This study guide provides a concise summary of key concepts from each lecture module. For detailed explanations, clinical images, and references, consult the full lecture handouts on padovaid.com.
Principles of Antibiotic Therapy
The Antibiotic Resistance Crisis
- Antimicrobial resistance (AMR) is a global emergency; the WHO Priority Pathogen List identifies critical threats including carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and ESBL/carbapenemase-producing Enterobacterales
- Resistance rates are particularly high in southern and eastern Europe (Italy included) for MRSA, CRE, and MDR Acinetobacter
- The antibiotic discovery pipeline is slowing: antibiotics are a societal trust requiring stewardship
The Ten Principles of Effective Antibiotic Therapy
- Develop an accurate differential diagnosis — The medical history is 80% of diagnosis. Positive cultures are not always proof of infection (consider colonization vs. contamination)
- Only use antibiotics when they alter the clinical course — Source control (e.g., drainage, debridement) is often more important than antibiotics alone
- Empirically target microbes in the differential diagnosis — Know the spectrum of activity and local resistance patterns; distinguish community-acquired vs. nosocomial pathogens
- Lower the threshold for empirical therapy in critically ill patients — Antibiotic timing is critical in septic shock; each hour of delay increases mortality
- Host factors affect the spectrum of empirical therapy — Immunocompromise broadens the differential; corticosteroids are the “credit cards” of immunosuppressive therapy
- Use PK/PD principles to optimize treatment selection and dosing — Key variables: volume of distribution (Vd), clearance, and site-specific penetration. ICU underdosing is the rule, not the exception (DALI study)
- De-escalate therapy based on microbiology and biomarker response — Use CRP and procalcitonin trends to guide de-escalation; interpret S/I/R within EUCAST or CLSI context
- If therapy isn’t working, consider source control or alternative diagnosis before assuming resistance — Biofilms are a key source of antibiotic failure. Remember the FAIL mnemonic: Focus (wrong site), Antimicrobial (wrong drug/dose), Immune (host factors), Locus (undrained source)
- Distinguish new infection from failure of initial therapy — Superinfection or a second source requires reassessment, not simply broader coverage
- Shorter is better — Duration should be evidence-based; short-course therapy is noninferior for many infections
PK/PD Indices
- Time-dependent killing (β-lactams, carbapenems): Optimize ƒT>MIC — extended/continuous infusion improves target attainment
- Concentration-dependent killing (aminoglycosides, fluoroquinolones): Maximize Cmax/MIC or AUC/MIC
- AUC/MIC-dependent (vancomycin, fluoroquinolones): Total drug exposure over 24 hours relative to MIC determines efficacy
Extended or continuous infusion of β-lactams improves the probability of achieving PK/PD targets, particularly in critically ill patients with augmented renal clearance or infections with organisms near the MIC breakpoint.
Common Myths
- Myth: Bactericidal > bacteriostatic — In most clinical scenarios, there is no proven superiority of bactericidal agents; the distinction is less clinically meaningful than PK/PD optimization
- Myth: Oral therapy is inferior to IV — For well-absorbed oral agents (e.g., fluoroquinolones, linezolid, TMP-SMX), oral therapy achieves equivalent tissue concentrations
Antibiotic Allergies
Immunological Mechanisms (Gell and Coombs Classification)
| I |
IgE-mediated (immediate) |
Minutes to 1 hour |
Anaphylaxis, urticaria, angioedema |
| II |
Cytotoxic (IgG/IgM) |
Hours to days |
Hemolytic anemia, thrombocytopenia |
| III |
Immune complex |
1–3 weeks |
Serum sickness, drug fever |
| IV |
Delayed T-cell mediated |
Days to weeks |
Maculopapular rash, SJS/TEN, DRESS |
Severe Cutaneous Adverse Reactions (SCAR)
- Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN): Mucocutaneous necrosis with epidermal detachment; SJS <10% BSA, TEN >30% BSA. Medical emergency with high mortality
- DRESS (Drug Rash with Eosinophilia and Systemic Symptoms): Rash + fever + eosinophilia + internal organ involvement (liver, kidneys); onset 2–8 weeks after drug initiation
- AGEP (Acute Generalized Exanthematous Pustulosis): Rapid onset of sterile pustules on erythematous base
Any patient with a history of SCAR (SJS/TEN, DRESS, AGEP) to a specific drug must never be re-exposed to that drug. Desensitization is contraindicated for SCAR reactions.
