1. Sepsis & Septic Shock

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains the leading cause of death in ICUs worldwide. This section integrates the Sepsis-3 definitions (2016), Surviving Sepsis Campaign (SSC) 2021 Guidelines, and landmark RCTs through 2025.

▼1.1 Definitions — Sepsis-3 Criteria

The Sepsis-3 Task Force (JAMA 2016) redefined sepsis, retiring SIRS criteria due to poor specificity.

Term	Definition	Key Criteria
Sepsis	Life-threatening organ dysfunction from dysregulated host response to infection	Suspected infection + SOFA ≥2 from baseline
Septic Shock	Subset with profound circulatory/cellular/metabolic abnormalities	Vasopressor to maintain MAP ≥65 + Lactate >2 mmol/L despite adequate fluid
qSOFA	Bedside screening tool (not diagnostic)	RR ≥22, AMS, SBP ≤100; ≥2 → high risk

⚡ SOFA Score Components

Respiratory: PaO₂/FiO₂ ratio (0–4 points)
Coagulation: Platelets (0–4 points)
Liver: Bilirubin (0–4 points)
Cardiovascular: MAP / vasopressors (0–4 points)
CNS: GCS (0–4 points)
Renal: Creatinine / urine output (0–4 points)

🔑 Pearl: SIRS criteria are no longer part of the sepsis definition. qSOFA ≥2 should prompt urgent assessment for organ dysfunction but does NOT define sepsis — SOFA does.

▼1.2 Pathophysiology

Sepsis involves dysregulated innate and adaptive immune responses triggered by PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) interacting with PRRs (pattern recognition receptors, esp. TLR4).

Phase 1 — Hyperinflammation: Cytokine storm (TNF-α, IL-1β, IL-6) → endothelial activation, capillary leak, microthrombi
Phase 2 — Immunosuppression: T-cell exhaustion, lymphopenia, macrophage deactivation → susceptibility to secondary infections
Microvascular dysfunction: Glycocalyx shedding, coagulation activation → DIC, distributive shock
Mitochondrial dysfunction: Bioenergetic failure → multi-organ failure despite adequate perfusion pressure

🔑 Pearl: "Immunoparalysis" (persistent lymphopenia, low HLA-DR expression on monocytes) predicts secondary infections and poor outcome. IL-7 and anti-PD-1 therapies are being investigated to reverse this state.

▼1.3 Initial Assessment & Risk Stratification

Rapid assessment within 30–60 minutes is critical. Identify source, severity, and host factors.

Parameter	Significance	Target
Lactate	Tissue hypoperfusion marker; prognostic	<2 mmol/L; clearance ≥10% at 2h
Blood cultures (×2)	Pathogen identification; guide de-escalation	Draw before antibiotics, <45 min delay
MAP	Organ perfusion pressure	≥65 mmHg (≥80 in chronic HTN)
Procalcitonin	Bacterial infection biomarker; de-escalation guide	PCT-guided: stop antibiotics if PCT <0.25 or ↓ ≥80%
Fluid responsiveness	Predict benefit from IV fluid	PLR, PPV, IVC collapsibility, passive leg raise

🔑 Pearl: Lactate ≥4 mmol/L = high-risk sepsis even without hypotension (equivalent mortality to septic shock). Immediate aggressive resuscitation warranted.

▼1.4 Hour-1 Bundle (SSC 2021)

The SSC 2021 updated the Hour-1 Bundle, reinforcing time-sensitive interventions. The bundle improves survival when completed within 1 hour of sepsis recognition.

⚡ Hour-1 Bundle — 5 Elements

1. Measure lactate — re-measure if initial >2 mmol/L
2. Blood cultures ×2 — before antibiotics (do not delay antibiotics >45 min)
3. Broad-spectrum antibiotics — within 1 hour of recognition
4. IV crystalloid 30 mL/kg — for hypotension or lactate ≥4 mmol/L (within 3h)
5. Vasopressors — if MAP <65 during/after fluids → norepinephrine first-line

🔑 Pearl: ANDROMEDA-SHOCK (JAMA 2019) — peripheral perfusion-targeted resuscitation (capillary refill time) vs. lactate-targeted showed no difference in 28-day mortality but may reduce risk of excessive fluid loading.

▼1.5 Fluid Resuscitation

Fluid choice and volume are debated. The SSC 2021 recommends balanced crystalloids over normal saline for resuscitation.

Fluid Type	Evidence	Recommendation
Balanced crystalloids (LR, PlasmaLyte)	SMART (NEJM 2018): ↓ MAKE30 vs NS	First-line — SSC 2021 weak recommendation
Normal saline 0.9%	Hyperchloremic metabolic acidosis, AKI risk	Acceptable if balanced not available
Albumin 4–5%	ALBIOS (NEJM 2014): no mortality benefit overall; may benefit septic shock subgroup	Consider if large volumes of crystalloid needed
Hydroxyethyl starch (HES)	VISEP, 6S trials: ↑ AKI, mortality	CONTRAINDICATED in sepsis

⚠ Warning: Fluid overload (positive cumulative balance) is independently associated with increased mortality. After initial resuscitation, use dynamic markers (PPV, PLR, VExUS) to guide further fluids. Conservative late fluid strategy is favored.

▼1.6 Vasopressors & Inotropes

Agent	Mechanism	Role	Dose
Norepinephrine	α₁ >> β₁	First-line vasopressor	0.01–3.3 mcg/kg/min
Vasopressin	V1 receptor	Add-on to NE; ↓ NE dose (VASST trial)	0.03–0.04 units/min (fixed dose)
Epinephrine	α₁, β₁, β₂	2nd add-on if NE + vasopressin insufficient	0.01–0.5 mcg/kg/min
Dobutamine	β₁ > β₂	Cardiogenic shock / cardiac compromise + sepsis	2–20 mcg/kg/min
Dopamine	D1, β₁, α₁ (dose-dependent)	Not recommended — ↑ arrhythmia vs NE (SOAP II)	Avoid in septic shock
Angiotensin II	AT1 receptor	Refractory vasodilatory shock (ATHOS-3)	20 ng/kg/min, titrate

🔑 Pearl: ATHOS-3 (NEJM 2017) — Angiotensin II significantly increased MAP response in high-output norepinephrine-dependent vasodilatory shock. Renin ≥ 167 pg/mL identifies best responders.

▼1.7 Empiric Antibiotics & Source Control

Administer empiric broad-spectrum antibiotics within 1 hour of sepsis recognition. Each hour of delay increases mortality ~7%.

Source	Likely Organisms	Empiric Antibiotic
Community — unknown source	GNRs, GPC, anaerobes	Pip-tazo 4.5g q6h or Meropenem 1g q8h
Pneumonia (CAP-sepsis)	S. pneumoniae, Legionella, GNRs	Ceftriaxone + Azithromycin ± Oseltamivir
Urinary source	E. coli, Klebsiella	Ceftriaxone 1g q24h (adjust per local resistance)
Intra-abdominal	GNRs, anaerobes, Enterococcus	Pip-tazo or Meropenem + consider Metronidazole
Healthcare-associated / MRSA risk	MRSA, Pseudomonas, ESBL	Vancomycin + Meropenem
Neutropenic fever	GNRs (Pseudomonas), Viridans strep	Cefepime 2g q8h or Pip-tazo

⚡ Source Control Principles (SSC 2021)

Identify and treat source within 6–12 hours of diagnosis
Drain abscesses, remove infected devices/catheters
Surgical consultation early if intra-abdominal source
De-escalate antibiotics by 48–72h based on cultures + PCT
Total duration: typically 7 days (shorter if clinically appropriate)

▼1.8 Adjunctive Therapies

Intervention	Evidence	SSC 2021 Recommendation
Hydrocortisone 200 mg/day	ADRENAL (NEJM 2018): no mortality benefit; ↓ time to shock reversal. APROCCHSS (NEJM 2018): mortality benefit with HC + Fludrocortisone	Suggest if refractory septic shock (NE ≥0.25 mcg/kg/min)
Stress ulcer prophylaxis	SUP-ICU (NEJM 2018): pantoprazole vs placebo — no mortality benefit, ↑ Clostridium difficile trend	Give only if GI bleeding risk factors present
DVT prophylaxis	LMWH superior to UFH for VTE prevention	Recommend pharmacological DVT prophylaxis
Glucose control	NICE-SUGAR (NEJM 2009): intensive control (81–108) ↑ mortality	Target glucose 140–180 mg/dL (7.8–10 mmol/L)
Vitamin C + Thiamine	CITRIS-ALI, VITAMINS: no benefit vs placebo	Not recommended routinely
RBC transfusion	TRISS (NEJM 2014): Hgb 7 g/dL threshold non-inferior	Transfuse if Hgb <7 g/dL (unless active bleeding/ACS)

📚 Key References

SSC 2021 — Evans L et al. Surviving Sepsis Campaign: International Guidelines. Intensive Care Med 2021;47:1181–1247.
Sepsis-3 — Singer M et al. JAMA 2016;315(8):801–810.
SMART Trial — Semler MW et al. NEJM 2018;378:819–828.
ATHOS-3 — Khanna A et al. NEJM 2017;377:419–430.
ADRENAL — Venkatesh B et al. NEJM 2018;378:797–808.

2. Pneumonia (CAP / HAP / VAP)

Pneumonia remains a leading cause of infection-related morbidity and mortality worldwide. This section covers Community-Acquired Pneumonia (CAP), Hospital-Acquired Pneumonia (HAP), and Ventilator-Associated Pneumonia (VAP) based on IDSA/ATS 2019 CAP Guidelines and IDSA/ATS 2016 HAP/VAP Guidelines.

