Antimicrobial Stewardship and Resistant Pathogens

Principles and Definitions of Antimicrobial Stewardship (ASP)

• Formal Definition of Antimicrobial Stewardship: Coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents. This is achieved by promoting the selection of the optimal antimicrobial drug regimen, which includes precise dosing, duration of therapy, and the appropriate route of administration.

• Core Concepts and Collateral Damage: ASP represents a working relationship between infection control and antimicrobial management. A primary focus is selecting antimicrobials from each class that cause the least "collateral damage." Issues classified as collateral damage include:

  • Methicillin-resistant Staphylococcus aureus (MRSA)

  • Extended-spectrum $\beta$-lactamase (ESBL)

  • Clostridium difficile ($C.\,difficile$)

  • Vancomycin-resistant enterococci (VRE)

  • Metalloenzymes and other carbapenemases

• Relationship Between Antimicrobial Use and Resistance:

  • Changes in antimicrobial use directly parallel changes in the prevalence of resistance.

  • Antimicrobial resistance is more prevalent in healthcare-associated bacterial infections than in community-acquired infections.

  • Patients with healthcare-associated infections (HAIs) caused by resistant strains are more likely to have received prior antimicrobials than control patients.

  • Hospital areas with the highest rates of antimicrobial use also exhibit the highest rates of antimicrobial resistance.

  • Increasing the duration of patient exposure to antimicrobials significantly increases the likelihood of colonization with resistant organisms.

• Antimicrobial Approval Timeline (Historical Context):

  • 1930s-1940s: 1935 (Prontosil-Sulfa), 1942 (Benzyl penicillin), 1944 (Streptomycin), 1948 (Chlortetracycline), 1949 (Chloramphenicol).

  • 1950s: 1950 (Penicillin G), 1952 (Erythromycin, Isoniazid), 1955 (Tetracycline, Vancomycin), 1958 (Colistin).

  • 1960s: 1960 (Methicillin, Metronidazole), 1961 (Trimethoprim), 1964 (Gentamicin, Cephalothin), 1967 (Nalidixic acid, Doxycycline), 1968 (Clindamycin).

  • 1970s: 9 Cephalosporins, 1971 (Minocycline, Rifampin, Pyrazinamide), 1972 (Amoxicillin), 1975 (Tobramycin), 1976 (Amikacin).

  • 1980s: 17 Cephalosporins, 5 Penicillins, 1984 (Amoxicillin/Clavulanate), 1985 (Imipenem), 1986 (Aztreonam, Norfloxacin), 1987 (Ciprofloxacin).

  • 1990s: 8 Cephalosporins, 1990 (Clarithromycin), 1991 (Azithromycin), 1992 (Piperacillin/Tazobactam), 1993 (Levofloxacin), 1994 (Cefepime), 1996 (Meropenem), 1999 (Moxifloxacin, Quinupristin/Dalfopristin).

  • 2000s: 2000 (Linezolid), 2001 (Ertapenem), 2003 (Daptomycin), 2005 (Tigecycline, Doripenem), 2009 (Telavancin).

  • 2010s: 2010 (Ceftaroline), 2011 (Fidaxomicin), 2014 (Dalbavancin, Oritavancin, Tedizolid, Ceftolozane/Tazobactam), 2015 (Ceftazidime/Avibactam), 2017 (Delafloxacin, Meropenem/Vaborbactam), 2018 (Plazomicin, Omadacycline, Eravacycline), 2019 (Imipenem/Relebactam, Lefamulin, Cefiderocol).

Goals and Organizational Support for ASP

• Primary Goal: To optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, such as toxicity, selection of pathogenic organisms (e.g., $C.\,difficile$), and the emergence of resistant pathogens.

• Secondary Goal: To reduce healthcare costs without adversely impacting the quality of care.

• Benefits of ASP:

  • Improved patient outcomes.

  • Reduced adverse events.

  • Improved rates of antibiotic susceptibilities.

  • Targeted antibiotic use.

  • Optimization of resource utilization across the continuum of care.

• Endorsing Organizations: Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), American Society of Health-System Pharmacists (ASHP), American Academy of Pediatrics, Infectious Diseases Society for Obstetrics and Gynecology, Pediatric Infectious Diseases Society (PIDS), and the Society for Hospital Medicine.

• Core Elements of Hospital ASP (CDC):

  • Leadership Commitment: Dedicating human, financial, and IT resources.

  • Accountability: Appointing a single leader responsible for program outcomes.

  • Drug Expertise: Appointing a single pharmacist leader.

  • Action: Implementing at least one recommended action (e.g., antibiotic time-out after $48\,\text{hours}$).

  • Tracking: Monitoring prescribing and resistance patterns.

  • Reporting: Regular information sharing with clinical staff.

  • Education: Educating clinicians on resistance and prescribing.