Penicillin Allergy: Epidemiology and Myths
- ~10% of patients report a penicillin allergy, but >90% are not truly allergic when properly evaluated
- Patients labelled “penicillin-allergic” receive broader-spectrum, more expensive, and more toxic alternatives (vancomycin, fluoroquinolones, carbapenems) — leading to worse outcomes and increased resistance
- IgE-mediated penicillin allergy wanes over time: ~80% of patients lose sensitivity within 10 years
PEN-FAST Risk Stratification
The PEN-FAST score stratifies patients by allergy risk based on history:
| Penicillin reaction ≤5 years ago |
2 |
| Exact features: anaphylaxis/angioedema/severe cutaneous |
2 |
| Not treated/unknown treatment |
1 |
| First dose |
0 |
| After multiple doses (sensitization) |
0 |
- Score 0: Low risk → Direct oral amoxicillin challenge
- Score 1–2: Low risk → Consider direct challenge
- Score 3: Medium risk → Skin testing ± graded challenge
- Score ≥4: Higher risk → Formal allergy evaluation with skin testing
Diagnostic Testing and Drug Challenges
- Direct oral amoxicillin challenge: Safe for low-risk patients (PEN-FAST 0–2); the PALACE trial demonstrated safety with <5% mild reaction rate
- Skin testing: Uses major (penicilloyl-polylysine) and minor determinants; negative predictive value >95%
- Desensitization: Indicated only when no alternative antibiotic exists and the patient has a confirmed IgE-mediated allergy; involves graded dose escalation under monitoring
Cross-Reactivity Between β-Lactams
- The historical 10% cross-reactivity rate between penicillins and cephalosporins is incorrect (based on early, impure preparations)
- True cross-reactivity is determined by shared R1 side chains, not the β-lactam ring itself
- Carbapenems: Cross-reactivity with penicillins is <1%; safe in most penicillin-allergic patients
- Monobactams (aztreonam): No cross-reactivity with penicillins (except with ceftazidime, which shares a side chain)
Fever of Unknown Origin (FUO)
Part 1: Temperature Regulation and Pathogenesis of Fever
Normal Body Temperature
- Wunderlich’s 37°C (98.6°F) is an overestimate; modern mean oral temperature is ~36.8°C (98.2°F)
- Evidence-based fever thresholds: Early morning oral ≥37.2°C or any oral ≥37.8°C
- Circadian rhythm: Nadir 4–6 AM, zenith 4–6 PM, amplitude ~0.5°C
- Elderly patients may fail to mount a febrile response to serious infection
Fever vs. Hyperthermia
| Set point |
Elevated |
Normal |
| Mechanism |
Pyrogen-mediated PGE₂ raises thermostat |
Heat generation exceeds dissipation |
| Patient sensation |
Chills, shivering |
Feels hot, seeks cooling |
| Antipyretics |
Effective |
Ineffective |
| External cooling |
Counterproductive (triggers shivering) |
Essential treatment |
| Examples |
Infection, inflammation |
Heat stroke, malignant hyperthermia, anticholinergic toxicity |
Do NOT apply cooling blankets or ice baths to febrile patients with infection. This triggers shivering, increases metabolic heat production, and worsens discomfort. Use antipyretic medications instead. Reserve external cooling for true hyperthermia.
