Physician/pharmacist champions        │
│                                              │
│  3️⃣ DRUG EXPERTISE                           │
│     ├─ Pharmacist co-leads ASP               │
│     └─ Infectious disease specialist         │
│                                              │
│  4️⃣ ACTION - IMPLEMENT INTERVENTIONS         │
│     ├─ Prospective audit & feedback          │
│     ├─ Preauthorization                      │
│     ├─ Formulary restrictions                │
│     └─ Clinical pathways/guidelines          │
│                                              │
│  5️⃣ TRACKING                                 │
│     ├─ Monitor antibiotic use                │
│     ├─ Track resistance patterns             │
│     └─ Measure outcomes                      │
│                                              │
│  6️⃣ REPORTING                                │
│     ├─ Regular feedback to prescribers       │
│     └─ Report to leadership                  │
│                                              │
│  7️⃣ EDUCATION                                │
│     ├─ Update clinical staff                 │
│     └─ Patient/family education              │
│                                              │
└──────────────────────────────────────────────┘

Stewardship Interventions 💊

1. Prospective Audit and Feedback (PAF)

Most effective stewardship intervention

Process:

• Review antimicrobial orders 24-48 hours after initiation
• Assess appropriateness (spectrum, dose, duration, indication)
• Provide recommendations to prescriber
• Document outcomes

Example PAF Recommendation:

"Patient with uncomplicated E. coli UTI currently on IV meropenem (Day 3). Susceptibilities show pansensitive organism. Recommend: De-escalate to oral ciprofloxacin 500mg BID to complete 7-day course. Rationale: Carbapenem-sparing, narrower spectrum, oral therapy for clinically stable patient. Estimated cost savings: $1,200 per day."

2. Preauthorization/Restriction

Restrict broad-spectrum or high-risk agents requiring ID/ASP approval:

• Carbapenems
• Daptomycin
• Newer β-lactam/β-lactamase inhibitor combinations
• Echinocandins
• Linezolid

3. IV-to-PO Conversion

Criteria for Conversion: ✅ Hemodynamically stable ✅ Afebrile for 24+ hours ✅ Functioning GI tract ✅ Oral agent with appropriate bioavailability available

High-Bioavailability Agents (>90%):

• Fluoroquinolones (levofloxacin, moxifloxacin, ciprofloxacin)
• Linezolid
• Metronidazole
• Trimethoprim-sulfamethoxazole
• Fluconazole
• Voriconazole

4. Dose Optimization

Pharmacokinetic/Pharmacodynamic (PK/PD) Principles:

Antibiotic Class	PK/PD Parameter	Target	Dosing Strategy
β-Lactams	%T>MIC (Time above MIC)	40-70% of dosing interval	Frequent dosing or extended infusions
Fluoroquinolones	AUC/MIC ratio	≥125 for Gram-negatives	Higher doses, once daily
Aminoglycosides	Cmax/MIC ratio	≥8-10	High-dose, extended-interval (once daily)
Vancomycin	AUC/MIC ratio	400-600	Weight-based dosing, monitor AUC₂₄

💡 Extended Infusion Strategy: For β-lactams treating serious Gram-negative infections:

• Piperacillin-tazobactam: 3.375g IV over 4 hours q8h (instead of 30-min infusion)
• Meropenem: 2g IV over 3 hours q8h (instead of 30-min infusion)
• Benefit: Prolongs %T>MIC, improves outcomes in critically ill patients

Duration Optimization: Shorter is Often Better ⏱️

Evidence-Based Duration Recommendations:

Infection Type	Traditional Duration	Recommended Duration	Key Evidence
Community-Acquired Pneumonia	7-10 days	5 days (if clinically stable by day 3)	Similar outcomes with shorter course
Uncomplicated UTI (women)	7 days	3 days (fluoroquinolone or TMP-SMX)	Non-inferiority demonstrated
Intra-abdominal Infection	Until resolution of symptoms	4 days (after source control)	STOP-IT trial
Hospital-Acquired/Ventilator-Associated Pneumonia	14-21 days	7 days (8 days if Pseudomonas)	Reduced resistance, similar cure rates
Cellulitis	10-14 days	5-6 days (if improving)	Expert recommendations, clinical stability
Streptococcal Pharyngitis	10 days	10 days (DO NOT shorten)	Prevents rheumatic fever

⚠️ Exceptions Requiring Longer Therapy:

• Endocarditis (4-6 weeks)
• Osteomyelitis (≥6 weeks)
• Prosthetic joint infection (≥6 weeks)
• Deep-seated abscesses without adequate drainage
• Immunocompromised hosts
• Staphylococcus aureus bacteremia (2-6 weeks depending on source)

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Real-World Examples 🏥

Example 1: De-escalation After Culture Results

Clinical Scenario:

Patient: 68-year-old male, admitted with fever, hypotension, and elevated WBC. Suspected abdominal source.