Antimicrobial Stewardship Team and Pharmacist Roles

• Core Members:

  • Director: Infectious Diseases Physician (ID MD).

  • Clinical Pharmacist: Infectious Diseases trained (ID PharmD).

  • Other Members: Clinical Microbiologist, Information System Specialist, Infection Control Professional, and optionally a Hospital Epidemiologist.

• ID Pharmacist Qualifications:

  • Doctor of Pharmacy (PharmD).

  • Pharmacy Practice Residency (PGY1).

  • Infectious Diseases Specialty Residency (PGY2).

  • Board Certified Infectious Diseases Pharmacist (BCIDP).

• Required Collaborations: The ASP team must collaborate with the Infection Control Committee and the P&T Committee for pathway approvals, budgetary reviews, restriction policies, and review of the yearly antibiogram.

ASP Clinical Strategies and Interventions

• Proactive Core Strategies:

  • Prospective Audit with Intervention and Feedback: Provides targeted feedback to physicians and reports financial impacts. Highly recommended with moderate-quality evidence.

  • Formulary Restriction and Pre-authorization: Immediate reductions in use and cost. Direct control over empiric choices. Highly recommended with moderate-quality evidence.

• Comparison of Strategies:

  • Pre-authorization: Reduces unnecessary initiation, optimizes empiric choice, decreases costs. Disadvantages include loss of prescriber autonomy, potential delays in therapy, and being resource-intensive in real-time.

  • Prospective Audit and Feedback: Increases program visibility, maintains prescriber autonomy, and provides educational benefits. Disadvantages include being labor-intensive and prescribers being reluctant to change therapy if the patient is stable.

• Additional Prioritized Elements:

  • Parenteral to Oral Conversion: Strong recommendation (A-I). Decreases length of stay and costs when patient condition allows.

  • Guidelines and Clinical Pathways: Should incorporate local resistance patterns (A-I).

  • Dose Optimization: Based on PK/PD parameters. $\beta$-lactam activity correlates with Time > MIC. Fluoroquinolones and Aminoglycosides are concentration-dependent, utilizing $C_{\text{max}}:\text{MIC}$ or $\text{AUC}:\text{MIC}$.

  • Streamlining/De-escalation: Eliminating redundant therapy based on culture results (A-II).

  • Antimicrobial Cycling: Not currently recommended due to insufficient data.

Microbiology and Pathogenesis of Staphylococcus aureus

• Microbial Characteristics: Facultative Gram-positive coccus forming grapes/clusters. It is coagulase-positive.

• Epidemiology: A commensal organism colonizing the nares, axillae, vagina, pharynx, and damaged skin. Colonization occurs in $30\text{--}50\%$ of healthy adults, with $10\text{--}20\%$ persistently colonized.

• Transmission: Primarily via the hands of healthcare workers. Person-to-person contact is the main route.

• Virulence Determinants:

  • Accessory Gene Regulator ($agr$): A polymorphic operon controlling virulence factors (exoproteins, exotoxins, adhesion).

    • Group I: HA-MRSA.

    • Group II: VISA.

    • Group III: CA-MRSA.

    • Group IV: Exfoliation-producing strains.

  • Toxins: $\alpha$-toxin, $\beta$-toxin, Enterotoxins (A-K) which can cause Toxic Shock Syndrome Toxin (TSST)-1, and Panton-Valentine Leukocidin (PVL), commonly found in CA-MRSA.

Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistance

• Mechanism of Resistance: Conferred by the mecA gene which encodes Penicillin-Binding Protein 2a (PBP2a), which has a low affinity for $\beta$-lactams.

• Classification by SCCmec Type:

  • Type I: $34.3\,\text{kb}$, lacks other resistant genes.

  • Type II: $53.0\,\text{kb}$, multiple non-$\beta$-lactam resistance.

  • Type III: $66.9\,\text{kb}$, associated with multiple drug resistance.

  • Type IV: $20.9\text{--}24.3\,\text{kb}$, resistant primarily to $\beta$-lactams (common in CA-MRSA).

  • Type V: $28.0\,\text{kb}$, lacks other antibiotic resistance genes.

• Vancomycin Interaction Criteria (CLSI):

  • Susceptible (S): $\text{MIC} \le 2\,\mu g/mL$.

  • Intermediate (I): $\text{MIC} \, 4\text{--}8\,\mu g/mL$.

  • Resistant (R): \text{MIC} > 16\,\mu g/mL.

• Vancomycin Resistance Spectrums:

  • hVISA (Heteroresistant VISA): Strains susceptible to Vancomycin ($\text{MIC} \le 2$) but containing subpopulations able to grow in higher concentrations. Often associated with treatment failure.

  • VISA (Vancomycin-Intermediate S. aureus): Characterized by a thicker cell wall, less peptidoglycan cross-linking, increased false binding sites (D-Ala-D-Ala), and slower growth rates. Does NOT possess van genes like vanA or vanB.