The Febrile Cascade
Pathogen-associated molecular patterns (PAMPs) → macrophage activation → release of pyrogenic cytokines (IL-1, IL-6, TNF-α, IFN-α) → PGE₂ production in hypothalamus → EP3 receptor activation on warm-sensitive neurons → thermoregulatory set point elevation → fever
Biologic Benefits of Fever
- Phylogenetically conserved across vertebrates (significant survival advantage)
- Reduces bacterial replication; enhances phagocytosis, T-cell proliferation, and antibody generation
- Hypothermic critically ill patients have worse outcomes than febrile patients
Part 2: Fever of Unknown Origin
Definitions
- Petersdorf-Beeson (1961): Fever >38.3°C on several occasions, lasting >3 weeks, undiagnosed after 1 week of hospital investigation
- Durack-Street Classification (1991): Four categories — Classic FUO, Nosocomial FUO, Neutropenic FUO, HIV-associated FUO
Etiologic Categories and Trends
| Infections |
40–50% |
25–35% |
| Noninfectious inflammatory diseases (NIID) |
15–20% |
30–40% |
| Malignancies |
15–20% |
10–15% |
| Undiagnosed |
10–15% |
15–25% |
- Infections have declined due to better imaging (CT, PET/CT) and molecular diagnostics
- NIID have increased proportionally (giant cell arteritis, adult-onset Still disease)
- In developing countries, infections still account for 50–70% of FUO
FUO in Special Populations
- Children: Kawasaki disease (urgent — risk of coronary artery complications), EBV, osteomyelitis, juvenile idiopathic arthritis
- Elderly: Giant cell arteritis and polymyalgia rheumatica predominate; undiagnosed FUO in the elderly carries poor prognosis
- Returned travelers: Malaria is the #1 cause (27–48%); also dengue, typhoid, hepatitis A/E, amebic liver abscess
Fever Patterns
| Continuous/sustained |
<0.5°C variation |
Pneumonia, rickettsiosis, typhoid, falciparum malaria |
| Intermittent/quotidian |
Daily spikes with return to normal |
Abscesses, endocarditis, osteomyelitis |
| Tertian/quartan |
Every 48h/72h |
P. vivax/ovale (tertian), P. malariae (quartan) |
| Saddle-back (biphasic) |
Two fever phases with afebrile interval |
Dengue, yellow fever |
| Pel-Ebstein |
Weekly cycles of fever/afebrile periods |
Hodgkin disease, brucellosis |
Diagnostic Approach
- History and physical (repeated) — travel, occupation, animal exposure, medications, family history
- Laboratory: CBC, CMP, LFTs, ESR/CRP, blood cultures (×3), directed serology
- Imaging: CT abdomen/pelvis (most important modality); ¹⁸FDG-PET/CT (sensitivity 86–98%, very useful early)
- Invasive procedures: Bone marrow biopsy (yield ~25%), lymph node biopsy, liver biopsy as directed
Empiric antimicrobial therapy should generally be withheld in FUO until a diagnosis is established, as it may mask underlying pathology. Exceptions: febrile neutropenia, suspected miliary TB, and suspected temporal arteritis (start corticosteroids immediately to prevent vision loss).
Intra-abdominal Infections
Part 1: Peritonitis
Classification
| Primary (spontaneous) |
No surgical source; monomicrobial |
~1% of peritonitis |
| Secondary |
Identifiable source (perforation, ischemia) |
80–90% |
| Tertiary |
Persistent/recurrent after treatment; often less virulent organisms |
ICU patients |
- Complicated infections: Extend beyond the organ of origin with peritoneal spillage
- Uncomplicated: Contained within a single organ
Microbiology
- Primary peritonitis: Monomicrobial in >95% of cases; gram-negative enteric bacteria predominate (69%, mainly E. coli) in cirrhotic patients