▼2.1 CAP — Diagnosis & Severity Assessment

CAP is defined as an acute infection of the pulmonary parenchyma in a patient who acquired the infection outside of a hospital.

Diagnosis: New infiltrate on CXR/CT + ≥2 of: fever, productive cough, pleuritic pain, auscultatory findings, leukocytosis, or hypoxemia.

Severity Score	Parameters	Use
CURB-65	Confusion, Urea >7 mmol/L, RR ≥30, BP <90/60, Age ≥65	Score 0–1: outpatient; 2: admission; ≥3: ICU consider
PSI (PORT)	Multifactorial; Class I–V	Class I–II: outpatient; III: observation; IV–V: admit
ATS Minor Criteria	9 criteria (RR, PaO₂/FiO₂, multilobar, confusion, BUN, WBC, plt, temp, hypotension)	≥3 of 9 → ICU admission (IDSA/ATS 2019)

⚡ IDSA/ATS Major Criteria for Severe CAP (→ ICU)

Need for invasive mechanical ventilation
Septic shock requiring vasopressors
Either alone = severe CAP → ICU admission

▼2.2 CAP — Treatment (IDSA/ATS 2019)

Setting	Patient Type	Preferred Regimen
Outpatient	No comorbidities, no antibiotics in 3 months	Amoxicillin 1g TID or Doxycycline 100mg BID
Outpatient	Comorbidities (DM, CKD, liver/heart disease)	Amoxicillin-clavulanate + Azithromycin, or Respiratory FQ (Levofloxacin/Moxifloxacin)
Inpatient (non-ICU)	Standard	β-lactam (ceftriaxone/ampicillin-sulbactam) + Macrolide, or Respiratory FQ alone
ICU	No Pseudomonas risk	β-lactam + Azithromycin or Respiratory FQ
ICU	Pseudomonas risk	Anti-pseudomonal β-lactam (Pip-tazo/Cefepime) + FQ or Aminoglycoside
ICU	MRSA risk (prior infection, colonization, cavitary)	Add Vancomycin or Linezolid

Duration: Minimum 5 days for CAP; extend if slow clinical response. Use PCT to guide de-escalation.

🔑 Pearl: Legionella and pneumococcal urinary antigens should be sent for hospitalized patients with severe CAP. Legionella responds to macrolides or fluoroquinolones — NOT beta-lactams alone.

▼2.3 Hospital-Acquired & Ventilator-Associated Pneumonia

HAP: Pneumonia ≥48h after hospital admission, not incubating at admission.
VAP: Pneumonia ≥48–72h after endotracheal intubation.

Feature	HAP	VAP
Common pathogens	MSSA/MRSA, GNRs (Klebsiella, E. coli, Pseudomonas)	Same + Acinetobacter, Stenotrophomonas
Diagnosis	New CXR infiltrate + clinical signs	CPIS or clinical criteria; BAL quantitative culture ≥10⁴ CFU/mL
Empiric therapy	Pip-tazo or cefepime; add vanco if MRSA risk	Anti-pseudomonal + MRSA coverage based on risk factors
De-escalation	48–72h based on cultures	8 days total (non-fermenting GNRs may need longer)

⚡ VAP Prevention Bundle

Head-of-bed elevation 30–45°
Oral decontamination with chlorhexidine (evidence debated)
Spontaneous breathing trials + sedation holidays daily
Subglottic secretion drainage (Hi-Lo Evac tube)
Avoid unnecessary H₂ blocker/PPI (↑ VAP risk)

▼2.4 COVID-19 — Management (2024 Update)

Severity	Definition	Treatment
Mild	SpO₂ >94%, no risk factors	Supportive; consider Nirmatrelvir/ritonavir (Paxlovid) within 5 days of symptom onset if high-risk
Moderate	SpO₂ 90–94%, requires supplemental O₂	Remdesivir 200→100 mg IV × 3–5 days; Dexamethasone if O₂ needed
Severe	SpO₂ <90%, NIV/HFNC	Dexamethasone 6 mg/day × 10 days + Remdesivir + Baricitinib or Tocilizumab if inflammatory markers elevated
Critical	Mechanical ventilation	Low tidal volume (6 mL/kg IBW), prone positioning ≥16h/day if PaO₂/FiO₂ <150; Dexamethasone + IL-6 inhibitor

🔑 Pearl: RECOVERY trial — Dexamethasone 6 mg/day × 10 days reduced 28-day mortality in patients requiring O₂ (NNT ~8 for ventilated, ~25 for O₂ only). Harmful in those not requiring O₂.

▼2.5 Influenza & Respiratory Viruses

Influenza: Treat with Oseltamivir 75 mg BID × 5 days within 48h of symptom onset. Start empirically in hospitalized patients regardless of test result if high clinical suspicion. Baloxavir (single dose) is alternative for uncomplicated flu, cap-dependent endonuclease inhibitor.

Virus	Test	Treatment
Influenza A/B	Rapid Ag (low sens), PCR	Oseltamivir 75mg BID × 5d; ICU: 150mg BID × 10d
RSV	PCR	Supportive; Palivizumab (prophylaxis in high-risk infants); Nirsevimab for adults >60y
SARS-CoV-2	Rapid Ag, PCR	See above; Paxlovid for high-risk outpatients
Adenovirus	PCR	Supportive; Cidofovir in severe immunocompromised
Metapneumovirus	PCR	Supportive

▼2.6 Pneumocystis (PCP) & Aspergillosis

PCP (Pneumocystis jirovecii pneumonia): Occurs in HIV (CD4 <200), transplant, steroid-treated patients.

Presents with subacute onset dyspnea, dry cough, diffuse bilateral ground-glass opacities, elevated LDH, low SpO₂ with exertion. β-D-glucan elevated.

Treatment: TMP-SMX (Bactrim DS) 15–20 mg/kg/day TMP component IV/PO × 21 days. Add Prednisone 40 mg BID × 5d → 40 mg QD × 5d → 20 mg QD × 11d if PaO₂ <70 mmHg or A-a gradient >35.

Invasive Pulmonary Aspergillosis (IPA):

Risk: prolonged neutropenia, hematologic malignancy, SOT, high-dose steroids, COVID-19-associated
Diagnosis: CT (halo sign, air crescent sign), BAL galactomannan ≥1.0, serum GM ≥0.5
Treatment: Voriconazole 6 mg/kg IV q12h × 2 doses → 4 mg/kg q12h (first-line). Alternative: Isavuconazole or Liposomal amphotericin B

🔑 Pearl: COVID-19-Associated Pulmonary Aspergillosis (CAPA) occurs in ~10% of ICU COVID patients, even without classic immunosuppression. Maintain high index of suspicion in deteriorating ICU patients — check galactomannan and BAL cultures.

📚 Key References

IDSA/ATS CAP 2019 — Metlay JP et al. Am J Respir Crit Care Med 2019;200(7):e45–e67.
IDSA/ATS HAP/VAP 2016 — Kalil AC et al. Clin Infect Dis 2016;63(5):e61–e111.
RECOVERY Trial — Horby P et al. NEJM 2021;384:693–704.

3. CNS Infections

CNS infections are medical emergencies requiring immediate diagnosis and treatment. Delay in antibiotics in bacterial meningitis increases mortality significantly. This section covers bacterial meningitis, viral encephalitis, brain abscess, TBM, and cryptococcal meningitis.

▼3.1 Bacterial Meningitis

Age Group	Common Organisms	Empiric Treatment
Neonates <1 month	GBS, E. coli, Listeria	Ampicillin + Cefotaxime (or Gentamicin)
Infants 1–3 months	GBS, E. coli, S. pneumoniae, N. meningitidis	Ampicillin + Cefotaxime + Vancomycin
Adults 18–50y	S. pneumoniae, N. meningitidis	Vancomycin + Ceftriaxone 2g q12h
Adults >50y / immunosuppressed	S. pneumoniae, Listeria, GNRs	Vancomycin + Ceftriaxone + Ampicillin
Post-neurosurgery/trauma	Staph, GNRs (Pseudomonas, Acinetobacter)	Vancomycin + Cefepime or Meropenem

⚠ Dexamethasone: Give Dexamethasone 0.15 mg/kg q6h × 4 days — administer 15–20 minutes BEFORE or with first antibiotic dose. Benefit proven in S. pneumoniae meningitis (↓ hearing loss, neurologic sequelae). Discontinue if non-pneumococcal.

CSF Interpretation:

Parameter	Normal	Bacterial	Viral	TBM/Fungal
Opening pressure (cmH₂O)	10–20	>30	Normal/slightly ↑	↑↑
WBC (cells/µL)	<5	100–10,000 (PMN)	10–500 (lymph)	10–500 (lymph)
Protein (mg/dL)	<45	>200	50–100	100–500
Glucose (mg/dL)	>60% serum	<45 (<40%)	Normal	Low
Gram stain	Neg	Positive 60–90%	Neg	India ink (crypto)

🔑 Pearl: Do NOT delay antibiotics for LP. If CT needed first (papilledema, focal neuro signs, immunocompromised, new seizure), blood cultures × 2 + antibiotics FIRST, then CT → LP. Each hour delay ↑ mortality ~30%.

▼3.2 Viral Meningitis & Encephalitis

Viral Meningitis: Usually self-limited; most common cause is Enteroviruses. CSF: lymphocytic pleocytosis, normal glucose. Treatment supportive.

Viral Encephalitis: AMS + fever ± focal neurologic signs/new-onset seizures. Start IV Acyclovir empirically until HSV-1 excluded by PCR.

