sepsis of unknown source

Sepsis = life-threatening organ dysfunction from dysregulated host response to infection (Sepsis-3). Source-undifferentiated sepsis requires broad empiric cover targeting the most likely sources (lung, urine, abdomen, skin, line) while pursuing rapid source identification. Antibiotics within 1 hour of recognition in septic shock; within 3 hours for sepsis without shock. Cover gram-positives + gram-negatives ± anaerobes based on clinical context.

sepsis of unknown source — initial management

blood cultures × 2 sets (peripheral + line if CVC present) BEFORE antibiotics — do not delay antibiotics >45 min for cultures
empiric antibiotics within 1 h (septic shock) or 3 h (sepsis without shock)
first-line: piperacillin-tazobactam 4.5 g IV q6h
if penicillin allergy: ceftriaxone 2 g IV daily + metronidazole 500 mg IV q8h (or meropenem if anaphylaxis)
add vancomycin 25–30 mg/kg IV load if: line infection, MRSA risk, skin/soft tissue source, shock
if immunocompromised / neutropaenic: see febrile neutropaenia — antipseudomonal monotherapy
IV crystalloid 30 mL/kg within first 3 h for hypotension or lactate ≥4 mmol/L
noradrenaline first-line vasopressor — target MAP ≥65 mmHg
source investigation: CXR, urinalysis + culture, lactate, consider CT abdomen/pelvis, examine skin and lines
NARROW antibiotics as soon as source and susceptibilities identified — reassess at 48–72 h

local antibiogram

Empiric regimens assume Canadian resistance patterns. Local antibiogram data should guide gram-negative cover — ESBL and fluoroquinolone resistance vary significantly between centres.

definitions (Sepsis-3)

term	definition
sepsis	infection + acute organ dysfunction (SOFA ≥2 above baseline)
septic shock	sepsis + vasopressor requirement to maintain MAP ≥65 + lactate >2 mmol/L despite adequate resuscitation

qSOFA (bedside screening — not diagnostic)

altered mental status (GCS <15)
respiratory rate ≥22/min
systolic BP ≤100 mmHg

≥2 criteria → assess for organ dysfunction (full SOFA, lactate). qSOFA is a screening prompt, not a diagnostic criterion — low sensitivity but good specificity for poor outcomes.

source identification

Systematic approach — the most common sources of undifferentiated sepsis:

source	proportion	key investigations
respiratory	~35%	CXR, sputum culture, consider CT chest
urinary	~25%	urinalysis, urine culture
abdominal	~15%	CT abdomen/pelvis with contrast
skin/soft tissue	~10%	clinical examination, wound cultures
line-related	~10%	differential time to positivity of line vs peripheral cultures
other (endocarditis, meningitis, bone/joint)	~5%	guided by clinical suspicion

Every patient gets: blood cultures × 2, CXR, urinalysis + culture, and a thorough physical examination (skin, lines, surgical sites, joints, spine).

empiric antibiotics — detail

standard (community-acquired, immunocompetent)

clinical scenario	regimen
undifferentiated, no specific source	piperacillin-tazobactam 4.5 g IV q6h
likely respiratory source	ceftriaxone 2 g IV + azithromycin 500 mg IV (CAP protocol)
likely urinary source	ceftriaxone 2 g IV daily
likely abdominal source	piperacillin-tazobactam 4.5 g IV q6h (or ceftriaxone + metronidazole)
likely skin/soft tissue	cefazolin 2 g IV q8h (non-purulent) or vancomycin (purulent / MRSA risk)
likely line-related	vancomycin 25–30 mg/kg IV load + piperacillin-tazobactam

healthcare-associated / resistant organism risk

piperacillin-tazobactam 4.5 g IV q6h + vancomycin
if ESBL risk or prior resistant gram-negatives: meropenem 1 g IV q8h + vancomycin
“double gram-negative cover” (β-lactam + aminoglycoside) is not routinely recommended — SSC 2021 recommends against it except in septic shock where multidrug-resistant organisms are suspected

penicillin allergy

allergy severity	approach
non-immune (GI upset)	piperacillin-tazobactam safe
distant mild rash	ceftriaxone 2 g IV + metronidazole
confirmed anaphylaxis	meropenem 1 g IV q8h (negligible cross-reactivity) ± vancomycin
anaphylaxis to ALL β-lactams (extremely rare)	aztreonam 2 g IV q8h + vancomycin + metronidazole — consult ID

resuscitation

fluid

30 mL/kg IV crystalloid within first 3 hours for hypotension or lactate ≥4 mmol/L — reassess after each bolus
balanced crystalloid (Ringer’s lactate) preferred over 0.9% saline (less hyperchloraemic metabolic acidosis)
no benefit of albumin over crystalloid for initial resuscitation
reassess fluid responsiveness (passive leg raise, pulse pressure variation, IVC assessment) — avoid fluid overload

vasopressors

noradrenaline first-line — target MAP ≥65 mmHg
add vasopressin 0.03 U/min if noradrenaline >0.25 µg/kg/min (catecholamine-sparing)
consider dobutamine if cardiac output remains low despite adequate MAP and volume status
ProCESS (2014): protocolised resuscitation (EGDT) not superior to usual care — target-driven but not protocol-mandated

corticosteroids

hydrocortisone 200 mg/day IV (50 mg q6h) for refractory septic shock (vasopressor-dependent despite adequate fluids)
not for sepsis without shock

reassessment at 48–72 h

review culture results → narrow antibiotics (de-escalation)
if no source identified and cultures negative: reassess the diagnosis — consider non-infectious mimics (pancreatitis, PE, adrenal crisis, drug reaction, malignancy)
if not improving: repeat cultures, advanced imaging (CT, echocardiography for endocarditis), consider ID consultation
lactate clearance ≥20% in first 6 hours associated with improved outcomes — trend serial lactate

duration

scenario	duration
bacteraemia — uncomplicated (gram-negative, source controlled)	7 days
bacteraemia — S. aureus	minimum 14 days IV (28 days if endocarditis or metastatic infection)
source-specific	per source guidelines (CAP 5 days, UTI 7 days, IAI 4 days post-source control)
culture-negative sepsis (clinically treated)	5–7 days — reassess need at 5 days

traps

every hour of delay in antibiotics increases mortality in septic shock by ~7.6% (Kumar (2006)) — this does not mean giving antibiotics “just in case” to stable patients with unclear diagnoses
lactate is not specific to sepsis — elevated lactate occurs with seizures, mesenteric ischaemia, liver failure, epinephrine, salbutamol, metformin, and thiamine deficiency
qSOFA is a screening tool with poor sensitivity — a score of 0–1 does not exclude sepsis in a patient who looks unwell
“pan-culturing” without clinical context leads to false positives and unnecessary antibiotics — culture from suspected source, not reflexively
do not anchor on the first positive culture — a single blood culture positive for CoNS is usually a contaminant; S. aureus bacteraemia is never a contaminant
S. aureus bacteraemia always warrants echocardiography and at minimum 14 days IV therapy — never treat as “simple” bacteraemia
remove unnecessary lines and catheters as part of source control — the simplest intervention is often the most effective