- Secondary peritonitis: Polymicrobial — E. coli, Klebsiella, Bacteroides fragilis, streptococci, enterococci; Candida in ~20% of acute perforations
- CAPD peritonitis: Gram-positive organisms 60–80% (primarily coagulase-negative staphylococci)
Primary Peritonitis (Spontaneous Bacterial Peritonitis)
- Occurs primarily in cirrhotics with ascites
- Diagnosis: Ascitic fluid PMN ≥250 cells/mm³; inoculate blood culture bottles at bedside for improved sensitivity
- Albumin supplementation: 1.5 g/kg within 6 hours + 1 g/kg on day 3 significantly reduces mortality (16% vs. 35%) in patients with renal impairment
- Prophylaxis: Short-term (ceftriaxone during GI hemorrhage) and long-term (fluoroquinolone or TMP-SMX) for patients with prior SBP or high-risk features
Pathophysiology of Secondary Peritonitis
- Peritoneal contamination → protein-rich fluid exudation → PMN recruitment → fibrin deposition → attempts at localization
- Outcomes: Spontaneous resolution, abscess formation, or diffuse peritonitis if defenses are overwhelmed
Treatment Principles
- Source control is the cornerstone — surgical/percutaneous drainage, repair of perforation
- Empiric antibiotics covering gram-negatives, anaerobes, ± enterococci based on risk
- Duration: Typically 4–7 days after adequate source control for community-acquired infections
Part 2: Appendicitis and Hepatobiliary Infections
Appendicitis
- Most common surgical emergency of the abdomen; lifetime risk ~7–9%
- Classic presentation: Periumbilical pain migrating to RLQ (McBurney point) over 6–24 hours
- Examination signs: Rovsing sign, psoas sign, obturator sign
- Classic pathogenesis: Luminal obstruction → mucus accumulation → ischemia → microbial invasion → perforation. However, fecaliths are found in a minority of cases; dysbiosis may be an alternative mechanism
- CT with contrast: Sensitivity and specificity >95%
- Management: Surgery (laparoscopic appendectomy) remains standard; antibiotic-first strategies increasingly used for uncomplicated appendicitis
Liver Abscess
Amebic vs. Pyogenic:
| Etiology |
Entamoeba histolytica |
Polymicrobial or Klebsiella pneumoniae |
| Geography |
Tropics, Mexico, Latin America |
Worldwide |
| Number |
Usually solitary, right lobe |
Often multiple |
| Treatment |
Metronidazole + luminal agent |
Drainage + prolonged antibiotics |
- Epidemic K. pneumoniae pyogenic liver abscess: Hypervirulent strains causing community-acquired disease; associated with metastatic complications (endophthalmitis, CNS abscess)
Biliary Tract Infections
- Cholecystitis: Inflammation of the gallbladder, usually from cystic duct obstruction
- Cholangitis: Charcot triad (fever + jaundice + RUQ pain); Reynolds pentad adds altered mental status and hypotension
- Biliary drainage is the primary therapeutic intervention; antibiotics are adjunctive
The Immunocompromised Host
The Net State of Immunosuppression
A composite of host factors, underlying disease, treatment effects, and comorbidities that determines overall infection risk. Includes:
- Disease severity and duration
- Immunosuppressive medications (type, dose, duration)
- Prior treatments (fludarabine, ATG, alemtuzumab have prolonged effects)
- Comorbidities (diabetes, organ dysfunction, malnutrition)
- Coinfections (CMV, EBV, HIV)
- Microbiome disruption
Types of Immunosuppression and Associated Pathogens
| Neutropenia |