Virus	Clinical Clues	Diagnosis	Treatment
HSV-1	Temporal lobe involvement, temporal hemorrhage on MRI, olfactory/memory sx	CSF HSV PCR (sens 96%, spec 99%)	Acyclovir 10 mg/kg IV q8h × 14–21 days
HSV-2	Neonatal, recurrent aseptic meningitis (Mollaret's)	CSF HSV-2 PCR	Acyclovir 10 mg/kg q8h
VZV	Dermatomal rash, elderly/immunosuppressed	CSF VZV PCR, anti-VZV Ab	Acyclovir 10–15 mg/kg q8h
CMV	Immunocompromised (HIV CD4 <50, transplant)	CSF CMV PCR, CMV antigenemia	Ganciclovir + Foscarnet
EBV	Young adults, lymphadenopathy	CSF EBV PCR, heterophile Ab	Supportive
Rabies	Animal bite, hydrophobia, aerophobia, ascending paralysis	Skin biopsy, DFA, saliva PCR	Post-exposure prophylaxis only (PEP); once symptomatic — near-fatal
Japanese Encephalitis	SE Asia, rice field exposure, extrapyramidal signs	JE IgM in CSF/serum	Supportive; vaccine prevention

▼3.3 Brain Abscess

Brain abscess presents with headache + fever + focal deficits (classic triad in <50%). CT/MRI shows ring-enhancing lesion(s) with perilesional edema.

Source	Common Organisms	Antibiotic
Otogenic/sinusitis	Streptococci (Milleri group), anaerobes, GNRs	Metronidazole + Ceftriaxone
Dental/odontogenic	Fusobacterium, Peptostreptococcus, Streptococci	Metronidazole + Ceftriaxone
Hematogenous (IE, lung)	Viridans strep, S. aureus	Based on source + sensitivities; Vancomycin empirically
Post-neurosurgery	Staph, GNRs	Vancomycin + Cefepime
Immunocompromised	Toxoplasma, Nocardia, Aspergillus, Cryptococcus	Empiric pyrimethamine/sulfadiazine ± voriconazole

Management: Neurosurgical aspiration or drainage for lesions >2.5 cm or mass effect. Medical management alone for small (<2.5 cm), accessible lesion, known organism. Duration: 4–8 weeks IV antibiotics, then PO if appropriate.

▼3.4 Tuberculous Meningitis (TBM)

TBM is the most severe form of extrapulmonary TB. Subacute onset (days–weeks) with headache, fever, meningism, CN palsies (VI, III, VII), signs of basilar meningitis.

British MRC Grade: Grade I (GCS 15, no focal neuro), Grade II (GCS 11–14 or focal neuro), Grade III (GCS ≤10).

CSF: Lymphocytic pleocytosis 100–500, protein 100–500, low glucose, AFB smear (40–90% sensitivity with multiple samples), ADA elevated (>10 U/L), Xpert MTB/RIF (sensitivity ~60%).

⚡ TBM Treatment

Intensive phase (2 months): HRZE (INH + Rifampicin + Pyrazinamide + Ethambutol)
Continuation phase (7–10 months): HR (INH + Rifampicin) — total 9–12 months
Dexamethasone (British MRC Trial): 0.3–0.4 mg/kg/day tapering over 6–8 weeks — reduces mortality and severe disability at 6 months. Give in ALL grades.
Pyridoxine 25 mg/day with INH to prevent peripheral neuropathy

🔑 Pearl: TBM paradoxical reaction (worsening after starting treatment) occurs in 15–40%. Managed with corticosteroids. Thalidomide has been used in refractory paradoxical reactions in children.

▼3.5 Cryptococcal Meningitis

Caused by Cryptococcus neoformans (HIV/immunocompromised) or C. gattii (immunocompetent). Subacute meningitis with very high ICP is hallmark.

Diagnosis: CSF India ink (sens 60–80%), Cryptococcal Ag (CrAg) in CSF and serum (sens >95%), culture.

Phase	Duration	Treatment (HIV-associated)
Induction	2 weeks	Liposomal Amphotericin B 3–4 mg/kg/day + Flucytosine 100 mg/kg/day (ACTA trial 2018)
Consolidation	8 weeks	Fluconazole 400 mg/day
Maintenance	≥1 year (until CD4 >200 × 3 months on ART)	Fluconazole 200 mg/day

⚠ ICP Management — Critical: Elevated ICP (opening pressure >25 cmH₂O) is the leading cause of early mortality. Perform therapeutic LP daily to reduce OP to <20 cmH₂O or by 50%. Consider lumbar drain or VP shunt for persistent elevation. DO NOT give corticosteroids for ICP in crypto meningitis — worsens outcomes.

▼3.6 Neurocysticercosis (NCC)

Most common parasitic infection of CNS worldwide (endemic in SE Asia, Latin America, sub-Saharan Africa). Caused by larval stage of Taenia solium. Most common presentation: new-onset seizures in endemic area.

MRI stages: Vesicular (viable cyst, scolex visible) → Colloidal (ring-enhancing, inflammation) → Granular-nodular (calcifying) → Calcified (inactive).

⚡ NCC Treatment

Antiparasitic (cysticidal): Albendazole 400 mg BID × 8–30 days ± Praziquantel 50 mg/kg/day × 15 days (combination superior for multiple cysts)
Corticosteroids: MUST accompany antiparasitic therapy to control inflammation — Dexamethasone or Prednisone
Anti-epileptics: Treat seizures; can discontinue AED in calcified NCC if seizure-free × 1–2 years
Avoid antiparasitic in: Calcified lesions (inactive, no benefit), ocular NCC (may worsen), encephalitic NCC (↑ inflammation)

4. Bloodstream Infections & Endocarditis

Bacteremia and infective endocarditis represent a spectrum of intravascular infections with high mortality. Key principles: blood cultures before antibiotics, source identification and control, echocardiography for all S. aureus bacteremia.

▼4.1 Bacteremia — Approach & Management

Draw 2 sets of blood cultures (each set = 1 aerobic + 1 anaerobic bottle, 20 mL total) from different sites before starting antibiotics. Sensitivity increases from 73% (1 set) to 94% (2 sets) to 99% (3 sets).

Organism	True Bacteremia?	Action
S. aureus	Always significant	Echocardiogram (TTE/TEE), extended treatment, infectious disease consult
CoNS (S. epidermidis)	Contaminant if single bottle; true if 2+ sets or with device	Remove device if possible; treat with Vancomycin
E. coli / GNR	Usually significant (single set)	Find source; treat targeted
Streptococcus viridans	Significant — always evaluate for IE	Echo mandatory; penicillin/ceftriaxone
Candida spp.	Always significant — candidemia	Ophthalmology exam, remove all vascular access, Echinocandin
Bacillus, Propionibacterium	Usually contaminant unless immunocompromised/device	Clinical context

🔑 Pearl: S. aureus bacteremia rule: ALWAYS get echocardiogram. TEE superior to TTE for detecting vegetations (sens 90–95% vs 40–60%). TEE recommended if TTE non-diagnostic, prosthetic valve, intracardiac device, or high pretest probability of IE.

▼4.2 Staphylococcal Bacteremia

Feature	MSSA	MRSA
Preferred treatment	Nafcillin/Oxacillin 2g IV q4h (or Cefazolin 2g IV q8h — non-inferior in most infections)	Vancomycin (target AUC/MIC 400–600) or Daptomycin 8–10 mg/kg/day
IE treatment duration	4–6 weeks (native valve); 6 weeks (prosthetic)	6 weeks minimum
Uncomplicated bacteremia	14 days IV antibiotics minimum	14 days IV minimum; extend if metastatic foci
Complications	Endocarditis, septic arthritis, osteomyelitis, epidural abscess, psoas abscess — screen clinically

⚡ Complicated vs Uncomplicated S. aureus Bacteremia

Complicated: IE, metastatic infection, persistent bacteremia >72h despite appropriate antibiotics, no removable source → ≥4 weeks treatment
Uncomplicated: Native valve, no metastatic foci, removable source removed, responds within 72h → 14 days
ID consult shown to reduce 90-day mortality in S. aureus bacteremia (Lahey et al., CID 2009)

▼4.3 Infective Endocarditis — Diagnosis (Modified Duke Criteria)

Category	Criteria
Major — Microbiology	Typical organism (S. aureus, viridans strep, HACEK, S. bovis, Enterococcus) in ≥2 blood cultures drawn >12h apart; OR ≥3/4 positive cultures; OR single positive Coxiella burnetii or IgG titer >1:800
Major — Imaging	Echo: vegetation, abscess, new dehiscence, new valvular regurgitation; OR 18F-FDG PET/CT (prosthetic valve) — added in ESC 2023
Minor	Predisposing cardiac condition/IVDU; Fever ≥38°C; Vascular phenomena (emboli, mycotic aneurysm, Janeway lesions); Immunologic phenomena (Osler nodes, Roth spots, RF+, GN); Microbiological (pos culture not meeting major)

Definite IE: 2 major, OR 1 major + 3 minor, OR 5 minor.
Possible IE: 1 major + 1 minor, OR 3 minor.

🔑 Pearl: S. bovis (now classified as S. gallolyticus) bacteremia/IE is associated with colorectal polyps or cancer in 20–50% of cases — colonoscopy is MANDATORY for all S. bovis/gallolyticus bloodstream infections.