Initial Empiric Therapy (Day 1): Meropenem 1g IV q8h + vancomycin 15mg/kg IV q12h

Culture Results (Day 3):

• Blood cultures: Escherichia coli (2/2 bottles)
• Sensitivities: Pansensitive (including ampicillin-sulbactam, ceftriaxone, fluoroquinolones)

Stewardship Recommendation:

Action: De-escalate meropenem → ceftriaxone 2g IV q24h, DISCONTINUE vancomycin

Rationale:

1. ✅ Organism identified - no need for empiric broad-spectrum coverage
2. ✅ No MRSA isolated - discontinue vancomycin
3. ✅ Pansensitive E. coli - narrow to 3rd-generation cephalosporin
4. ✅ Carbapenem-sparing strategy preserves gut microbiome, reduces resistance pressure
5. ✅ Patient clinically improving, hemodynamically stable
6. ✅ Once afebrile >24h and tolerating PO, consider switch to oral ciprofloxacin

Expected Duration: 7 days total (IV + PO)

Outcome: Successfully completed therapy, saved carbapenem exposure, reduced cost by ~$800/day

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Example 2: MRSA Pneumonia Treatment Selection

Clinical Scenario:

Patient: 45-year-old female with severe CA-MRSA necrotizing pneumonia, ICU admission, intubated

Sputum Culture: MRSA, susceptibilities:

• Vancomycin: MIC 1.5 mcg/mL (susceptible)
• Linezolid: Susceptible
• Clindamycin: Susceptible (D-test negative)
• Daptomycin: N/A (inactivated by pulmonary surfactant)

Treatment Decision Matrix:

Option 1: Vancomycin monotherapy

• ⚠️ Concern: MIC 1.5 is "high-susceptible" - may have suboptimal lung penetration
• ⚠️ Target AUC₂₄/MIC >400 difficult to achieve with MIC 1.5

Option 2: Linezolid monotherapy

• ✅ Excellent lung penetration (>90% bioavailability)
• ✅ Penetrates into epithelial lining fluid
• ⚠️ No activity against toxin production

✅ BEST CHOICE: Linezolid 600mg IV q12h + Clindamycin 600mg IV q8h

Rationale:

1. Linezolid: Bacteriostatic but excellent lung penetration, covers MRSA
2. Clindamycin: Inhibits exotoxin production (PVL toxin), important in necrotizing infections
3. Dual mechanism approach for severe infection
4. Continue until clinical improvement, then discontinue clindamycin
5. May convert linezolid to PO when extubated

Monitoring:

• Weekly CBC (linezolid: thrombocytopenia, anemia risk)
• Repeat imaging
• Clinical status (fever, WBC, oxygenation)

Duration: 7-14 days depending on clinical response

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Example 3: CRE Bloodstream Infection

Clinical Scenario:

Patient: 72-year-old male, hospital day 14 post-liver transplant, develops fever and hypotension

Blood Cultures (Day 1): Gram-negative rods growing in aerobic bottles

Initial Empiric Therapy: Meropenem 2g IV q8h (extended infusion over 3 hours)

Day 3 - Final Identification: Klebsiella pneumoniae

• Sensitivities: Resistant to all penicillins, cephalosporins, carbapenems, fluoroquinolones
• Susceptible: Colistin, tigecycline, ceftazidime-avibactam
• Carbapenemase detected: KPC-producing CRE

Treatment Decision:

✅ RECOMMENDED: Ceftazidime-Avibactam 2.5g IV q8h (adjusted for renal function)

Why NOT alternative options?

• ❌ Tigecycline: FDA black box warning, lower cure rates in bacteremia, poor serum levels
• ❌ Colistin monotherapy: High nephrotoxicity risk in transplant patient, resistance emergence
• ⚠️ Colistin + meropenem combination: Consider if ceftazidime-avibactam unavailable

Additional Stewardship Actions:

1. Source control: Remove/replace infected central line
2. Infectious Disease consultation: Documented
3. Infection control notification: Implement contact precautions, flag for surveillance
4. Duration: 14 days for CRE bacteremia (longer than typical 7-day course)
5. Monitor: Daily renal function, LFTs, clinical response
6. Repeat cultures: Document clearance at 48-72 hours

Outcome: Bacteremia cleared by Day 4, completed 14-day course, surveillance cultures negative

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Example 4: Antibiotic Timeout at 48-72 Hours

Clinical Scenario:

Patient: 55-year-old female admitted with "sepsis" from emergency department

ED Presentation: Fever 38.9°C, WBC 14,000, received 30mL/kg fluid bolus, started on broad-spectrum antibiotics

ED Empiric Therapy: Vancomycin 15mg/kg IV + piperacillin-tazobactam 3.375g IV q6h

Admission Diagnosis: "Sepsis, unclear source"