AML induction, HSCT |
Gram-negative bacilli, S. aureus, Candida, Aspergillus |
| T-cell deficiency |
Allo-HSCT, calcineurin inhibitors, CAR-T |
CMV, HSV/VZV, Pneumocystis, Aspergillus, Cryptococcus, TB, Toxoplasma |
| Humoral/B-cell |
Rituximab, CAR-T, CLL, myeloma |
S. pneumoniae, H. influenzae, HBV reactivation, norovirus |
| Asplenia |
Splenectomy, sickle cell |
S. pneumoniae, H. influenzae, N. meningitidis, Capnocytophaga |
| Combined defect |
Allo-HSCT + GVHD |
All of the above |
Timing of Infections Post-Transplant
| 0–30 days |
Surgical site infections, gram-negative bacteremia, Candida, HSV reactivation |
| 30–180 days |
CMV, Pneumocystis, Aspergillus, EBV/PTLD, hepatitis B/C |
| >180 days |
Community-acquired infections, late CMV, VZV, Cryptococcus, PML |
Prevention Strategies
- Pre-transplant screening: TB (IGRA), HBV, HCV, HIV, Strongyloides, endemic fungi, VZV serology
- TMP-SMX prophylaxis: Cornerstone — covers Pneumocystis, Toxoplasma, Nocardia, and many bacteria
- Antiviral prophylaxis: Letermovir (CMV in allo-HSCT), acyclovir/valacyclovir (HSV/VZV)
- Antifungal prophylaxis: Risk-stratified — posaconazole for high-risk (AML, allo-HSCT, GVHD); fluconazole for intermediate-risk
- Vaccination: Complete before immunosuppression when possible; HSCT recipients must be fully revaccinated; live vaccines contraindicated during immunosuppression
Febrile Neutropenia
Definitions and Risk
- Neutropenia: ANC <500 cells/mm³ (or <1000 and expected to decline)
- Febrile neutropenia: Single temperature ≥38.5°C or ≥38.0°C sustained for ≥1 hour during neutropenia
- Medical emergency: Any delay in antibiotics increases mortality
Fever may be the only sign of life-threatening infection in a severely neutropenic patient. Classic inflammatory signs (fluctuance, exudate, purulent sputum, pyuria) are markedly attenuated or absent at ANC <100 cells/mm³.
Risk by Disease Type
| Acute myeloid leukemia (AML) |
Highest |
| High-risk ALL, relapsing leukemia |
High |
| Low-risk ALL, CLL, myeloma |
Moderate |
| Non-Hodgkin lymphoma |
Lower |
| Solid tumors |
Lowest |
Phases of Infection During Neutropenia
- Phase I (days 1–10): CoNS, Enterobacterales, viridans streptococci, HSV, ± Candida
- Phase II (days 10–27): Add MRSA, VRE, resistant gram-negatives, Stenotrophomonas
- Phase III (>27 days): Add invasive molds (Aspergillus, Mucorales, Fusarium)
Changing Epidemiology
- Historical gram-positive predominance shifting toward gram-negative resurgence
- Resistant organisms of concern: ESBL-producing Enterobacterales, CRE, MDR P. aeruginosa, MRSA, VRE
- Colonization with resistant bacteria is the strongest predictor of resistant infection
Prophylaxis
- Antibacterial: Fluoroquinolone prophylaxis is controversial (reduces BSI but selects for resistance; no clear mortality benefit)
- Antifungal: Posaconazole for high-risk patients (AML/MDS induction, allo-HSCT); reduces IFD from 8% to 2% (NNT = 16)
- Pneumocystis: TMP-SMX for ALL, fludarabine, alemtuzumab, idelalisib, or corticosteroids ≥10–20 mg/day × 4 weeks
- Antiviral: Acyclovir/valacyclovir for HSV/VZV-seropositive patients; screen ALL patients for HBV before chemotherapy
Risk Stratification
MASCC Score (for identifying low-risk patients): Score >21 = Low risk. Variables include burden of illness, hypotension, COPD, solid tumor, outpatient status, dehydration, age.
CISNE Score (solid tumors, clinically stable): Score ≥3 = High risk.