▼4.4 Infective Endocarditis — Treatment (AHA 2023 / ESC 2023)

Organism	Native Valve	Prosthetic Valve
Viridans strep (MIC ≤0.12)	Penicillin G or Ceftriaxone × 4 weeks; 2 weeks if uncomplicated	6 weeks; add Gentamicin × 2 weeks
MSSA	Nafcillin/Cefazolin × 4–6 weeks	Nafcillin + Rifampicin × 6 weeks + Gentamicin × 2 weeks
MRSA	Vancomycin × 6 weeks	Vancomycin + Rifampicin × 6 weeks + Gentamicin × 2 weeks
Enterococcus (ampicillin-sensitive)	Ampicillin + Ceftriaxone × 6 weeks (ACES trial) — non-inferior to ampicillin + gentamicin, less nephrotoxicity	6 weeks
HACEK group	Ceftriaxone 2g/day × 4 weeks	6 weeks

⚡ Surgical Indications in IE (AHA 2023)

Urgent/Emergency: Acute severe valvular regurgitation with hemodynamic compromise; Aortic/mitral IE with valve obstruction; Fistula into cardiac chamber; Prosthetic valve dehiscence
Elective: Persistent infection despite ≥5–7 days antibiotics; Recurrent embolism; Vegetation >10 mm with mobile features; Perivalvular abscess; PVE caused by Staph or fungus

▼4.5 CLABSI & Candidemia

CLABSI Definition: BSI in patient with central vascular catheter >2 days, no other source of infection.

Management: Remove CVC immediately (especially for S. aureus, Candida, Pseudomonas, Mycobacterium). Exchange over guidewire acceptable only for CoNS with antibiotic lock therapy in select patients.

Candidemia:

Remove CVC within 24h of positive culture (mortality ↓)
Ophthalmology exam for candida endophthalmitis (10–15% of candidemia)
Echo to rule out endocarditis
Treatment: Echinocandin (Caspofungin 70→50 mg/day, Micafungin 100 mg/day) — first-line. Transition to Fluconazole if C. albicans/parapsilosis (fluconazole-susceptible) after clinical stability.
Duration: 14 days after last positive culture AND resolution of symptoms

🔑 Pearl: C. glabrata (now Nakaseomyces glabrata) and C. krusei (now Pichia kudriavzevii) have intrinsic or acquired fluconazole resistance — use Echinocandin or Voriconazole. C. parapsilosis has intrinsic Echinocandin MIC elevation — Fluconazole preferred if susceptible.

5. HIV/AIDS & Antiretroviral Therapy

HIV remains a major global pandemic with ~39 million people living with HIV worldwide (UNAIDS 2023). With effective ART, HIV is now a chronic manageable disease. This section covers WHO/DHHS 2024 guidelines on HIV testing, staging, ART initiation, and OI management.

▼5.1 HIV Testing, Staging & Natural History

Diagnosis: 4th-generation HIV Ag/Ab combination assay (detects HIV-1/2 Ab + HIV-1 p24 Ag) — window period 18–45 days. Confirmatory: HIV-1/HIV-2 antibody differentiation assay → if reactive, HIV-1 NAT (viral load).

WHO Clinical Stage	CD4 Count	Key Features
Stage 1 (Asymptomatic)	>500	PGL; no symptoms or mild
Stage 2 (Mild)	350–500	Minor mucocutaneous, recurrent URTIs, herpes zoster
Stage 3 (Advanced)	200–350	Unexplained weight loss >10%, chronic diarrhea >1 month, oral candida, pulmonary TB, severe bacterial infections
Stage 4 (AIDS-defining)	<200 (or <15%)	PCP, CMV retinitis, toxoplasmosis, cryptococcal meningitis, MAC, Kaposi sarcoma, HIV encephalopathy, wasting syndrome

🔑 Pearl: Acute HIV syndrome (2–4 weeks after infection): mononucleosis-like illness, high viral load, rapid CD4 decline. Highest infectivity period. Treat immediately — reduces reservoir size and protects against immune damage.

▼5.2 ART — DHHS 2024 Preferred Regimens

ART should be initiated in ALL HIV-infected individuals regardless of CD4 count. Early ART reduces AIDS events, non-AIDS morbidity (CVD, renal, hepatic), and transmission.

Regimen	Components	Notes
BIC/TAF/FTC (Biktarvy)	Bictegravir + TAF + Emtricitabine	DHHS preferred; high barrier to resistance, well tolerated, once daily
DTG/ABC/3TC (Triumeq)	Dolutegravir + Abacavir + Lamivudine	Preferred if HLA-B*5701 negative (ABC hypersensitivity); once daily
DTG + TAF/FTC	Dolutegravir + TAF + Emtricitabine	Separate pills; preferred in many guidelines; renal-friendly (TAF)
CAB/RPV LA (Cabenuva)	Cabotegravir + Rilpivirine IM	Long-acting injectable, every 1–2 months; for virologically suppressed, VL <50 copies/mL. Requires HBsAg negative, no resistance to either drug
LEN/CAB (Sunlenca/Apretude)	Lenacapavir SC q6mo + Cabotegravir	Highly treatment-experienced; lenacapavir approved 2022 (capsid inhibitor)

⚡ INSTI (Integrase Strand Transfer Inhibitor) Advantages

High barrier to resistance: DTG, BIC >> RAL, EVG
Fewer drug interactions than PIs or NNRTIs
DTG: avoid in first trimester (neural tube defect risk data conflicting — updated WHO 2022: use acceptable throughout pregnancy)
BIC and DTG: watch for creatinine rise (tubular secretion inhibition — not true GFR change)
Interaction: Cation-containing antacids, Ca, Mg, Fe — separate by 2–4h

▼5.3 Opportunistic Infection Prophylaxis & Treatment

OI	CD4 Threshold (start Px)	Primary Prophylaxis	Treatment (acute)
PCP	<200 or <14%	TMP-SMX DS 1 tab QD	TMP-SMX 15–20 mg/kg/day × 21d + Prednisone if PaO₂ <70
Toxoplasmosis	<100 + anti-Toxo IgG+	TMP-SMX DS QD (same as PCP Px)	Pyrimethamine + Sulfadiazine + Leucovorin × 6 weeks
MAC	<50	Azithromycin 1200 mg weekly (or 600 mg BIW)	Azithromycin + Ethambutol ± Rifabutin × ≥12 months
CMV retinitis	<50 (screen with fundoscopy)	No prophylaxis; monitor with regular fundoscopy	Ganciclovir IV 5 mg/kg q12h × 14–21d, then maintenance; or Intravitreal injection
Cryptococcal meningitis	<100 (in endemic areas — WHO 2022)	Screen CrAg: if positive → preemptive Fluconazole 800 mg/day × 2 weeks → 400 mg/day × 8 weeks	Liposomal AmB + Flucytosine × 2 weeks → Fluconazole
Candida (esophageal)	Any CD4 (usually <100)	Not routinely recommended	Fluconazole 200–400 mg/day × 14–21d

⚠ IRIS — Immune Reconstitution Inflammatory Syndrome: Occurs in 10–30% after ART initiation. Paradoxical worsening of existing OI or unmasking of subclinical OI as immune system recovers. Most common with TB, Cryptococcus, CMV. Management: Continue ART (unless life-threatening); add corticosteroids for severe IRIS; for TBM-IRIS: Prednisone 1.5 mg/kg × 2 weeks → 0.75 mg/kg × 2 weeks.

▼5.4 HIV-TB Co-infection

TB is the leading cause of death in HIV-infected individuals. HIV increases TB risk 20–30× (lifetime risk 5–10%/year vs 5–10% lifetime in HIV-negative).

⚡ ART Timing in HIV-TB Co-infection

CD4 <50: Start ART within 2 weeks of TB treatment (SAPiT, CAMELIA trials — ↓ mortality)
CD4 50–500: Start ART within 8 weeks of TB treatment
TBM: Delay ART 4–8 weeks after TB treatment start (CAMELIA, ACTG A5221 — early ART in TBM ↑ severe IRIS without mortality benefit)
Drug interactions: Rifampicin is potent CYP3A4/P-gp inducer — reduces PI levels ↓80–90%, NNRTI (NVP) ↓35–58%. Use Efavirenz (EFV 600–800 mg) or DTG 50 mg BID with rifampicin. Avoid rifampicin with most PIs and EVG/c.
LTBI treatment in HIV: 3HP (INH + Rifapentine weekly × 3 months) — preferred if no active TB and no drug interactions

▼5.5 ART Monitoring, Failure & Resistance

Parameter	Timing	Target
HIV RNA (viral load)	Baseline, 2–4 weeks after start, 4–8 weeks, then q3–6 months when stable	Undetectable (<50 copies/mL) by 24 weeks
CD4 count	Baseline; q3–6 months until >500 × 2 consecutive; then annually if VL suppressed	Increase ≥50–100 cells/µL per year initially
Resistance testing	At diagnosis (baseline), at treatment failure	Guide regimen selection
Metabolic panel, LFT, CBC	Baseline, at 4–8 weeks, then q6 months	Screen for drug toxicity

Virologic failure: VL >200 copies/mL on 2 consecutive measures after ≥6 months ART. Causes: non-adherence (most common), resistance, drug interactions, pharmacokinetic issues. Always check adherence first before switching.

📚 Key References

DHHS Adult/Adolescent ART Guidelines 2024 — clinicalinfo.hiv.gov
WHO Consolidated Guidelines on HIV 2021 — WHO Geneva
PARTNER Study (Lancet 2016) — No HIV transmission in serodiscordant couples with VL <200; U=U (Undetectable = Untransmittable)
ADVANTAGE Trial (NEJM 2023) — Lenacapavir + cabotegravir for treatment-naive

6. Tuberculosis

TB caused by Mycobacterium tuberculosis complex. Thailand is a high-burden country. ~10.6 million new cases worldwide per year (WHO 2022). Remains top infectious disease killer globally.

▼6.1 Pulmonary TB — Diagnosis

Classic presentation: productive cough >2–3 weeks, night sweats, weight loss, hemoptysis, low-grade fever. CXR: upper lobe cavitation, fibro-nodular infiltrates, hilar lymphadenopathy.

