---

Harrison's Chapters 147-150: Complete Teaching Guide

---

CHAPTER 147 - Infections Acquired in Health Care Facilities

---

What Are Healthcare-Associated Infections (HAIs)?

---

1. The Four "Big Four" Device-Associated HAIs

A. Central Line-Associated Bloodstream Infections (CLABSIs)

• Caused by bacteria (or fungi) entering the blood via an intravascular catheter
• Most common organisms: Coagulase-negative staphylococci, Staphylococcus aureus, Gram-negative bacilli, Candida species
• Prevention (the "bundle"):
  • Maximal sterile barrier precautions during insertion
  • Chlorhexidine skin antisepsis
  • Avoid femoral site when possible
  • Daily review of line necessity - remove when not needed
  • Antiseptic-impregnated dressings

B. Catheter-Associated Urinary Tract Infections (CAUTIs)

• The most common device-associated HAI by volume
• Most cases are asymptomatic bacteriuria - do not treat unless symptomatic (overtreating drives resistance)
• Prevention: Only insert catheters when truly necessary; use aseptic technique; remove catheters as soon as possible

C. Ventilator-Associated Pneumonia (VAP)

• Bacteria from the oropharynx or stomach colonize the trachea via the endotracheal tube
• Prevention bundle: Head-of-bed elevation at 30-45°, daily sedation vacations, oral decontamination with chlorhexidine, subglottic secretion drainage

D. Surgical Site Infections (SSIs)

• Can be superficial, deep, or organ-space
• Prevention: Appropriate perioperative antibiotics (within 1 hour before incision, discontinued within 24 hours), normoglycemia, normothermia, avoid unnecessary hair removal (clip, don't shave)

---

2. Transmission in Healthcare - The Basics

---

3. The Major Pathogens You Must Know

Clostridioides difficile (C. diff)

• Most frequent hospital-acquired infection in the United States
• Triggered by antibiotic disruption of normal gut flora
• Antibiotics most associated: fluoroquinolones and clindamycin
• Spores survive on surfaces for months - use bleach (sporicidal disinfectant) and soap and water (not alcohol gel) for hand decontamination
• Patients with suspected C. diff go on contact isolation

MRSA (Methicillin-Resistant Staphylococcus aureus)

• Screen high-risk patients on admission (active surveillance)
• Decolonization with intranasal mupirocin + chlorhexidine bathing reduces surgical site infections
• Contact precautions during hospital stay

Norovirus

• Common cause of healthcare-associated diarrhea; causes outbreaks in facilities
• Poorly inactivated by alcohol - requires soap and water and bleach cleaning

Tuberculosis

• Patients with suspected TB must be placed in airborne precautions (negative-pressure room)
• Healthcare workers must wear N95 respirators (fit-tested), not surgical masks
• Screen HCWs with interferon-gamma release assay (IGRA) - preferred over tuberculin skin test due to higher positive predictive value

Mold Infections (Aspergillus)

• Immunocompromised patients (neutropenic, SCT recipients) are at high risk from airborne Aspergillus spores
• Require positive-pressure HEPA-filtered rooms with sealed seams
• Construction near the hospital is a major trigger for outbreaks

---

4. Antimicrobial Stewardship

• Use the right drug, at the right dose, for the right duration
• Avoid unnecessary antibiotics
• Restrict broad-spectrum agents to preserve them for resistant infections
• Reduce C. diff rates and selection pressure for resistance

---

CHAPTER 148 - Infections in Transplant Recipients

---

The Big Picture: Why Are Transplant Patients Different?

1. Immunosuppression is required (for SOT/VCA, for life; for HCT, for months post-transplant)
2. The transplant surgery itself introduces infection risk (nosocomial organisms, donor-derived infections, anastomotic complications)

---

Understanding the Two Types of Transplant

---

The Net State of Immunosuppression

• The type and dose of immunosuppressive drugs
• Duration of immunosuppression
• Prior infections (especially with immunomodulating viruses like CMV, EBV)
• Underlying disease
• Metabolic factors (diabetes, uremia, malnutrition)
• Integrity of mucocutaneous barriers

---

The Predictable Timeline of Infections After SOT

Phase 1: First Month (0-30 days)

• Dominated by surgical/nosocomial complications
• Bacterial infections most common
• MDR organisms from prior colonization can strike
• Hepatitis C occurs if donor was HCV-positive
• Classic opportunistic infections at this stage = think donor-derived infection

Phase 2: 1-6 Months (Intermediate)