Empiric Therapy
| Escalation |
Anti-pseudomonal β-lactam monotherapy (pip-tazo, cefepime) |
Stable, low MDR risk |
| De-escalation |
Carbapenem ± aminoglycoside |
Unstable, MDR colonization, sepsis |
- Add vancomycin for: catheter infection, skin/soft tissue, MRSA colonization, severe sepsis
- Add antifungal if fever persists ≥4 days on adequate antibiotics
- Extended/continuous infusion of β-lactams improves PK/PD target attainment
Duration and Response Assessment
- FUO in neutropenia, afebrile ≥48–72 hours, clinically stable: Consider stopping antibiotics
- Documented infection: Treat for standard duration based on pathogen and site
- Persistent fever ≥4 days: CT chest, add mold-active antifungal, reassess
Infectious Diarrhea
Fundamental Classification
| Pathogenesis |
Toxin-mediated, no invasion |
Mucosal invasion, tissue destruction |
| Stool |
Watery, large-volume |
Bloody, mucoid, small-volume |
| Fever |
Absent or low-grade |
Often prominent |
| Fecal leukocytes |
Absent |
Present |
| Key pathogens |
ETEC, V. cholerae, rotavirus, norovirus |
Shigella, Campylobacter, Salmonella, STEC |
| Primary treatment |
Rehydration |
Rehydration + consider antibiotics |
Viral Pathogens
Rotavirus
- Most significant cause of severe pediatric diarrhea worldwide
- Pathophysiology: Villus blunting + brush border enzyme deficiency + NSP4 enterotoxin
- Two vaccines: RotaTeq (pentavalent), Rotarix (monovalent); must be given before 32 weeks of age
- SCID is a contraindication to vaccination
Norovirus
- Leading cause of epidemic gastroenteritis in adults; classic outbreaks on cruise ships, hospitals, long-term care facilities
- Self-limiting (48–72 hours); highly contagious via fomites and aerosolized particles
- No vaccine or specific treatment
Protozoan Pathogens
- Cryptosporidium: Second most common cause of noninflammatory diarrhea worldwide; self-limiting in immunocompetent; chronic and severe in AIDS (CD4 <100); treatment: nitazoxanide + immune reconstitution
- Giardia: Leading parasitic cause of chronic diarrhea; diagnosis by stool antigen or microscopy (multiple specimens needed); treatment: tinidazole (>90% cure) or metronidazole (~70% cure)
Key Bacterial Pathogens
Pathogenic E. coli
- ETEC: Most common cause of traveler’s diarrhea; heat-labile (LT) and heat-stable (ST) enterotoxins
- STEC (O157:H7): Hemorrhagic colitis → risk of hemolytic-uremic syndrome (HUS); antibiotics are contraindicated (may increase HUS risk)
Campylobacter jejuni
- Leading bacterial cause of gastroenteritis in developed countries; reservoir: poultry
- Complications: Guillain-Barré syndrome (~1 in 1,000 infections), reactive arthritis
Salmonella
- Non-typhoidal: Self-limiting gastroenteritis; bacteremia risk in extremes of age and immunocompromised
- Typhoid fever (S. typhi): Sustained fever, relative bradycardia, rose spots, step-ladder fever pattern
Shigella
- Bacillary dysentery; very low infectious dose (10–100 organisms); humans are the only reservoir
- S. dysenteriae produces Shiga toxin — most severe disease
Vibrio cholerae
- Severe secretory diarrhea (“rice-water stools”); cholera toxin activates adenylyl cyclase (↑cAMP) → massive fluid secretion
- Treatment: Aggressive rehydration (ORS or IV); antibiotics shorten duration
Traveler’s Diarrhea
- Attack rate 5–50% depending on destination; ETEC most common cause
- Prevention: Food and water precautions; bismuth subsalicylate provides modest protection
- Self-treatment: Azithromycin (preferred) or fluoroquinolone × 3 days; avoid loperamide in bloody diarrhea
Treatment Principles
- ORS is the cornerstone: Exploits sodium–glucose cotransport (SGLT1) — effective for >90% of acute diarrhea
- Zinc supplementation (children): Reduces duration and severity; WHO-recommended
- Antimotility agents (loperamide): Avoid in inflammatory/bloody diarrhea or STEC
- Specific antimicrobial therapy guided by pathogen identification
Malaria
Species and Key Features
| P. falciparum |
48h (tertian) |
Most severe/fatal; cytoadherence (PfEMP-1); no hypnozoites |
| P. vivax |
48h (tertian) |
Hypnozoites (relapses); infects reticulocytes; Duffy antigen receptor |
| P. ovale (curtisi/wallikeri) |
48h (tertian) |
Two sibling species; hypnozoites; mild disease |
| P. malariae |
72h (quartan) |
Can persist for decades; prefers older erythrocytes |
| P. knowlesi |
24h (quotidian) |
Zoonotic (macaques); Southeast Asia; can cause severe disease |
Epidemiology
- 263 million cases and 597,000 deaths globally (2023); 94% of cases and 95% of deaths in Africa
- Transmitted by female Anopheles mosquitoes; also via transfusion, needles, congenital
- Highest risk: Young children and pregnant women in endemic areas
Pathophysiology of P. falciparum
Three mechanisms drive pathology:
- Erythrocyte loss → anemia
- Sequestration — PfEMP-1 on infected RBCs binds endothelial receptors (CD36, ICAM-1, EPCR, CSA) causing microvascular obstruction. EPCR binding → cerebral malaria; CSA binding → placental malaria
- Inflammatory cascades → multi-organ dysfunction
Rosetting (iRBCs binding uninfected RBCs) and platelet-mediated clumping further obstruct microvessels.
