What is the best approach to manage infectious diseases in critically ill patients?

Managing Infectious Diseases in Critically Ill Patients

Core Principle: Early Appropriate Antimicrobial Therapy

The single most critical intervention is initiating broad-spectrum empiric antimicrobials within 1 hour of sepsis recognition, as inappropriate initial antibiotic therapy increases mortality up to fivefold in septic shock. 1

• Failure to initiate appropriate empiric therapy substantially increases morbidity and mortality in patients with sepsis and septic shock 1
• Delay in first antibiotic administration is directly associated with increased in-hospital mortality 1
• Inappropriate initial therapy is more common with multidrug-resistant organisms (MDROs), making empiric coverage decisions critical 1

Identifying the Infection Source

Primary Sources in Mechanically Ventilated Patients

Ventilator-associated pneumonia (VAP) is the most ubiquitous cause of fever and infection in mechanically ventilated patients. 2

• VAP incidence increases with intubation duration: approximately 3% per day in the first week, 2% per day in the second week, and 1% per day thereafter 2
• Look for new or progressive radiographic infiltrates, particularly unilateral air bronchograms which have the best predictive value 2
• Risk factors include witnessed aspiration, neurological disease, paralytic agents, nasogastric tubes, enteral feeding, and drugs that raise gastric pH 2

Catheter-Related Bloodstream Infections

• Examine daily for inflammation or purulence at the exit site, along the tunnel, and assess for signs of venous thrombosis or embolic phenomena 2
• If there is evidence of tunnel infection, embolic phenomenon, vascular compromise, or septic shock, remove the catheter immediately and culture it 2
• Obtain at least two blood cultures: one peripherally by venipuncture and one from the suspected catheter 2
• Culture a 5-7 cm intracutaneous segment of short-term catheters; with longer central venous catheters, culture both the intracutaneous segment and tip 2

Intra-Abdominal Infections

• Intra-abdominal infections are among the most common sites requiring source control interventions 2
• Rapidly identify the anatomical source through CT imaging within 12 hours of sepsis diagnosis 2
• Intervention for source control should be undertaken within the first 12 hours when feasible 2
• Undrainable foci such as abscesses or necrotic tissue perpetuate bacterial seeding even with appropriate antibiotics 2

Urinary Tract Infections

• Consider urinary catheters as potential sources, particularly in patients with prolonged catheterization 2
• Two-thirds of patients with nosocomial pneumonia have at least one other focus of infection, usually urinary or catheter-related 2

Diagnostic Workup Algorithm

Blood Cultures and Respiratory Sampling

• Obtain at least two sets of blood cultures before starting antimicrobials if no significant delay occurs 2
• Obtain respiratory secretions via expectoration, nasopharyngeal washing, deep tracheal suctioning, or bronchoscopic sampling 2
• Send samples for Gram stain, culture, and fungal stains 2

Imaging

• Obtain portable chest radiograph in erect sitting position during deep inspiration if possible 2
• Consider CT imaging for posterior-inferior lung bases, which are particularly sensitive for parenchymal or pleural disease 2
• If pleural effusions larger than 10 mm are present, aspirate and send for immediate Gram and fungal stains, culture, and biochemistry 2

Fungal Diagnostics

• Use 1,3-beta-D-glucan (BG) testing with sensitivity of 56-93% and specificity of 71-100% for invasive candidiasis 1
• BG has high negative predictive value, useful for discontinuing empirical antifungal therapy 1
• Combined mannan and anti-mannan IgG assay has 83% sensitivity and 86% specificity for candidemia 1

Empiric Antimicrobial Selection

Risk Stratification for MDROs

Patients with prolonged ICU stays are at highest risk for multidrug-resistant organisms including MRSA, vancomycin-resistant Enterococci, and resistant gram-negative bacilli (Acinetobacter, Pseudomonas). 2

Key risk factors for MDROs include: 1

• Prolonged hospital/chronic facility stay
• Recent antimicrobial use (within previous 3 months)
• Prior hospitalization
• Prior colonization or infection with multidrug-resistant organisms

Empiric Regimen Selection Factors

The empiric regimen must account for: 1

• Anatomic site of infection with respect to typical pathogen profile and antimicrobial penetration
• Prevalent pathogens within the community, hospital, and specific hospital ward
• Resistance patterns of those prevalent pathogens
• Immune defects such as neutropenia, splenectomy, poorly controlled HIV infection
• Patient comorbidities including diabetes, chronic liver or renal failure, presence of invasive devices

Specific Empiric Recommendations

For community-acquired pneumonia requiring ICU admission, use combination therapy with a β-lactam plus either a macrolide or respiratory quinolone, as this reduces mortality compared to monotherapy. 3

For intra-abdominal infections in surgical patients, initial empiric therapy should follow severity-based stratification and cover healthcare-associated pathogens with broad-spectrum carbapenems or extended-range penicillin/β-lactamase inhibitor combinations. 1

• For suspected bacterial co-infection in COVID-19 patients, use beta-lactam providing coverage for S. pneumoniae ± methicillin-susceptible S. aureus (e.g., amoxicillin + clavulanic acid or third-generation cephalosporins) 1
• Avoid macrolides and quinolones due to cardiac side effects when other QT-prolonging agents are used 1

For candidemia, remove indwelling central venous catheters as early as possible in all patients, as CVC removal is associated with higher treatment success and lower mortality rates. 1