• Classic opportunistic infections emerge (if not on prophylaxis):
  • Pneumocystis jirovecii pneumonia (PCP)
  • CMV disease
• Reactivation of latent infections: TB, Chagas disease, endemic mycoses, cryptococcosis
• Viral threats: BK virus, adenovirus, RSV, hepatitis B, EBV (and EBV-associated PTLD)
• Invasive fungal infections: Aspergillus, other molds (especially after lung transplant)

Phase 3: Beyond 6 Months (Late)

• Patients with good graft function: more severe community-acquired infections
• Patients with rejection/poor graft function: prolonged risk of opportunistic infection
• CMV prophylaxis is typically stopped; resume vigilance

---

Organ-Specific Infection Risks

---

Important Specific Infections in Transplant Recipients

CMV (Cytomegalovirus)

• Most important viral infection in transplant recipients
• D+/R- (donor seropositive, recipient seronegative) = highest risk
• Prevention: antiviral prophylaxis (valganciclovir) or preemptive monitoring with PCR

BK Virus

• Ubiquitous polyomavirus
• BK nephropathy is the #1 specific complication in kidney transplant recipients; can cause graft loss
• Treatment: reduce immunosuppression (no specific antiviral)

Nocardia

• Aerobic gram-positive bacillus from soil
• Infects predominantly immunocompromised people via inhalation
• Presents with pulmonary nodules (may cavitate) ± CNS dissemination (25%)
• Always do brain MRI in all Nocardia patients (brain abscess may be asymptomatic)
• Treatment: linezolid is universal (empiric while awaiting susceptibilities); most also respond to TMP/SMX, amikacin, imipenem
• Duration: 6-12 months

PCP (Pneumocystis jirovecii Pneumonia)

• Prophylaxis: TMP/SMX (preferred) dramatically reduces incidence

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Paradoxical worsening at the site of prior infection when immunosuppression is tapered
• Management: treat underlying infection + careful augmented immunosuppression

---

Pretransplant Evaluation: The "Check Before You Cut" Principle

• CMV, EBV, HSV, VZV, HIV, HBV, HCV, syphilis, TB, endemic fungi (based on geography), Chagas (if from endemic area), toxoplasma (for cardiac transplant)
• Active infections must be treated before elective transplant
• Immunizations must be given before transplant - live vaccines are contraindicated after transplant when patient is immunosuppressed

---

Prevention of Infections in Transplant Recipients

1. Minimize exposures: Hand hygiene, avoid sick contacts, food safety (no raw/undercooked meat/eggs), safe water, avoid gardening/landscaping with mold exposure
2. Immunizations: Complete before transplant; live vaccines contraindicated post-transplant
3. Chemoprophylaxis (key examples):

---

CHAPTER 149 - Treatment and Prophylaxis of Bacterial Infections

---

Why This Chapter Matters More Than Any Other

"Among drugs used in human medicine, they [antimicrobials] are distinctive in that their use promotes the occurrence of drug resistance in the pathogens they are designed to treat as well as in other 'bystander' organisms."

• Harrison's 22E

---

How Antibacterial Drugs Work: Mechanisms of Action

1. Inhibition of Cell Wall Synthesis

• Bind to penicillin-binding proteins (PBPs) - enzymes that cross-link peptidoglycan
• Block the final step of peptidoglycan synthesis → cell wall weakening → osmotic lysis
• Bactericidal

• Bind the D-Ala-D-Ala terminus of peptidoglycan precursors
• Block transglycosylase and transpeptidase
• Active against Gram-positive bacteria only
• Vancomycin: critical for MRSA; monitor AUC/MIC for dosing

2. Inhibition of Protein Synthesis (all bacteriostatic unless noted)

• Concentration-dependent killing + significant post-antibiotic effect
• Extended-interval dosing (once daily) is preferred - more effective, potentially less nephrotoxic
• Active vs Gram-negative bacilli (Enterobacterales, Pseudomonas, Acinetobacter)
• Synergistic with beta-lactams against staph and enterococcal endocarditis
• Nephrotoxic and ototoxic - monitor renal function; ototoxicity can be irreversible

3. Inhibition of Folate Synthesis

4. Inhibition of DNA/RNA Synthesis

• Inhibit DNA gyrase and topoisomerase IV - trap enzyme-DNA complexes, generating lethal double-strand DNA breaks
• Bactericidal, concentration-dependent
• Selective for bacterial enzymes (mammalian enzymes structurally different)

• Bind β subunit of bacterial RNA polymerase - block mRNA elongation
• Highly selective for bacterial over mammalian RNA polymerases
• Never use as monotherapy (rapid resistance development)