Test	Sensitivity	Specificity	Notes
Sputum AFB smear (×3)	40–60%	~99%	Rapid, cheap; send 3 early morning specimens
Xpert MTB/RIF Ultra	90% (smear-neg: 63%)	96%	Also detects RIF resistance (surrogate for MDR-TB); WHO preferred front-line test
MGIT culture (liquid)	~80% (smear-neg)	~99%	Gold standard; results in 10–14 days; DST takes additional 7–10 days
IGRA (QuantiFERON-TB Gold+)	~80%	~99%	Tests LTBI; not useful for active TB diagnosis; unaffected by BCG
TST (Mantoux)	~70%	~60% (lower in BCG vaccinated)	TS >10 mm (HIV+ or immunocompromised: >5 mm) = positive

▼6.2 TB Treatment (WHO 2022)

Drug	Code	Dose (kg-based)	Key Toxicity
Isoniazid	H	5 mg/kg/day (max 300 mg)	Hepatotoxicity, peripheral neuropathy (give Pyridoxine B6)
Rifampicin	R	10 mg/kg/day (max 600 mg)	Hepatotoxicity, orange discoloration, CYP inducer (major drug interactions)
Pyrazinamide	Z	25 mg/kg/day (max 2000 mg)	Hepatotoxicity, hyperuricemia, arthralgia
Ethambutol	E	15–20 mg/kg/day (max 1600 mg)	Optic neuritis (check visual acuity monthly; reduce dose in CKD)

⚡ Standard TB Treatment Regimen

Intensive phase (2 months): HRZE — daily, directly observed therapy (DOT)
Continuation phase (4 months): HR — daily; total 6 months for drug-susceptible pulmonary TB
CNS TB / bone/joint TB: 9–12 months total
Monitor LFTs at baseline, 2 weeks, monthly. Stop if ALT >3× ULN + symptoms, or >5× ULN asymptomatic
4-month regimen: STUDY 31/ACTG A5349 (NEJM 2021) — 2 months HRZE + 2 months rifapentine + moxifloxacin (2HRZE/2PaM) non-inferior to 6-month standard regimen

▼6.3 MDR-TB & XDR-TB

MDR-TB: Resistant to both INH and Rifampicin.
Pre-XDR-TB: MDR/RR-TB + resistant to any fluoroquinolone.
XDR-TB (WHO 2021 revision): MDR/RR-TB + resistant to any FQ AND at least one of Bedaquiline or Linezolid.

Regimen	Components	Duration
BPaLM (WHO 2022 preferred)	Bedaquiline + Pretomanid + Linezolid + Moxifloxacin	6 months (ZeNix, TB-PRACTECAL trials)
BPaL	Bedaquiline + Pretomanid + Linezolid 600 mg	6–9 months (pre-XDR/XDR-TB)
Shorter MDR-TB (9–12 month)	Bdq-Lfx-Eto-Cfz-Z-Hh-E (if FQ-susceptible)	9 months total

🔑 Pearl: Bedaquiline prolongs QT interval — baseline ECG and monitoring q2–4 weeks required. Avoid combination with other QT-prolonging drugs. Maximum QTcF 500 ms — withhold if exceeded. Linezolid causes peripheral neuropathy and myelosuppression — monitor CBC weekly.

▼6.4 Latent TB Infection (LTBI)

LTBI = infection without active disease. ~25% of world population infected. Reactivation risk: HIV (5–10%/yr), biologic therapy (anti-TNF: ~2–5%), CKD, DM, silicosis, malnutrition, corticosteroids.

Who to test: HIV, transplant candidates, anti-TNF therapy, close contacts of active TB, immigration from high-burden country, prisoners, healthcare workers.

Regimen	Duration	Notes
3HP (INH + Rifapentine weekly)	3 months (12 doses)	WHO preferred 2020; DOT or self-administered; caution with ART (rifapentine is CYP inducer)
1HP (INH + Rifapentine daily)	1 month	Shortest; non-inferior to 9H (WHIP3TB trial); increasing use
4R (Rifampicin daily)	4 months	Non-inferior to 9H; fewer side effects; preferred if INH resistance concern
9H (INH daily)	9 months	Traditional; still used in resource-limited settings

▼6.5 Extrapulmonary TB

Site	Clinical Features	Diagnosis	Treatment Duration
Lymphadenitis	Most common EPTB; cervical; painless, matted, caseating	FNA or excision biopsy; AFB culture/histology	6 months
Pleural	Unilateral exudative effusion; ADA >40 U/L; lymphocytic	ADA, pleural biopsy, culture	6 months
Pericardial	Pericardial effusion, constrictive pericarditis	Pericardiocentesis; ADA, culture	6 months + Prednisone (IMPI trial — ↓ constrictive pericarditis)
CNS (TBM)	See Section 3.4	CSF analysis, Xpert	9–12 months
Bone/Joint (Pott's)	Vertebral destruction, psoas abscess, cord compression	MRI spine, CT-guided biopsy	9–12 months ± surgery for cord compression
Miliary TB	Disseminated; bilateral micronodular pattern on CXR; very high mortality	Culture (blood, sputum, bone marrow, liver); IGRA often negative in severe disease	6–12 months + consider steroids

7. Skin, Soft Tissue & Bone Infections

▼7.1 Cellulitis & Erysipelas

Erysipelas: Superficial dermis, sharply demarcated, raised edges, lymphangitis — caused by Group A Strep (GAS).
Cellulitis: Deeper dermis/subcutaneous tissue, poorly demarcated — GAS, S. aureus (MSSA or MRSA).

Treatment:

Non-purulent cellulitis (no abscess, no MRSA risk): Cephalexin 500 mg QID × 5–7 days (outpatient); Cefazolin IV if hospitalized
Purulent cellulitis/abscess with MRSA risk: TMP-SMX DS BID or Doxycycline 100 mg BID × 5–7 days (outpatient); Vancomycin IV if hospitalized
Mark skin borders to track progression; elevate limb

🔑 Pearl: Consider tinea pedis (foot fungal infection) as portal of entry and recurrence risk in lower extremity cellulitis. Treating tinea reduces cellulitis recurrence significantly.

▼7.2 Necrotizing Fasciitis

Feature	Type 1 (Polymicrobial)	Type 2 (Monomicrobial — GAS)
Organisms	Mixed GNRs + anaerobes + strep	Group A Strep ± S. aureus
Risk factors	DM, obesity, immunosuppression, bowel surgery	Healthy young adults; minor trauma
Clinical features	Rapidly spreading, crepitus, skin necrosis, "dishwater" fluid	Toxic shock, extreme pain out of proportion
LRINEC score	CRP, WBC, Na, glucose, Cr, Hgb — score ≥6 suggests NF (sens 59%, spec 97%)

⚠ Surgical Emergency: Immediate surgical debridement is the cornerstone of treatment. Do NOT delay for imaging if clinical diagnosis is clear. Mortality 25–35%; each hour delay ↑ mortality. HYPERBARIC OXYGEN — adjunctive, not substitute for surgery.

Antibiotics: Vancomycin + Pip-tazo (or Meropenem) + Clindamycin (anti-toxin effect, inhibits exotoxin production in GAS).

IVIG: Consider in streptococcal toxic shock syndrome — neutralizes superantigens.

▼7.3 Diabetic Foot Infection (DFI)

DFI classified by IDSA Severity: Mild (superficial, erythema 0.5–2 cm), Moderate (deeper/larger), Severe (systemic signs/sepsis).

Severity	Antibiotic Choice	Route/Duration
Mild (no MRSA risk)	Cefalexin or Amoxicillin-clavulanate	PO × 5–7 days
Mild (MRSA risk)	TMP-SMX DS or Doxycycline	PO × 5–7 days
Moderate (hospitalize)	Pip-tazo or Cefazolin + Metronidazole	IV, transition PO when stable × 2–3 weeks
Severe	Vancomycin + Pip-tazo or Meropenem	IV; extend if osteomyelitis

Osteomyelitis assessment: Probe-to-bone test (PPV 89% if positive); plain X-ray (late, weeks), MRI gold standard, bone biopsy for culture/histology.

▼7.4 Osteomyelitis

Most common organism: S. aureus (hematogenous and contiguous). Vertebral osteomyelitis (spondylodiscitis): usually hematogenous, S. aureus most common; TB common in endemic areas.

Type	Organisms	Antibiotics	Duration
Hematogenous (MSSA)	S. aureus	Nafcillin/Cefazolin IV → PO transition (Dicloxacillin, Cephalexin)	6 weeks IV or 2–6 weeks IV + PO (NEJM OVIVA trial)
Hematogenous (MRSA)	MRSA	Vancomycin → TMP-SMX + Rifampicin PO	6 weeks minimum
Contiguous (DFI)	Polymicrobial	Based on cultures + sensitivities; broad initially	6 weeks if hardware present; 3–6 weeks if resected bone
Vertebral (spondylodiscitis)	S. aureus, Strep, GNRs	Targeted based on blood culture/biopsy	6 weeks minimum; TB: 9–12 months

🔑 Pearl: OVIVA Trial (NEJM 2019) — Oral antibiotics non-inferior to IV antibiotics for bone/joint infections after initial stabilization (≥7 days IV). Oral step-down with bioavailable agents (FQ, TMP-SMX, rifampicin, linezolid) is now standard practice.

▼7.5 Septic Arthritis

Most common cause: S. aureus (all ages). In sexually active young adults: Neisseria gonorrhoeae most common. Risk: joint prosthesis, RA, immunosuppression, bacteremia.

Synovial fluid: WBC >50,000/µL (PMN predominant) highly suggestive; >100,000 more specific but not diagnostic alone. Glucose low, protein high. Crystal analysis to exclude gout/pseudogout.

