Antimicrobial Therapy and Mechanisms

Key Points on Signs and Symptoms of Infection

  • Signs/Symptoms of Infection
    • Fever
    • Hallmark of infectious disease
    • Possible manifestation of non-infection disease states
    • Can result from drug fever (e.g., b-lactams, sulfa drugs, Macrobid)
    • Local Signs
    • Superficial infections can be visually identified
    • Symptoms
    • Refer to affected organ systems
    • WBC Role
    • White blood cells defend against infection
    • Possible causes of increased levels: rheumatoid arthritis (RA), leukemia, drugs
  • Differential Diagnosis
    • Polymorphonuclear Leukocytes
    • Neutrophils
      • Presence of bands indicates infection (left shift)
    • Basophils
    • Eosinophils
    • Lymphocytes
    • Monocytes
    • Other Diagnostic Tests
    • Erythrocyte Sedimentation Rate (ESR)
    • C-reactive Protein (CRP)
    • Cytokines
    • Procalcitonin
      • Indicator of bacterial infection
  • Pathogen Identification
    • Direct Examination
    • Gram stain helps identify pathogens (+ or - and arrangement)
  • Manual Tests
    • Disk Diffusion
    • Evaluates antibiotic efficacy based on inhibition zone diameter
    • Broth Microdilution
    • Determines Minimum Inhibitory Concentration (MIC) simultaneously for multiple antibiotics
    • E-test Methods
    • Automated Tests
    • Vitek systems, Microscan Walkaway System, BD Phoenix, Sensititre (names sufficient to know)
  • Susceptibility Testing Considerations
    • Fastidious Organisms
    • Require specific conditions for growth e.g.,
      • Hemophilus influenzae
      • Neisseria gonorrhea
      • Streptococcus pneumoniae
    • Anaerobes
    • Mycobacteria
    • Double Disk Diffusion
    • Minimal Inhibitory Concentration (MIC)
    • Break Points for Susceptibility Testing
    • Susceptible: drug likely effective
    • Intermediate: uncertain efficacy, use highest safe dose
    • Resistant: unlikely to work
  • Clinical Applications for Antimicrobial Therapy
    • 90-60 Rule
    • Susceptible isolates 90% therapeutic success, resistant isolates 60% success
  • Types of Antimicrobial Therapy
    • Prophylaxis
    • Antibiotics given to high-risk individuals without active infection
    • Empiric Therapy
    • Antibiotics given when infection suspected without culture documentation
    • Definitive Therapy
    • Based on cultured infection
  • Factors in Selecting Presumptive Therapy
    • Severity and Acuity of Disease
    • Host Factors
    • Allergies, drug reactions, age, organ function, metabolic abnormalities, pregnancy status, concomitant drugs, disease state
    • Drug Factors
    • Pharmacokinetic and pharmacodynamic considerations (AUC:MIC ratio, Peak:MIC ratio, T>MIC for b-lactams)
    • Tissue penetration, drug toxicity, cost considerations
    • Combo Therapy
    • Broaden coverage, synergism (reduce adverse effects and resistance potential)
    • Disadvantages of Combo Therapy
    • Possible nephrotoxicity, antagonism, additive toxicity
  • Therapeutic Response Monitoring
    • Culture and sensitivity tests streamline therapy
    • Improvement parameters to diagnose infection: normalization of WBC and temperature, improvement in patient complaints, radiographic improvement, antimicrobial serum monitoring
  • Antimicrobial Failure Causes
    • Drug Selection Issues
    • Inappropriate drug choice, dose or route, malabsorption, accelerated drug elimination, poor infection site penetration
    • Host Factors
    • Immunosuppression, surgical drainage needs, necrotic tissue presence
    • Pathogen Factors
    • Resistance patterns
  • Classes of Antimicrobials
    • b-lactams
    • Penicillin
      • Effective against streptococci and mouth flora (Group A, B, C, G)
      • DOC for syphilis, ineffective against gram- and staphylococci
    • Aminopenicillins (amoxicillin & ampicillin)
      • Active against Hemophilus influenzae, slightly more active against Enterococci
      • DOC for Listeria monocytogenes and Enterococcus faecalis
      • Limited E. coli coverage