5. Disruption of Membrane Integrity

• Cationic cyclic polypeptides that disrupt cytoplasmic AND outer membrane (by binding LPS)
• Last-resort drugs for carbapenem-resistant Gram-negative infections
• Significant nephrotoxicity and neurotoxicity

• Lipopeptide; binds Gram-positive cytoplasmic membrane in the presence of calcium
• Creates channel → potassium efflux → membrane depolarization → cell death
• Active against MRSA, VRE, enterococci
• Not used for pneumonia (inactivated by pulmonary surfactant)

---

Key Antibiotic Classes for Clinical Practice

Beta-Lactams in Depth

• Penicillins → narrow spectrum (pen G, pen V) to anti-staphylococcal (oxacillin, nafcillin) to aminopenicillins (ampicillin) to anti-pseudomonal (piperacillin/tazobactam)
• Cephalosporins → generations 1-5 (increasing Gram-negative coverage, with ceftaroline adding MRSA activity in Gen 5)
• Carbapenems → broadest spectrum (imipenem, meropenem, ertapenem); reserved for MDR Gram-negatives
• Monobactams → aztreonam (Gram-negative only; safe in penicillin allergy because different ring structure)

Macrolides

• Azithromycin and clarithromycin: better absorbed and tolerated than erythromycin
• Coverage: Streptococcus pneumoniae, H. influenzae, atypical organisms (Legionella, Mycoplasma, Chlamydophila)
• QT prolongation is a significant concern (check ECG, drug interactions)
• Enterobacterales and Pseudomonas are intrinsically resistant (decreased permeability)

---

The "Axis" of Rational Prescribing

1. Spectrum - Does the drug cover the suspected/confirmed organism?
2. Pharmacokinetics/Pharmacodynamics (PK/PD) - Is the drug getting to the site of infection in adequate concentration?
   • Time-dependent killing (beta-lactams): maximize time above MIC
   • Concentration-dependent killing (aminoglycosides, fluoroquinolones): maximize peak concentration
3. Adverse effects - Is the patient at risk for specific toxicities?
4. Resistance - Will using this drug drive resistance? Is there a narrower alternative?
5. Duration - What is the shortest effective course? Shorter = less resistance, less toxicity, less C. diff

---

CHAPTER 150 - Bacterial Resistance to Antimicrobial Agents

---

Defining Resistance

• Susceptible: MIC predicts a likely clinical response to appropriately dosed drug
• Intermediate susceptible: May respond if drug is given at higher dose or concentrates at site of infection
• Resistant: Poor or no clinical response expected

---

The Three Categories of Resistance Mechanisms

Category 1: Alteration or Bypassing of Drug Targets

• MRSA produces PBP2a (encoded by mecA gene) - a new penicillin-binding protein with very low affinity for all beta-lactams
• Streptococcus pneumoniae acquires mosaic PBP genes with reduced beta-lactam binding

• Methylation of 23S rRNA by erm genes → macrolide, lincosamide, streptogramin B resistance (MLSB phenotype)
• 16S rRNA methylation → aminoglycoside resistance

• Point mutations in gyrA, gyrB, parC, parE genes reduce drug binding
• Each mutation adds one "step" of resistance; multiple mutations lead to high-level resistance

• Vancomycin resistance in enterococci (VRE): VanA/VanB operons reprogram peptidoglycan synthesis to use D-Ala-D-Lac instead of D-Ala-D-Ala → vancomycin can no longer bind
• Sulfonamide/trimethoprim resistance: acquire alternative DHPS or DHFR with low drug affinity

Category 2: Reduced Drug Access to Target

• Reduced OprD porin in Pseudomonas → carbapenem resistance
• Downregulation of OmpF/OmpC in Enterobacterales

• Pump drug out of the cell before it can act
• Can confer resistance to multiple drug classes simultaneously (multi-drug resistance)
• MexAB-OprM, MexXY (Pseudomonas), AcrAB-TolC (Enterobacterales)
• Significant in fluoroquinolone and tetracycline resistance

Category 3: Drug Modification (Enzymatic Inactivation)

• Enzymes that hydrolyze the beta-lactam ring → drug inactivated
• Extended-spectrum beta-lactamases (ESBLs): hydrolyze penicillins AND cephalosporins (including 3rd and 4th generation); common in E. coli, Klebsiella
• AmpC beta-lactamases: chromosomal (inducible) or plasmid; resistant to cephalosporins, not inhibited by clavulanate
• Carbapenemases (KPC, NDM, OXA-48, VIM): hydrolyze carbapenems = last-resort drugs; create "pan-resistant" organisms
  • KPC (Klebsiella pneumoniae carbapenemase) = most common in USA
  • NDM (New Delhi Metallo-beta-lactamase) = common in South Asia
  • OXA-48 = common in Mediterranean