Management:

Joint aspiration/drainage — daily aspiration or surgical drainage (arthroscopy preferred for knee/shoulder); open drainage for hip
Nafcillin/Cefazolin (MSSA) or Vancomycin (MRSA risk) × 2–4 weeks; Gonococcal: Ceftriaxone 1g/day × 7 days
Treat underlying STI (chlamydia co-treatment with doxycycline)

8. Urinary Tract Infections

▼8.1 Uncomplicated UTI (Cystitis)

Uncomplicated = healthy, non-pregnant women, no structural/functional urinary tract abnormalities. Most common organism: E. coli (80%), S. saprophyticus (5–15% in young women).

Drug	Dose	Duration	Notes
Nitrofurantoin	100 mg BID (macrocrystal)	5 days	First-line; only lower UTI (inadequate renal tissue concentration); avoid in CrCl <30
TMP-SMX DS	1 tab BID	3 days	First-line if local resistance <20%; avoid in sulfa allergy
Fosfomycin	3g single dose	1 dose	Convenient; active against ESBL E. coli; inferior to others for recurrent UTI
Fluoroquinolones	Ciprofloxacin 250 BID or 500 XR QD	3 days	Not first-line (preserve for complicated UTI/pyelonephritis); increasing resistance

▼8.2 Acute Pyelonephritis & Complicated UTI

Complicated UTI: Structural/functional abnormalities, male sex, pregnancy, diabetes, immunosuppression, renal transplant, hospital-acquired, indwelling urinary catheter, recent antibiotics.

Pyelonephritis severity:

Outpatient (mild–moderate): Ciprofloxacin 500 mg BID × 7 days or Levofloxacin 750 mg QD × 5 days (if local susceptibility >90%); TMP-SMX DS BID × 14 days if susceptible
Hospitalized: Ceftriaxone 1–2g/day IV or FQ IV; for ESBL risk/failure: Ertapenem or Meropenem
Duration: 7 days (FQ) to 14 days (beta-lactam); step-down to oral guided by culture sensitivity

⚠ Emphysematous Pyelonephritis: Gas-forming infection (usually E. coli in DM) — CT showing gas within renal parenchyma/perirenal space. Medical emergency — early nephrectomy/drainage + antifungal if Candida. High mortality (40–50%) if treated medically alone in severe class.

▼8.3 Catheter-Associated UTI (CAUTI)

CAUTI definition (NHSN): UTI in patient with urinary catheter >2 days, not present at admission + symptomatic (fever, rigors, altered mental status, discomfort, dysuria) + positive urine culture ≥10³ CFU/mL (catheterized specimen).

⚡ CAUTI Management

Catheter replacement or removal before treating and collecting culture — essential step
Treat symptomatically, not asymptomatic bacteriuria
Asymptomatic bacteriuria (ASB): Do NOT treat except pregnancy, urologic procedures, neutropenia
Duration: 7 days (prompt response), 10–14 days (delayed response), 5 days Levofloxacin (mild/moderate, not critically ill)
Antibiotic selection guided by culture + sensitivities; start broad empirically

▼8.4 UTI in Special Populations

Population	Special Considerations
Pregnancy	Treat ASB (↑ risk pyelonephritis, preterm labor). Safe: Nitrofurantoin (avoid near term), cephalexin, amoxicillin. Avoid: FQ, TMP-SMX (1st/3rd trimester), Nitrofurantoin term (>36 weeks). Duration: 7 days.
Men	All UTI considered complicated. Rule out prostatitis (tender prostate on exam, elevated PSA). Prostatitis treatment: FQ × 4–6 weeks (acute) or TMP-SMX × 4–6 weeks. Prolonged treatment due to prostate penetration.
Recurrent UTI (women)	≥2 episodes/6 months or ≥3/year. Options: post-coital prophylaxis, continuous low-dose (Nitrofurantoin 50–100 mg QD, TMP-SMX SS QD), self-start therapy, cranberry (modest benefit), vaginal estrogen (postmenopausal).
Renal transplant	High risk CAUTI and complicated UTI; Bactrim prophylaxis × 6–12 months post-transplant. Treat all culture-positive UTI (symptomatic and asymptomatic) in early post-transplant period.

9. Tropical & Travel Medicine

Tropical infectious diseases are endemic in Thailand and SE Asia. This section covers malaria, dengue, leptospirosis, scrub typhus, melioidosis, and pre-travel medicine — core topics for internal medicine physicians practicing in the region.

▼9.1 Malaria — Diagnosis & Treatment

Malaria caused by Plasmodium spp. (falciparum, vivax, ovale, malariae, knowlesi). P. falciparum causes most severe disease. P. knowlesi is emerging in SE Asia (macaque-transmitted, can be severe).

Diagnosis: Thick and thin blood smears (gold standard, sens 75–90%); Rapid Diagnostic Test (RDT) — HRP2 Ag for P. falciparum, pLDH for all species; PCR most sensitive.

Species	Uncomplicated Treatment	Notes
P. falciparum (or unknown)	Artemether-Lumefantrine (AL) — 6-dose regimen over 3 days; or Artesunate-Amodiaquine; or DHA-Piperaquine	ACT (Artemisinin-based combination therapy) is WHO first-line. Avoid monotherapy. Artemisinin resistance emerging in GMS (Cambodia, Myanmar, Thailand borders).
P. vivax / P. ovale	Chloroquine 25 mg/kg over 3 days (if susceptible) + Primaquine 0.25 mg/kg/day × 14 days	Primaquine for radical cure (hypnozoites). Check G6PD before primaquine — hemolysis risk. If G6PD deficient: weekly primaquine 0.75 mg/kg × 8 weeks.
P. malariae	Chloroquine × 3 days (no radical cure needed)	No hypnozoite stage; chloroquine still sensitive
P. knowlesi	ACT (treat like falciparum) or Chloroquine	Can cause severe malaria; daily life cycle so parasitemia rises rapidly

⚠ Severe Malaria (WHO 2022) — IV Artesunate:

Indication: Hyperparasitemia (>5%), cerebral malaria (coma/seizures), severe anemia (Hgb <7), respiratory distress, AKI, jaundice, hypoglycemia, circulatory collapse
IV Artesunate 2.4 mg/kg at 0, 12, 24h then daily — superior to IV quinine (AQUAMAT, SEAQUAMAT trials; ↓ mortality ~35%)
Follow with full oral ACT course once patient can swallow
Post-artesunate delayed hemolysis (PADH): monitor Hgb 2–4 weeks after treatment in hyperparasitemia cases

🔑 Pearl: Artemisinin partial resistance (ART-R): K13 propeller gene mutations (C580Y dominant in GMS). Clinically = slow parasite clearance. Solution: Use ACT with partner drug with longer half-life (DHA-Pip) and extend to 5 days if C580Y endemic area.

▼9.2 Dengue Fever

Dengue caused by DENV 1–4 (flavivirus). Transmitted by Aedes aegypti. Hyperendemic in Thailand — ~400,000 cases/year in SE Asia. Secondary infection with different serotype = severe dengue risk (antibody-dependent enhancement).

Phase	Duration	Clinical & Lab Features	Management
Febrile phase	Day 1–3	High fever, myalgia, headache, retroorbital pain, leukopenia, thrombocytopenia begins	Paracetamol (max 4g/day); NO NSAIDs/Aspirin; adequate hydration; IVF if cannot maintain oral
Critical phase	Day 4–6 (defervescence)	Plasma leakage: rising Hct (≥20% from baseline), pleural effusion, ascites; ↑↑ thrombocytopenia; shock (DSS); severe bleeding	Careful fluid management (crystalloid); watch for fluid overload; PLT transfusion if <10,000 or active severe bleeding; Packed RBC if hemorrhage
Recovery phase	Day 7–10	Reabsorption of plasma; bradycardia, convalescent rash; risk of fluid overload	Reduce/stop IV fluids; diuresis if needed; monitor for fluid overload

⚡ Warning Signs of Severe Dengue (WHO 2009)

Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation (ascites, pleural effusion)
Mucosal bleeding
Lethargy or restlessness
Liver enlargement >2 cm
Lab: rapid rise in Hct with rapid decline in PLT

🔑 Pearl: Dengue NS1 antigen — positive from Day 1–5 (peak Day 1–3). IgM/IgG — positive from Day 4–5. Use NS1 + PCR in early phase; IgM/IgG in late phase. Leukopenia + thrombocytopenia in a febrile traveler from SE Asia = dengue until proven otherwise.

▼9.3 Leptospirosis

Caused by Leptospira interrogans. Transmitted via contact with water/soil contaminated by infected animal urine (rodents). Seasonal peak: rainy season, flooding. Thailand: ~3,000–5,000 cases/year.

Clinical spectrum:

Anicteric (90%): Abrupt fever, headache, myalgia (calf muscles), conjunctival suffusion (pathognomonic) — self-limited 1–2 weeks
Weil's disease (5–10%): Jaundice + AKI + thrombocytopenia/bleeding. Severe: pulmonary hemorrhage syndrome (ARDS + hemoptysis), myocarditis, uveitis

Diagnosis: MAT (microscopic agglutination test) — gold standard but takes 2 weeks, needs paired sera. IgM ELISA (point-of-care): sens 50% in 1st week, rises to 90% by day 10. PCR (blood in 1st week, urine after 1st week).

Severity	Drug	Dose & Duration
Mild/Moderate	Doxycycline	100 mg PO BID × 7 days
Mild alternative	Amoxicillin	500 mg PO TID × 7 days
Severe (Weil's)	Penicillin G	1.5 MU IV q6h × 7 days
Severe alternative	Ceftriaxone	1g IV q24h × 7 days
Prophylaxis (post-exposure/flood)	Doxycycline	200 mg PO weekly

▼9.4 Scrub Typhus & Rickettsia

Scrub Typhus: Caused by Orientia tsutsugamushi; vector: chigger mite larva (Leptotrombidium). Endemic throughout Asia-Pacific. Pathognomonic: eschar (painless necrotic ulcer at bite site) + fever + lymphadenopathy.