Day 3 Stewardship Review (Antibiotic Timeout):

Question	Finding	Action
Does patient have infection?	• No fever since admission • WBC normalized (8,500) • No localizing symptoms • Likely viral syndrome or drug fever	✅ DISCONTINUE all antibiotics
Are cultures positive?	• Blood cultures: No growth at 5 days (final) • Urine culture: Contaminated specimen • Chest X-ray: Clear	✅ No evidence of bacterial infection
Is antibiotic choice appropriate?	N/A - No infection documented	N/A
Can we de-escalate/narrow?	N/A - Stop antibiotics entirely	N/A

Stewardship Recommendation: "Discontinue vancomycin and piperacillin-tazobactam. No evidence of bacterial infection. Patient clinically well, cultures negative, alternative diagnosis likely. Monitor off antibiotics."

Key Learning: Not all "sepsis" presentations require antibiotics. The antibiotic timeout at 48-72 hours is critical to reassess necessity.

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Common Mistakes ⚠️

Mistake 1: Using 3rd-Generation Cephalosporins for ESBL Infections

❌ Wrong: "The organism shows 'susceptible' to ceftriaxone on the lab report, so I'll use it."

✅ Correct: ESBL-producing organisms may appear susceptible in vitro but fail clinically due to:

• Inoculum effect: High bacterial load overwhelms antibiotic
• Inducible resistance: Enzyme production increases during therapy
• Poor outcome data: Clinical studies show high failure rates

Rule: Treat ESBL infections with carbapenems (severe) or carefully selected alternatives based on susceptibility testing and infection site (mild/moderate).

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Mistake 2: Inadequate Vancomycin Dosing

❌ Wrong: Standard dose of 1g IV q12h for all patients

✅ Correct: Weight-based dosing (15-20 mg/kg/dose) with AUC₂₄-guided monitoring

Why it matters:

• Underdosing leads to treatment failure and resistance
• Target AUC₂₄/MIC of 400-600 for serious MRSA infections
• Obesity, renal function, and MIC affect dosing requirements

Modern approach: Use Bayesian software or pharmacokinetic calculations to determine optimal dosing based on two levels.

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Mistake 3: Using Daptomycin for Pneumonia

❌ Wrong: "Patient has MRSA bacteremia from pneumonia. I'll use daptomycin 6 mg/kg."

✅ Correct: Daptomycin is inactivated by pulmonary surfactant and should NEVER be used for pneumonia.

Alternative choices for MRSA pneumonia:

• Vancomycin (if MIC ≤1)
• Linezolid (preferred for lung penetration)
• Ceftaroline (active against MRSA, excellent lung penetration)

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Mistake 4: Forgetting Renal Dose Adjustments

❌ Wrong: Continuing standard doses in patients with renal impairment

✅ Correct: Most antibiotics require dose adjustment based on CrCl

High-risk antibiotics requiring adjustment:

• β-lactams (especially carbapenems - seizure risk)
• Fluoroquinolones (QTc prolongation, tendon rupture)
• Aminoglycosides (nephrotoxicity, ototoxicity)
• Vancomycin (nephrotoxicity)
• Trimethoprim-sulfamethoxazole (hyperkalemia, crystalluria)

Exceptions (no/minimal adjustment needed):

• Ceftriaxone (biliary excretion)
• Moxifloxacin (hepatic metabolism)
• Doxycycline
• Linezolid
• Azithromycin

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Mistake 5: Prolonged Empiric Therapy Without Reassessment

❌ Wrong: Starting broad-spectrum antibiotics and continuing for 7-14 days without culture review

✅ Correct: Implement antibiotic timeout at 48-72 hours:

Timeout Checklist: □ Are cultures growing anything? □ Do susceptibilities allow narrower therapy? □ Is there documented infection or alternative diagnosis? □ Can IV be switched to PO? □ What is the planned total duration? □ Can antibiotics be discontinued entirely?

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Key Takeaways 🎯

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Further Study 📚

Official Guidelines:

1. CDC Core Elements of Antibiotic Stewardship: https://www.cdc.gov/antibiotic-use/core-elements/index.html
2. IDSA Implementing an Antibiotic Stewardship Program: https://www.idsociety.org/practice-guideline/antimicrobial-stewardship/
3. SIDP Antibiotic Stewardship Resources: https://www.sidp.org/Stewardship

Resistance Pattern References: 4. CDC Antibiotic Resistance Threats Report: https://www.cdc.gov/drugresistance/biggest-threats.html 5. WHO Priority Pathogens List: https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed

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🎓 You've now mastered the essential concepts of antimicrobial resistance patterns and stewardship strategies! Remember: Every antibiotic prescription is an opportunity for stewardship. Your role as a pharmacist in preserving these precious resources cannot be overstated. Use this knowledge to optimize therapy, prevent resistance, and improve patient outcomes.