Host Genetic Protection
- Sickle cell trait (HbAS): 60–90% protection against severe P. falciparum
- G6PD deficiency: May protect but increases hemolytic risk with primaquine/tafenoquine
- Blood group O: Reduced rosetting and severe disease
- Duffy-negative: Relative resistance to P. vivax
Clinical Spectrum
- Uncomplicated: Acute febrile illness (often >40°C) with headache, myalgia, nausea; absence of respiratory symptoms is characteristic
- Severe malaria (medical emergency): Cerebral malaria (coma), severe anemia, metabolic acidosis, hypoglycemia, renal failure, pulmonary edema/ARDS, shock
- All nonimmune patients with P. falciparum should be hospitalized
All travelers with fever within 3 months of visiting an endemic area should be considered to have malaria until proven otherwise. Patients presenting within 7 days of entering an endemic area are unlikely to have malaria.
Laboratory Diagnosis
| Thick and thin blood smears (gold standard) |
Speciation, quantification |
Requires expert microscopist |
| Rapid diagnostic tests (RDTs) |
Fast, point-of-care |
No quantification; HRP-2 deletions compromise sensitivity for P. falciparum |
| PCR |
Most sensitive; speciation |
Slow turnaround; not suitable for acute management |
- Thrombocytopenia is the most consistent ancillary finding (sensitivity ~60%) — consider malaria in any thrombocytopenic febrile returned traveler
Treatment
- Uncomplicated malaria (all species): Artemisinin-based combination therapy (ACT) — artemether-lumefantrine (Coartem) is the standard
- Chloroquine-sensitive non-falciparum: Chloroquine remains an option
- Radical cure for P. vivax/P. ovale: Primaquine or tafenoquine to eliminate hypnozoites (requires G6PD testing — contraindicated in deficiency and pregnancy)
- Severe malaria: IV artesunate is the drug of first choice; follow with full course of ACT when patient can take oral medication
Prevention
- Chemoprophylaxis for travelers: Atovaquone-proguanil, doxycycline, or tafenoquine (all areas); mefloquine as alternative
- Non-pharmacologic: Insecticide-treated bed nets (LLINs), DEET-based repellents
- Vaccines: RTS,S/AS01 (Mosquirix) and R21/Matrix-M approved for children in endemic regions
Invasive Fungal Infections (IFI)
Global Burden
1 million deaths annually from invasive fungal infections — equivalent to tuberculosis
- WHO Fungal Priority Pathogens List (2022): Critical priority — Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, Candida albicans
Antifungal Classes
| Polyenes |
Ergosterol binding → pore formation |
Amphotericin B (liposomal) |
Broadest: yeasts + molds + Mucorales |
| Azoles |
Inhibit lanosterol 14-α-demethylase |
Fluconazole, voriconazole, posaconazole, isavuconazole |
Variable; voriconazole is first-line for aspergillosis |
| Echinocandins |
Inhibit β-1,3-glucan synthase |
Caspofungin, micafungin, anidulafungin |
Candida (first-line) + Aspergillus; no Cryptococcus or Mucorales activity |
- Echinocandins: No activity against Cryptococcus or Mucorales; poor CNS/eye/urine penetration
- Fluconazole: No mold activity; C. krusei intrinsically resistant; C. glabrata dose-dependent susceptibility
- Voriconazole: No Mucorales activity
- Amphotericin B: Broadest spectrum but significant nephrotoxicity (liposomal formulation preferred)
Invasive Candidiasis
- Most common IFI in hospitalized patients; blood cultures detect only ~50% of cases
- Species shift: C. albicans decreasing; C. glabrata, C. parapsilosis, C. auris increasing
