3.1 Infectious Diseases: Antimicrobial Stewardship & Pharmacokinetics

Antimicrobial Stewardship & Pharmacokinetics

Antimicrobial stewardship programs (ASPs) are coordinated interventions designed to improve and measure the appropriate use of antimicrobials. The core goals of ASPs are to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms (e.g., Clostridioides difficile), and the emergence of resistance. Essential strategies include formulary restrictions, prospective audit and feedback, clinical pathways, intravenous-to-oral (IV-to-PO) transition protocols, and dose optimization based on pharmacokinetic and pharmacodynamic (PK/PD) principles. A crucial concept in ASPs is the "antimicrobial timeout," where clinicians reassess empiric therapy 48-72 hours after initiation, using culture and susceptibility results to de-escalate or target therapy.

Pharmacokinetics and Pharmacodynamics (PK/PD) Indexing

Optimizing antimicrobial dosing requires an understanding of how drug concentrations relate to the Minimum Inhibitory Concentration (MIC) of the offending pathogen over time.

Time-Dependent Killing (Time > MIC)

• Antibiotic Classes: Beta-lactams (penicillins, cephalosporins, carbapenems, monobactams).
• Mechanism: The efficacy of these agents correlates directly with the percentage of the dosing interval that the free (unbound) drug concentration remains above the MIC of the pathogen ($f$Time > MIC). For maximal bactericidal activity, penicillins require $f$Time > MIC of ~50%, cephalosporins ~60-70%, and carbapenems ~40%.
• Optimization Strategy: Maximizing exposure involves using extended or continuous infusions rather than simply increasing the dose. For example, administering piperacillin-tazobactam as an extended infusion over 4 hours instead of a standard 30-minute infusion significantly improves the likelihood of target attainment, particularly against pathogens with elevated MICs (e.g., Pseudomonas aeruginosa). Clinicians must account for physical stability when utilizing continuous infusions at room temperature, particularly with agents like ampicillin.

Concentration-Dependent Killing (Cmax/MIC)

• Antibiotic Classes: Aminoglycosides, Daptomycin.
• Mechanism: Efficacy correlates with the peak drug concentration achieved relative to the MIC ($f$Cmax/MIC). These agents also exhibit a significant post-antibiotic effect (PAE)—persistent suppression of bacterial growth even after the antibiotic concentration falls below the MIC.
• Optimization Strategy: Administering large, single daily doses (extended-interval aminoglycoside dosing) maximizes the peak concentration to achieve a Cmax/MIC ratio of at least 8-10. This approach also allows trough levels to fall sufficiently close to zero, minimizing cumulative toxicity to the renal proximal tubules and inner ear (nephrotoxicity and ototoxicity, respectively).

Exposure-Dependent Killing (AUC/MIC)

• Antibiotic Classes: Vancomycin, Fluoroquinolones, Macrolides, Tetracyclines.
• Mechanism: Efficacy correlates with the total drug exposure over 24 hours relative to the MIC (AUC$_{24}$/MIC).
• Optimization Strategy: For vancomycin, current consensus guidelines strongly recommend AUC/MIC-guided dosing (target 400-600 mg*h/L for MRSA with an assumed MIC of 1 mg/L) over traditional trough-only monitoring. This precision approach maximizes clinical efficacy while significantly mitigating the risk of acute kidney injury (AKI). Bayesian software programs or two-level (peak/trough) pharmacokinetic equations are typically used to calculate the AUC.

Key Mechanisms of Resistance and Targeted Therapy

Extended-Spectrum Beta-Lactamases (ESBL)

ESBLs are plasmid-mediated enzymes (most commonly CTX-M, TEM, and SHV types) that hydrolyze third-generation cephalosporins (e.g., ceftriaxone, cefotaxime) and monobactams (aztreonam) but do not affect carbapenems or cephamycins (cefoxitin, cefotetan).

• Pathogens: Most commonly found in Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli.
• Treatment: Carbapenems (meropenem, imipenem-cilastatin, ertapenem) remain the cornerstone of therapy for invasive ESBL infections. While some ESBL producers may appear susceptible in vitro to piperacillin-tazobactam or cefepime, the MERINO trial established that piperacillin-tazobactam yields higher mortality rates in severe infections (e.g., bacteremia) and should be avoided. Non-carbapenem options like fosfomycin, nitrofurantoin, or TMP-SMX can be used for uncomplicated cystitis to spare carbapenem use.

Carbapenem-Resistant Enterobacteriaceae (CRE)

CRE organisms harbor enzymes (carbapenemases) such as KPC (Klebsiella pneumoniae carbapenemase), NDM (New Delhi metallo-beta-lactamase), VIM, or OXA-48, rendering them resistant to nearly all standard beta-lactams including carbapenems.