  • VRSA (Vancomycin-Resistant S. aureus): Resulting from the conjugative transfer of the vanA gene from Enterococcus. Cases are rare (16 total cases noted).

Hospital-Associated (HA-MRSA) vs. Community-Associated (CA-MRSA)

• HA-MRSA Characteristics: Found in patients with traditional risk factors (hospitalization, surgery, dialysis, IVDU, prior antibiotics). Typically multidrug-resistant (USA100 and USA200).

• CA-MRSA Characteristics: Affects healthy individuals without traditional risk factors. Commonly presents as skin and soft tissue infections (SSTIs). Often yields broader susceptibility profiles but frequently expresses the PVL toxin. Primarily associated with molecular types USA300 and USA400. Includes SCCmec types IV and V.

• Clindamycin Inducible Resistance: Some MRSA isolates show resistance to Erythromycin but appear susceptible to Clindamycin. A "D-test" is used to identify inducible macrolide-lincosamide-streptogramin B resistance (iMLSB). A positive D-test (flattening of Clindamycin zone) indicates the organism is resistant to Clindamycin.

Gram-Negative Resistance Profiles

• Enterobacterales (Enterobacteriaceae): Facultative anaerobes/aerobes inhabiting the intestinal tract (Escherichia, Klebsiella, Proteus, etc.).

• Extended-Spectrum $\beta$-lactamase (ESBL):

  • Inactivate most penicillins, cephalosporins, and aztreonam.

  • Common enzymes: CTX-M (specifically CTX-M-15).

  • Surrogate Marker: Ceftriaxone nonsusceptibility ($\text{MIC} \ge 2\,\mu g/mL$).

  • Treatment: Carbapenems are preferred for infections outside the urinary tract. Avoid Cefepime and Piperacillin-tazobactam.

• Carbapenem-Resistant Enterobacterales (CRE):

  • Defined as resistant to at least one carbapenem or producing a carbapenemase.

  • KPCs (K. pneumoniae carbapenemases): Most common in the US (Class A).

  • Metallo-$\beta$-lactamases (MBLs): NDM, VIM, IMP. NDM-1 confers resistance to all $\beta$-lactams except Aztreonam.

  • Treatment for CRE: Ceftazidime-avibactam, Meropenem-vaborbactam, or Imipenem-relebactam.

• Multidrug-Resistant Pseudomonas aeruginosa (MDR-PA):

  • Mechanisms: OprD porin loss (reduces carbapenem entry) and MexAB-OprM efflux pump overproduction.

  • Treatment: Ceftolozane-tazobactam, Ceftazidime-avibactam, or Imipenem-cilastatin-relebactam.

• Multidrug-Resistant Acinetobacter:

  • Classified as an urgent threat (700 estimated deaths in 2017).

  • Resistance: AmpC expression is common; loss of OprD porins.

  • Treatment: Sulbactam (high dose), Minocycline, Cefiderocol, or Eravacycline.

The MERINO Trial

• Study Design: Multicenter, open-label, non-inferiority RCT comparing Piperacillin-Tazobactam (PTZ) and Meropenem (MER) for ESBL E. coli or Klebsiella bloodstream infections.

• Dosing: MER $1\,g$ IV q8h vs. PTZ $4.5\,g$ IV q6h.

• Results:

  • 30-day Mortality: PTZ ($12.3\%$) vs. MER ($3.7\%$).

  • Conclusion: Trial terminated early as PTZ failed to meet non-inferiority. Meropenem remains the treatment of choice for ESBL bloodstream infections.

Clinical Case Reports

• Inpatient MRSA Case: 64-year-old woman with septic arthritis/bacteremia post-ankle fracture.

  • Failed Vancomycin ($6\,\text{week}$ courses) and Linezolid (not tolerated due to side effects).

  • Received Daptomycin ($8\,mg/kg/day$ then $6\,mg/kg/day$).

  • Eventually required below-knee amputation (BKA). Successfully cleared infection with Minocycline and TMP/SMX.

• Outpatient CA-MRSA Case: 19-year-old male athlete with axillary boils.

  • Abscess I&D performed. Cephalexin empiric therapy failed.

  • Cultures revealed MRSA susceptible to Clindamycin, Gentamicin, Rifampin, Tetracycline, and TMP/SMX ($MIC \le 2$).

• Pathogen Trends (CDC 2020 Data):

  • Carbapenem-Resistant Acinetobacter: $+78\%$ increase in infections.

  • Multidrug-Resistant Pseudomonas aeruginosa: $+32\%$ increase.

  • Vancomycin-Resistant Enterococcus: $+14\%$ increase.

  • Methicillin-Resistant Staphylococcus aureus: $+13\%$ increase.