• CVCs should be urgently removed in patients with septic shock 1
• Initiate systemic antifungal therapy with echinocandins, azoles, or polyenes based on severity and risk factors 1

Hemodynamic Resuscitation

Restore mean arterial pressure to 65-70 mmHg using norepinephrine as the first-line vasopressor agent. 1

• Initial hemodynamic resuscitation should be achieved within 3 hours 1
• Norepinephrine is more efficacious than dopamine and more effective for reversing hypotension in septic shock 1
• Septic shock is defined by requirement for vasopressors to maintain MAP ≥65 mmHg and serum lactate >2 mmol/L in the absence of hypovolemia 1

Antimicrobial Stewardship and De-escalation

De-escalation Strategy

Implement de-escalation therapy consisting of initial wide-spectrum antimicrobials followed by reassessment when culture results are available. 1

• De-escalation is a protective factor independently associated with reduced in-hospital mortality 1
• De-escalation is feasible in patients with polymicrobial infections such as healthcare-associated intra-abdominal infections 1
• Positive cultures in critically ill patients may represent contamination; antibiotic stewardship requires careful interpretation 1

Duration of Therapy

For intra-abdominal infections with adequate source control, limit total antimicrobial therapy to 4-7 days. 4

• Short courses of 3-5 days are appropriate for complicated intra-abdominal infections with adequate source control 4
• Longer durations have not been associated with improved outcomes and increase antimicrobial resistance risk 4
• If there are no signs of persistent leukocytosis or fever, shorten antimicrobial therapy for patients demonstrating positive response 1

Transition to Oral Therapy

Criteria for transitioning to oral step-down therapy: 4

• Patient should be afebrile with normalizing white blood cell count
• Patient tolerating oral diet
• Adequate source control achieved
• Microbiologic susceptibility confirmed
• Hemodynamically stable without ongoing septic shock or organ dysfunction

Pharmacokinetic Considerations in Critical Illness

Renal Dose Adjustments

For hemodialysis patients, administer β-lactam antibiotics at full milligram dose after each hemodialysis session to prevent drug removal during the session. 3

• Never administer antibiotics before hemodialysis, as this results in immediate drug removal and subtherapeutic levels 3
• For levofloxacin, use 50% of normal dose every 48 hours in end-stage renal disease, administered after hemodialysis 3
• Consider serum drug concentration monitoring for antibiotics in severe renal impairment 3

Dosing Optimization

• Use once-a-day administration (where applicable) or continuous administration of beta-lactam antibiotics to decrease personal protective equipment use 1
• Ensure attainment of pharmacokinetics/pharmacodynamics targets through adequate dosing and administration schemes 1

Critical Pitfalls to Avoid

Diagnostic Pitfalls

• Clinical diagnosis using fever, leukocytosis, purulent sputum, and new infiltrates is too nonspecific in intubated patients 2
• Absence of infiltrates on portable chest radiograph does not exclude pneumonia, abscess, or empyema 2
• Immunocompromised patients may have severe pneumonia without fever, cough, sputum production, or leukocytosis 2
• Only one-quarter of VAP cases are associated with bacteremia, so negative blood cultures do not rule out pneumonia 2

Treatment Pitfalls

• The most critical factor in sepsis recurrence is failure to identify and control the anatomical source within 12 hours 2
• Infected intravascular devices remaining in place serve as persistent sources of bacteremia 2
• Do not continue antibiotics beyond 7 days if source control is adequate and clinical signs have resolved 4
• Do not use standard Bactrim dosing without renal adjustment in renal impairment, as this leads to drug accumulation and toxicity 4

Drug Interaction Pitfalls

• Monitor prothrombin time during ceftriaxone treatment in patients with impaired vitamin K synthesis or low vitamin K stores 5
• Concomitant use of ceftriaxone with Vitamin K antagonists may increase bleeding risk; monitor coagulation parameters frequently 5
• Consider more frequent INR monitoring (every 2-3 days) during acute pneumonia treatment in patients on warfarin 3

Infection Control for Highly Pathogenic Diseases

Isolation Precautions

For highly infectious diseases, admit patients to high-level isolation units with negative pressure rooms, N95 or FFP2 masks for healthcare workers, and closed doors. 1

• Apply standard precautions including hand hygiene, personal protective equipment, prevention of needle sticks, environment cleaning, and appropriate waste handling 1
• Use droplet precautions with surgical masks for healthcare workers within 1-2 meters of the patient 1
• Minimize manual ventilation duration during resuscitation procedures 1
• Perform endotracheal intubation with rapid sequence induction by the most skilled person available wearing personal protective equipment 1

Laboratory Sampling

• Perform sampling in the isolation room of the emergency department or in the high-level isolation unit 1
• Use point-of-care bedside laboratory tests if possible 1
• Perform all analyses in a biosafety level 3/4 laboratory if point-of-care testing unavailable 1
• Once inactivated via formalin, samples can be tested in routine laboratory 1

Prevention Strategies

VAP Prevention

• Use orotracheal rather than nasotracheal intubation 2
• Maintain semi-recumbent positioning (30-45 degrees) unless contraindicated 2
• Consider subglottic secretion drainage and oral chlorhexidine gluconate for oropharyngeal decontamination 2

General ICU Infection Prevention

• Apply standard measures to prevent ventilator-associated pneumonia and other healthcare-associated infections according to local and individual patient-level resistance 1
• Systematically apply standard precautions and cough and respiratory etiquette 1
• Ensure adequate hydration in patients receiving ceftriaxone to prevent urolithiasis 5