- Risk factors: Central venous catheters, TPN, broad-spectrum antibiotics, ICU >3 days, abdominal surgery
- Treatment: Echinocandin first-line (hemodynamically unstable or prior azole exposure); step down to fluconazole if susceptible species and clinically stable
- Source control: CVC removal improves outcomes
- All patients with candidemia need dilated funduscopic exam for endophthalmitis (echinocandins don’t penetrate vitreous — need fluconazole/voriconazole for ocular disease)
- Duration: 14 days after first negative blood culture
Cryptococcosis
- ~220,000 cases and 180,000 deaths annually; leading cause of meningitis in HIV-infected adults in Africa
- Two species: C. neoformans (immunocompromised, worldwide) and C. gattii (immunocompetent, Pacific NW/tropics)
- Virulence factors: Polysaccharide capsule (anti-phagocytic), melanin, phospholipase, urease
- Diagnosis: India ink (low sensitivity), cryptococcal antigen (CrAg) in serum/CSF (highly sensitive), CSF culture; elevated opening pressure is common and must be managed
- AMBITION Trial: Single high-dose liposomal amphotericin B (10 mg/kg) + flucytosine + fluconazole shown noninferior to standard 7-day amphotericin; now WHO-recommended
- Management of elevated ICP: Serial therapeutic lumbar punctures or lumbar drain — critical intervention; aim to reduce opening pressure by ≥50% or to <20 cm H₂O
Invasive Aspergillosis
- Most common invasive mold infection in immunocompromised patients
- Major risk factors: Prolonged neutropenia (>10 days), allogeneic HSCT, high-dose corticosteroids, GVHD
- Pathogenesis: Airborne conidia → bronchial colonization → angioinvasion → hemorrhagic infarction and dissemination
- Diagnosis:
- CT: Halo sign (ground-glass surrounding nodule) early; air-crescent sign late (during neutrophil recovery)
- Galactomannan (serum/BAL): Highly specific for Aspergillus; serum sensitivity improved with serial monitoring
- β-D-glucan: Pan-fungal; many false positives
- Treatment: Voriconazole or isavuconazole first-line; liposomal amphotericin B as alternative
- Prognosis depends on immune recovery; mortality 30–50% even with treatment
Mucormycosis
- Caused by Rhizopus, Mucor, Rhizomucor, Lichtheimia species
- Risk factors: Diabetic ketoacidosis, deferoxamine therapy, prolonged neutropenia, corticosteroids, breakthrough on voriconazole (no Mucorales activity)
- Clinical forms: Rhinocerebral (most common), pulmonary, cutaneous, disseminated
- Diagnosis: Tissue biopsy showing wide, ribbon-like, pauciseptate hyphae with 90° branching; galactomannan and β-D-glucan are typically negative
- Treatment: Liposomal amphotericin B + aggressive surgical debridement; isavuconazole or posaconazole as step-down or alternatives
- Prognosis: Mortality 40–80% depending on site and underlying condition; early diagnosis and surgery are critical
Antifungal Toxicities
- Amphotericin B: Nephrotoxicity (liposomal formulation reduces risk), infusion reactions (premedicate), electrolyte wasting (K⁺, Mg²⁺)
- Azoles: Hepatotoxicity (monitor LFTs); QTc prolongation; visual disturbances (voriconazole); CYP450 drug interactions (posaconazole and voriconazole are strong CYP3A4 inhibitors — critical interaction with calcineurin inhibitors, sirolimus, venetoclax, vinca alkaloids); TDM recommended for voriconazole and posaconazole
- Echinocandins: Generally well-tolerated; liver enzyme elevation; infusion reactions (histamine-mediated)
For full lecture content, clinical images, and references, visit www.padovaid.com.