    • Penicillinase-resistant Penicillins (nafcillin, methicillin, oxacillin, dicloxacillin)
      • Effective against Staphylococci, especially MSSA
      • No efficacy against MRSA, enterococci, GN organisms, and Bacteroides
    • b-lactam/b-lactamase Inhibitor Combinations
      • e.g., ampicillin/sulbactam, amoxicillin/clavulanate
      • Increase coverage to include staphylococci, anaerobes, and some GNRs; no PSA coverage
      • Piperacillin/tazobactam and Ceftolozane/tazobactam have broader spectrum and activity against PSA
    • Cephalosporins
    • 1st Generation (Cefazolin, Cephalexin)
      • Effective against strep, staph, limited GNR (E. coli, Klebsiella), no enterococci or anaerobes
    • 2nd Generation (Cefoxitin, Cefotetan, Cefuroxime)
      • Similar to 1st generation plus improved GNR coverage
    • 3rd Generation (Ceftriaxone, Cefotaxime, Ceftazidime)
      • Excellent strep coverage, good GNR coverage
      • Limited anaerobic coverage
    • 4th Generation (Cefepime)
      • Broad-spectrum; effective against MSSA, GNRs, and PSA; no anaerobes
    • 5th Generation (Ceftaroline, Cefiderocol)
      • Active against MRSA, with noted restrictions to enterococci and anaerobes
    • Carbapenems (Imipenem, Meropenem)
    • Used for serious infections; broad spectrum but can cause seizures and nephrotoxicity
    • Monobactams (Aztreonam)
    • Effective only for Gram-negative organisms (low allergy potential)
    • Fluoroquinolones (Ciprofloxacin, Levofloxacin)
    • Activity varies by the specific pathogen; potential for toxicity (e.g., tendonitis)
    • Aminoglycosides (Gentamicin, Tobramycin)
    • Excellent coverage for Gram-negative, including PSA, but no coverage for Gram-positive
    • Risk of nephrotoxicity
    • Glycopeptides (Vancomycin, Televancin)
    • Vancomycin is mainstay for MRSA and C. diff; potential for ototoxicity
    • Tetracyclines (Doxycycline, Minocycline)
    • Broad-spectrum but limited for Gram-negative; some activity for MRSA
  • Bacterial Resistance Mechanisms
    • Efflux Pumps: common resistance mechanism, easily overcome
    • Energy-independent Drug Degradation: a more harmful resistance mechanism, e.g., b-lactamase production
    • Energy-dependent Drug Modification: resistance requiring energy, typically less common
    • Alteration of Drug Targets: significant resistance, e.g., MRSA PBP changes
  • Examples of Antibiotics
    • Vancomycin: binds D-ala-D-ala in cell walls; intermediate resistance can occur through increased peptidoglycan
    • Other Glycopeptides: Telavancin offers dosing advantages but increased nephrotoxicity
    • Linezolid: protein synthesis inhibitor with unique coverage
    • Daptomycin: membrane-targeting cyclic lipopeptide, limited to Gram + infections
    • Polymyxin: active against Gram -; high nephrotoxicity when used IV
  • Infective Endocarditis (IE)
    • At-Risk Populations: older adults, drug users, card disease, prosthetic heart valves
    • Common Pathogens: Staphylococci, Streptococci, Enterococci
    • Clinical Manifestations: fever, heart murmur, embolic events, lab findings indicating systemic inflammation
    • Diagnostic Criteria: Duke criteria for classification into definite or possible IE
    • Antibiotic Regimens: vary by pathogen, include combinations for synergy and lower resistance risk
  • B-lactam Allergies
    • Type 1 Reactions: IgE mediated, can cause anaphylaxis
    • Cross-Reactivity: may occur between different classes based on side-chain structure
    • Penicillin Alternatives: select based on reported allergies with consideration for cross-reactivity potential
  • Catheter-Related Bloodstream Infections (CRBSIs)
    • Common Pathogens: include Staphylococcus aureus, coagulase-negative staphylococci, GNRs, enterococci
    • Empiric Therapy Recommendations: tailored to coverage for Gram-positive and negative bacteria diagnosed through culture and sensitivity testing
    • Infection Control: careful insertion practices and maintenance to reduce risk factors associated with CRBSIs.