Clinical features: Fever, headache, myalgia, rash (maculopapular, trunk → extremities), hepatosplenomegaly. Severe: ARDS, myocarditis, meningoencephalitis, AKI.

Diagnosis: Clinical (eschar + fever in endemic area); Weil-Felix test (OX-K positive, low sensitivity/specificity); IgM ELISA; PCR (eschar swab, blood); Immunofluorescence (gold standard).

⚡ Rickettsial Diseases — Treatment

Scrub Typhus: Doxycycline 100 mg PO/IV BID × 7 days — dramatically responsive (fever usually defervesces within 24–48h = therapeutic confirmation)
Murine Typhus (R. typhi, flea vector): Doxycycline × 7 days
Rocky Mountain Spotted Fever (R. rickettsii): Doxycycline × 5–7 days (even in children — risk of staining teeth is outweighed by mortality risk)
Azithromycin: Alternative in pregnancy or children, mild disease — inferior to doxycycline; emerging azithromycin-resistant O. tsutsugamushi strains in Asia
Chloramphenicol: Alternative in pregnancy (but inferior; teratogenic in late pregnancy)

🔑 Pearl: Eschar in scrub typhus is often hidden — check groin, axilla, behind ears, under breasts, scalp. Never miss it. Therapeutic test with doxycycline: fever resolution within 24–48h = virtually diagnostic. Non-response to doxycycline should prompt reconsideration of diagnosis.

▼9.5 Melioidosis

Caused by Burkholderia pseudomallei — soil/water organism. Endemic in NE Thailand (Khon Kaen), Northern Australia, SE Asia. Highest incidence in NE Thailand: 5.5/100,000/year. Risk factors: DM (most common — 60%), alcoholism, CKD, thalassemia, occupational soil exposure (rice farmers).

Clinical forms: Pneumonia (51%), bacteremia (40%), localized infection (skin/soft tissue, liver/spleen abscess, genitourinary), neurological (2% — flaccid paraparesis).

Phase	Drug	Dose & Duration
Intensive (IV)	Ceftazidime IV 50 mg/kg (max 6g) q8h OR Meropenem 1g q8h (severe/CNS)	Minimum 10–14 days; extend to 4–8 weeks for deep-seated infections (osteomyelitis, liver abscess, neuromelioidosis)
Eradication (Oral)	TMP-SMX (TMP 10 mg/kg/day in 2 divided doses) ± Doxycycline	3–6 months (reduces relapse from 26% to 10%)

⚠ Intrinsic Resistance: B. pseudomallei is intrinsically resistant to penicillin, ampicillin, 1st/2nd generation cephalosporins, gentamicin, streptomycin, colistin. Do NOT use these agents.

🔑 Pearl: Melioidosis can mimic TB (cavitary pneumonia, weight loss, chronicity). In a diabetic patient from NE Thailand with cavitary lung disease, culture negative for AFB — always send cultures for melioidosis. Blood culture sensitivity only 60%; send multiple cultures (blood, sputum, urine, pus).

▼9.6 Travel Medicine & Pre-travel Vaccines

Vaccine/Prophylaxis	Indication	Regimen
Hepatitis A	Travel to endemic areas (Asia, Africa, Central/South America)	2-dose series (0, 6–12 months); single dose gives 95% protection within 4 weeks
Hepatitis B	Most travelers; healthcare workers	3-dose (0,1,6 months) or accelerated (0,7,21d + booster 12m); HepA+B combined available
Typhoid	Travel to SE Asia, South Asia, Africa	Injectable Vi polysaccharide × 1 dose (2y protection) or Oral Ty21a × 4 doses q2d (5y)
Japanese Encephalitis	Rural/prolonged stay in SE Asia	Ixiaro: 2 doses 28 days apart; booster at 1 year then q3 years
Yellow Fever	Travel to Sub-Saharan Africa, tropical South America; required for entry to some countries	Single dose; lifelong protection (WHO 2016 — no longer recommend boosters)
Rabies pre-exposure	Animal handlers, prolonged rural travel, activities near bats	3-dose IM series (0, 7, 21–28 days); simplifies post-exposure management (only 2 additional doses needed)
Malaria chemoprophylaxis	Travel to endemic areas; depends on destination species/resistance	Atovaquone-Proguanil (Malarone) — start 1–2d before, during, 7d after; or Doxycycline — start 1–2d before, during, 4 weeks after

⚡ Approach to Fever in Returning Traveler

Most common causes: Malaria, Dengue, Typhoid, Rickettsial disease, Chikungunya, COVID-19
Always ask: where traveled, activities, food/water consumed, animal exposures, sexual exposures, vaccinations, prophylaxis adherence
Incubation period clue: <21 days = malaria, dengue, typhoid, rickettsial; >21 days = hepatitis, TB, leishmaniasis
MANDATORY tests: thick/thin smears + malaria RDT (even if not highly endemic — P. falciparum can be rapidly fatal)
Dengue, typhoid, rickettsial disease: clinical diagnosis with supporting serology
Eosinophilia + travel = parasitic infection (Strongyloides, Toxocara, Schistosoma, Filaria)

10. Antimicrobial Stewardship & MDR Organisms

Antimicrobial resistance (AMR) is a global health crisis. By 2050, AMR could cause 10 million deaths/year (O'Neill Report). Thailand has one of the highest rates of ESBL-producing Enterobacteriaceae and Carbapenem-resistant Acinetobacter in SE Asia. This section covers stewardship principles and management of key resistant pathogens.

▼10.1 Antimicrobial Stewardship Program (ASP)

ASP = coordinated interventions to improve and measure the appropriate use of antimicrobials with the goal of achieving optimal clinical outcomes while minimizing adverse effects of antimicrobials use.

⚡ Core ASP Strategies

Prospective audit and feedback: ID pharmacist or physician reviews antibiotic use and provides real-time recommendations — most evidence-based strategy
Preauthorization / formulary restriction: Require approval for high-tier antibiotics (carbapenems, polymyxins, linezolid)
De-escalation: Narrow spectrum once cultures available; reduce duration based on PCT
IV-to-oral switch: Bioavailable oral agents (FQ, TMP-SMX, metronidazole, fluconazole, linezolid) — switch at 48–72h if tolerated
Rapid diagnostics: Film array, MALDI-TOF, rapid susceptibility testing → earlier de-escalation
Duration optimization: Most infections: 5–7 days; avoid prolonged broad-spectrum without defined indication

Biomarker	Role in Stewardship	Threshold
Procalcitonin (PCT)	Bacterial infection marker; guide duration/de-escalation; reduce unnecessary AB use	Stop AB if PCT <0.25 µg/L or ↓ ≥80% from peak (PRORATA, SAPS trials)
CRP	Less specific than PCT; follow trend rather than absolute value	Normal <10 mg/L; ↓ trend with treatment
Lactate	Severity/perfusion marker; guide resuscitation	Normalize to <2 mmol/L
1,3-β-D-Glucan	Invasive fungal infection (not Cryptococcus/Zygomycetes); negative = de-escalate empiric antifungal	>80 pg/mL suggestive; >200 highly specific

▼10.2 MRSA — Treatment & Decolonization

Indication	Drug	Dose / Target	Notes
Serious/systemic MRSA (BSI, IE, pneumonia, bone)	Vancomycin	15–20 mg/kg q8–12h; target AUC/MIC 400–600 (ASHP 2020 guidelines)	Monitor AUC (Bayesian); avoid trough-only monitoring; nephrotoxic — monitor SCr daily in ICU
BSI/bacteremia — vancomycin intolerant or failure	Daptomycin	8–10 mg/kg/day IV	Do NOT use for pneumonia (inactivated by surfactant). Monitor CK weekly. Check for daptomycin MIC before use.
MRSA pneumonia	Linezolid	600 mg IV/PO q12h	Superior lung penetration vs vancomycin (ZEPHyR trial); 100% oral bioavailability. Monitor for myelosuppression, serotonin syndrome, peripheral neuropathy (>4 weeks use).
SSTI/outpatient MRSA	TMP-SMX DS	1–2 tabs BID × 5–10 days	Good CA-MRSA coverage; check local susceptibility. Add cephalosporin for beta-hemolytic Strep coverage if cellulitis (CA-MRSA often lacks beta-strep activity).
Severe MRSA SSTI (hospitalized)	Vancomycin IV or Daptomycin 4 mg/kg/day	—	Transition to oral step-down once improving

⚡ MRSA Decolonization Protocol (Search and Destroy)

Mupirocin 2% nasal ointment BID × 5 days (nares)
Chlorhexidine gluconate 4% whole-body wash daily × 5 days
Decolonize close contacts simultaneously
Indication: Recurrent MRSA SSTI, pre-surgical decolonization, household contacts of index case
Confirm decolonization with nasal swab culture 1–4 weeks after completion

▼10.3 ESBL-Producing Organisms

ESBL (Extended-Spectrum Beta-Lactamase) — hydrolases that inactivate penicillins, cephalosporins (including 3rd/4th gen), and aztreonam. Most common: CTX-M type. Organisms: E. coli (most common), Klebsiella pneumoniae. Co-resistance: fluoroquinolones (60–80%), TMP-SMX (40–70%).