• Acetyltransferases, nucleotidyltransferases, phosphotransferases
• Add chemical groups that prevent binding to 30S ribosome

---

How Resistance Spreads: Genetics of Resistance

1. Spontaneous chromosomal mutations during DNA replication (e.g., quinolone resistance)
2. Horizontal gene transfer (HGT) - acquisition of new genes from other bacteria:
   • Plasmids: self-replicating circular DNA; can carry multiple resistance genes; transferred by conjugation
   • Transposons: "jumping genes" that can move between chromosomes and plasmids
   • Integrons: gene-capture systems that can incorporate many resistance genes at once
   • Bacteriophages: viral transfer (transduction)

---

The CDC's Urgent Threats: Know These

---

Factors That Drive Resistance Amplification

1. Reservoir size - How many resistant organisms exist in the patient population?
2. Selection pressure - Every antibiotic use selects for resistant organisms over susceptible ones
3. Transmission - Resistant strains spread via contaminated hands of HCWs, surfaces, shared equipment (poor infection control)

• Prior antibiotic treatment
• Prior infection with resistant pathogens
• Prior hospitalizations

---

The CDC's Five Core Actions to Combat Resistance

1. Infection prevention and control - hand hygiene, contact precautions, environmental cleaning
2. Antimicrobial stewardship - right drug, right dose, right duration, right indication
3. Diagnostics - better/faster diagnostic methods; prompt culture before antibiotics
4. Vaccines - prevent infections so antibiotics are never needed
5. New antibiotics development - pipeline must keep pace with resistance

---

Multidrug Resistance (MDR) - Clinical Implications

• Ceftazidime-avibactam (for KPC and OXA-48 producers)
• Meropenem-vaborbactam (for KPC)
• Cefiderocol (siderophore cephalosporin; works against most CRE including NDM)
• Imipenem-cilastatin-relebactam
• Aztreonam-avibactam (for NDM, in combination)
• Polymyxins (colistin): last-resort with significant toxicity
• [Per IDSA 2024 guidance on antimicrobial-resistant Gram-negative infections]

---

Summary: How the Four Chapters Connect

Patient enters hospital
        ↓
Chapter 147: HAI prevention - keep them from getting infected
(hand hygiene, device care, isolation, stewardship)
        ↓
If immunosuppressed (transplant patient):
Chapter 148: Know the timeline, know the organism based on 
the net state of immunosuppression and type of transplant
        ↓
When infection occurs:
Chapter 149: Choose the right antibiotic - understand the 
mechanism of action, spectrum, PK/PD, adverse effects
        ↓
When the bug is resistant:
Chapter 150: Understand WHY it's resistant (mechanism) 
and how to overcome it; prevent future resistance through 
stewardship and infection control

---

Key Clinical Pearls for Becoming a Great Doctor

1. Never miss C. diff - it is the most common hospital-acquired infection in the USA; always think of it in patients on antibiotics with diarrhea
2. Transplant timeline - first month = surgical/bacterial; 1-6 months = CMV/PCP/Aspergillus; after 6 months = community-acquired and reactivations
3. Nocardia = always get brain MRI even if there are no neuro symptoms (25% have silent brain abscesses)
4. Penicillin allergy is overdiagnosed - carefully evaluate it; most patients labeled "PCN-allergic" can receive cephalosporins and carbapenems safely
5. Aminoglycosides: once-daily dosing, monitor renal function; never use alone for serious infections except synergy with cell wall agents for endocarditis
6. Daptomycin does not work for pneumonia (inactivated by surfactant) - a famous exam and clinical trap
7. MIC matters - a drug result of "susceptible" means the drug is predicted to work if dosed correctly at the infection site. A "resistant" result is a hard stop.
8. Efflux pumps cause multi-drug resistance with a single genetic change - this is why resistance to fluoroquinolones, tetracyclines, and multiple other drugs can emerge simultaneously in one organism
9. Resistance is a global commons problem - your prescribing today affects what drugs will work in your city in 5 years. Stewardship is not bureaucracy; it is patient care.
10. Polymyxins (colistin) = nephrotoxic, neurotoxic, last resort for pan-resistant Gram-negatives. Using them means the bacteria have already won most battles.

---