• Treatment: Therapy depends heavily on the specific carbapenemase produced. Novel beta-lactam/beta-lactamase inhibitors like ceftazidime-avibactam and meropenem-vaborbactam are first-line for KPC producers. Cefiderocol, a novel siderophore cephalosporin that exploits the bacterial iron-transport system, provides activity against highly resistant metallo-beta-lactamases (NDM, VIM) where avibactam and vaborbactam fail.

AmpC Beta-Lactamases

AmpC enzymes are chromosomally mediated cephalosporinases that mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and early beta-lactamase inhibitor combinations.

• Pathogens: The SPACE or SPICE organisms commonly possess inducible AmpC genes: Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter.
• Inducible Resistance: These organisms may initially test susceptible to ceftriaxone, but exposure to the antibiotic acts as an inducer. This triggers derepression of the AmpC gene, leading to rapid hyperproduction of the enzyme and resulting in clinical failure mid-treatment.
• Treatment: Cefepime (a fourth-generation cephalosporin) is stable against AmpC hydrolysis, enters the bacterial cell quickly, and has a low affinity for the AmpC enzyme, making it a preferred agent. Carbapenems are also highly effective. Ceftriaxone and piperacillin-tazobactam should generally be avoided for invasive infections caused by high-risk AmpC producers (like Enterobacter cloacae and Klebsiella aerogenes).

Methicillin-Resistant Staphylococcus aureus (MRSA)

MRSA resistance is mediated by the mecA gene, which resides on a mobile genetic element (Staphylococcal cassette chromosome mec, or SCCmec). This gene encodes for an altered penicillin-binding protein (PBP2a) with extremely low affinity for nearly all beta-lactams (except ceftaroline). Community-acquired MRSA (CA-MRSA) frequently carries the Panton-Valentine leukocidin (PVL) toxin, associated with severe necrotizing pneumonia and aggressive skin/soft tissue infections.

• Treatment:
  • Vancomycin: The historical gold standard. Requires therapeutic drug monitoring (target AUC/MIC 400-600).
  • Linezolid: An oxazolidinone with excellent oral bioavailability (100%). It is particularly useful for MRSA pneumonia due to excellent lung epithelial lining fluid penetration. It carries risks of reversible bone marrow suppression (thrombocytopenia), optic neuritis (with prolonged use > 28 days), and serotonin syndrome due to its weak, reversible, non-selective monoamine oxidase inhibitor (MAOI) activity. Concurrent use with SSRIs/SNRIs should be carefully monitored.
  • Daptomycin: A cyclic lipopeptide that causes rapid depolarization of the bacterial membrane. It is indicated for MRSA bacteremia and right-sided endocarditis but is strictly contraindicated in pneumonia because it is irreversibly deactivated by pulmonary surfactant. Daptomycin can cause rhabdomyolysis, requiring baseline and weekly monitoring of creatine phosphokinase (CPK).
  • Ceftaroline: A fifth-generation cephalosporin with unique structural properties that allow it to bind tightly to PBP2a.

Vancomycin-Resistant Enterococcus (VRE)

VRE usually involves Enterococcus faecium with modified peptidoglycan precursors. The normal D-alanyl-D-alanine terminus is altered to D-alanyl-D-lactate (VanA and VanB phenotypes) or D-alanyl-D-serine (VanC phenotype), eliminating vancomycin's binding target. The VanA phenotype confers high-level resistance to both vancomycin and teicoplanin, whereas VanB confers resistance to vancomycin alone.

• Treatment: Linezolid, daptomycin, and tigecycline are active against VRE. High-dose daptomycin (8-12 mg/kg/day) is frequently utilized for severe VRE bacteremia to overcome relative insensitivity and prevent the rapid emergence of resistance during therapy. Combination therapy with a beta-lactam (e.g., ampicillin or ceftaroline) may be considered for synergistic activity in refractory bacteremia or endocarditis.

Antipseudomonal Agents

Pseudomonas aeruginosa is a formidable non-fermenting Gram-negative rod notorious for intrinsic and acquired multidrug resistance via efflux pumps, porin channel down-regulation, and beta-lactamase production.

• Beta-lactams: Piperacillin-tazobactam, cefepime, ceftazidime, ceftolozane-tazobactam.
• Carbapenems: Meropenem, imipenem-cilastatin, doripenem. Ertapenem does NOT have antipseudomonal activity (remember the acronym APE: lacks activity against Acinetobacter, Pseudomonas, and Enterococcus).
• Fluoroquinolones: Ciprofloxacin and levofloxacin (moxifloxacin lacks adequate antipseudomonal activity). Due to high rates of fluoroquinolone resistance, they are generally avoided as monotherapy for empiric Pseudomonas coverage.
• Aminoglycosides: Tobramycin, amikacin, gentamicin. These agents exhibit excellent Pseudomonas activity but distribute poorly into the lungs. They are typically used strictly as part of a combination regimen for empiric coverage to broaden the spectrum, rather than as monotherapy outside of the lower urinary tract.