Infection Severity	Preferred Treatment	Alternative (Step-Down)
Severe / sepsis / BSI	Meropenem 1g q8h or Ertapenem 1g/day	Imipenem; carbapenem sparing only if isolate susceptible to alternative
Complicated UTI (non-severe)	Ertapenem 1g/day IV or Temocillin (Europe)	Nitrofurantoin (cystitis only, if susceptible); Fosfomycin
Oral step-down (if susceptible)	TMP-SMX or Ciprofloxacin (if MIC susceptible)	Fosfomycin for UTI step-down; Nitrofurantoin (bladder only)
Empiric ESBL UTI (low severity)	MERINO Trial (JAMA 2018): pip-tazo inferior to meropenem for ESBL bacteremia (↑ 30-day mortality). Use carbapenem for ESBL BSI.	Pip-tazo NOT reliable for ESBL BSI despite in vitro sensitivity

🔑 Pearl: MERINO Trial (JAMA 2018) settled the debate: Piperacillin-tazobactam is NOT non-inferior to meropenem for ESBL bloodstream infections. 30-day mortality was 12.3% (pip-tazo) vs 3.7% (meropenem). Always use carbapenem for ESBL bacteremia.

▼10.4 Carbapenem-Resistant Organisms (CRE, CRAB, CRPA)

WHO Critical Priority pathogens. Carbapenem resistance mechanisms: carbapenemase production (KPC, NDM, OXA-48, IMP, VIM), porin loss + AmpC, efflux pumps.

Organism	Common Mechanism	Treatment Options
CRE-KPC (K. pneumoniae KPC)	KPC carbapenemase (serine-based)	Ceftazidime-Avibactam (CAZ-AVI) — avibactam inhibits KPC; Meropenem-Vaborbactam; Imipenem-Cilastatin-Relebactam
CRE-NDM (New Delhi Metallo-β-lactamase)	MBL (metallo, zinc-based); not inhibited by avibactam	Ceftazidime-Avibactam + Aztreonam (combination — AZT not hydrolyzed by MBL, CAZ-AVI protects AZT from ESBL); Colistin + carbapenem (high-dose, ↑ nephrotoxicity); Fosfomycin combo
CRAB (A. baumannii)	OXA carbapenemases (OXA-23, OXA-51)	Sulbactam-Durlobactam (FDA approved 2023 — β-lactam/β-lactam inhibitor combination; high activity vs CRAB); Colistin + Meropenem (double carbapenem or high-dose extended infusion); Tigecycline (high-dose); Cefiderocol (siderophore cephalosporin)
CRPA (Pseudomonas aeruginosa)	Multifactorial (efflux, OprD loss, MBL)	Ceftolozane-Tazobactam (MDR-PA without MBL); Cefiderocol; Imipenem-Relebactam; combination therapy for severe infections

⚠ Colistin Dosing: Colistimethate sodium (CMS) — dose in colistin base activity (CBA). Loading dose 5 mg/kg CBA IV (max 300 mg CBA) then maintenance 2.5–5 mg/kg/day divided q12h. Adjust for CrCl. Nephrotoxicity major concern (40–60%). Inhaled colistin adjunct for pneumonia.

▼10.5 Antifungal Stewardship

Drug Class	Agents	Spectrum	Key Notes
Triazoles	Fluconazole, Voriconazole, Itraconazole, Posaconazole, Isavuconazole	Fluconazole: Candida (not krusei/glabrata-often resistant), Cryptococcus. Voriconazole: Aspergillus, mold coverage. Posa/Isavu: Mucor coverage.	All: major CYP450 interactions. VRC: TDM essential (trough 1–5.5 µg/mL); variable oral absorption of ITR/VRC. Isavuconazole: fewer interactions, shorter QTc.
Echinocandins	Caspofungin, Micafungin, Anidulafungin	Candida (all species including FLC-resistant); No Cryptococcus, limited Aspergillus (salvage)	First-line for candidemia. Minimal drug interactions. IV only. Safe in hepatic impairment (caspofungin: reduce maintenance in Child-Pugh B). C. parapsilosis: intrinsic ↑ MIC.
Polyenes	Amphotericin B (deoxycholate, liposomal, lipid complex)	Broadest spectrum: Candida, Cryptococcus, Aspergillus, Mucor	Nephrotoxic (deoxycholate). Liposomal (L-AmB) preferred: less nephrotoxicity, equivalent/better efficacy. Premedicate with saline + antipyretics. Monitor K, Mg daily (renal wasting).
Flucytosine (5-FC)	Flucytosine	Candida, Cryptococcus (always in combination)	Never monotherapy (resistance emerges rapidly). Use with L-AmB for cryptococcal meningitis induction. TDM: peak 70–90 µg/mL, trough 20–40 µg/mL. Myelosuppression, hepatotoxicity.

▼10.6 Key Antibiotic Pharmacology & PK/PD

Antibiotic Class	PK/PD Index	Dosing Optimization	Clinical Implication
β-Lactams (penicillins, cephalosporins, carbapenems)	Time-dependent — %T>MIC (40–70%)	Prolonged/extended infusion (3–4h), increased frequency, continuous infusion	Meropenem 2g over 3h q8h vs standard 1g over 30min — better target attainment for high MIC organisms
Aminoglycosides (Gentamicin, Amikacin)	Concentration-dependent — Cmax/MIC (>8–10)	Once-daily dosing (extended interval) — higher peak, same/less nephrotoxicity	Gentamicin 5–7 mg/kg q24h (Hartford nomogram); monitor trough <1 µg/mL to avoid toxicity
Fluoroquinolones	Concentration + time-dependent — AUC/MIC (>100–125 for GNR)	Once-daily dosing capitalizes on both parameters	Ciprofloxacin for pseudomonal infections: ensure AUC/MIC target; dose 400 mg IV q8h not q12h
Vancomycin	AUC-dependent — AUC₂₄/MIC (400–600)	Bayesian AUC monitoring (preferred over trough alone)	Traditional trough 15–20 µg/mL abandoned (over-targeting → nephrotoxicity). AUC-guided safer.
Colistin	AUC-dependent — AUC/MIC	Loading dose essential; renal dose adjustment of maintenance	Colistin + rifampicin/meropenem often synergistic for CRAB. Inhaled adjunct reduces systemic toxicity.

⚡ Antibiotic IV→PO Switch Candidates (High Bioavailability)

Fluoroquinolones (Ciprofloxacin, Levofloxacin, Moxifloxacin) — ~95–100% bioavailability
Metronidazole — ~99%
Fluconazole — ~90%
TMP-SMX — ~90–100%
Linezolid — ~100%
Doxycycline — ~93%
Clindamycin — ~90%
Switch criteria: Afebrile ≥24h, improving clinically, tolerating PO, functioning GI tract, no malabsorption

📚 Key References

IDSA 2022 AMR Guidance — Tamma PD et al. Clin Infect Dis 2022;75(2):187–202.
MERINO Trial (JAMA 2018) — Harris PNA et al. JAMA 2018;320(10):984–994.
ASHP/SIDP Vancomycin TDM 2020 — Rybak MJ et al. Am J Health Syst Pharm 2020;77(11):835–864.
WHO AMR Action Plan 2023 — World Health Organization.
OVIVA Trial (NEJM 2019) — Li HK et al. NEJM 2019;380(5):425–436.
ZEPHyR Trial (CID 2012) — Wunderink RG et al. — Linezolid vs Vancomycin for MRSA pneumonia.

🩺 Practice Questions

Q1. A 58-year-old man with DM2 presents with 5 days of fever, headache, and productive cough. He farms rice in Khon Kaen. CXR shows right upper lobe cavitation. AFB smear ×3 is negative. WBC 18,000, CRP 210. Blood culture pending. What is the most important diagnosis to consider and what is the initial treatment?

Answer: Melioidosis

Cavitary pneumonia + diabetic patient + rural NE Thailand + AFB negative = melioidosis until proven otherwise. Also consider TB (AFB smear low sensitivity). Start Ceftazidime 2g IV q8h (or Meropenem if severe) as intensive phase while awaiting cultures. Send blood cultures ×2, sputum culture for B. pseudomallei, urine culture. If TB also strongly suspected, may need to start both — discuss with ID. Eradication phase: TMP-SMX × 3–6 months after clinical response.

Q2. Blood cultures from a 45-year-old with fever and PICC line grow Candida parapsilosis. CVC removed. What is the preferred antifungal and why is it different from other Candida species?

Answer: Fluconazole (if susceptible)

C. parapsilosis has intrinsically elevated MICs to echinocandins (FKS1 polymorphism) — echinocandin failure is documented. Unlike other Candida species where echinocandins are first-line, C. parapsilosis should be treated with Fluconazole 400 mg/day if susceptible. If resistant to fluconazole: use Voriconazole or Liposomal AmB. Must also: get ophthalmology exam, echo (rule out endocarditis), treat for 14 days after last positive culture.

Q3. A 32-year-old HIV-positive man (CD4 = 45, not on ART) develops headache and fever for 2 weeks. CSF: opening pressure 32 cmH₂O, WBC 12 lymphocytes, protein 110, glucose 42 (serum 90). India ink positive. CrAg titer 1:1024. What is the treatment strategy including ART timing?

Answer: Cryptococcal Meningitis with High ICP

Treatment: Liposomal AmB 3–4 mg/kg/day + Flucytosine 100 mg/kg/day × 14 days (induction) → Fluconazole 400 mg/day × 8 weeks (consolidation) → 200 mg/day maintenance until CD4 >200 × 3 months on ART. ICP management: daily therapeutic LPs to reduce OP to <20 cmH₂O or by 50%. DO NOT give corticosteroids (↑ mortality in crypto meningitis). ART timing: Delay 4–5 weeks after starting antifungal (COAT trial — early ART ↑ mortality in cryptococcal meningitis, unlike other OIs).