Gram negative sepsis

**Definition (Sepsis-3):** Life-threatening organ dysfunction caused by a dysregulated host response to infection (SOFA score increase ≥2). Septic shock = sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥65 mmHg AND lactate >2 mmol/L despite adequate fluid resuscitation. qSOFA (bedside screen): RR ≥22, altered mentation, SBP ≤100 (≥2 = high risk).

**Common organisms:** E. coli (most common overall; urinary and GI/biliary source), Klebsiella pneumoniae, Pseudomonas aeruginosa (hospital-acquired, burns, neutropenia, ventilator, cystic fibrosis), Enterobacter, Serratia, Proteus, Bacteroides (anaerobic GI source), Neisseria meningitidis (meningococcemia, Waterhouse-Friderichsen syndrome), Acinetobacter. Also Salmonella and Vibrio vulnificus (liver disease, raw shellfish).

**Pathophysiology:** - Lipopolysaccharide (LPS/endotoxin) in the outer membrane: lipid A is the toxic component. LPS binds LPS-binding protein, then CD14/TLR4/MD-2 complex on macrophages, monocytes, and endothelium. This activates NF-κB and causes release of TNF-α, IL-1, IL-6, and IL-8. - Effects: fever; endothelial activation with increased permeability and vasodilation (NO release) leading to hypotension and warm shock initially (high cardiac output, low SVR), later cold shock with myocardial depression; complement activation (C3a, C5a); activation of the coagulation cascade (via tissue factor and the Hageman factor/factor XII pathway) leading to DIC (↓platelets, ↑PT/PTT, ↑D-dimer, ↓fibrinogen, schistocytes); neutrophil activation; ARDS; AKI (acute tubular necrosis); lactic acidosis. - Early: respiratory alkalosis, then anion-gap metabolic acidosis. - Gram-negatives also have endotoxin released on cell lysis, which is why rapid bactericidal therapy can transiently worsen the picture (Jarisch-Herxheimer-like reaction, more classic with spirochetes). - Gram-positive sepsis, in contrast, relies on superantigens (TSST-1) or peptidoglycan/lipoteichoic acid (TLR2).

**Clinical presentation:** Fever or hypothermia, tachycardia, tachypnea, hypotension, altered mental status, warm flushed skin early, oliguria, leukocytosis or leukopenia with bandemia, elevated lactate. Petechiae/purpura suggest meningococcemia or DIC. Ecthyma gangrenosum (necrotic skin lesions) suggests Pseudomonas.

**Diagnosis:** Blood cultures ×2 (before antibiotics, but do not delay therapy), lactate, CBC, CMP, coagulation studies, UA/urine culture, CXR, and cultures from other suspected sources. Procalcitonin may help support bacterial etiology.

**Management (Surviving Sepsis Campaign):** - Recognize early and give broad-spectrum IV antibiotics within 1 hour in septic shock/high suspicion. Empirical gram-negative coverage: antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, or carbapenem) ± aminoglycoside or fluoroquinolone for high risk. Add MRSA coverage (vancomycin) if risk factors. Carbapenems for ESBL producers. Use ceftriaxone for community-acquired, less resistant infections or meningococcus. - Crystalloid resuscitation (30 mL/kg for hypotension or lactate ≥4), balanced crystalloids preferred. - Vasopressors if MAP <65: norepinephrine first-line; add vasopressin; consider hydrocortisone for refractory shock. - Source control (drain abscess, remove infected catheter, relieve obstructed infected urinary or biliary tract). - Supportive care: ventilation (low tidal volume for ARDS), DVT prophylaxis, glucose control, stress ulcer prophylaxis if risk factors. - Drotrecogin alfa (activated protein C) and anti-endotoxin/anti-TNF therapies failed and are not used.

**High-yield associations/pearls:** - Urosepsis (E. coli, Klebsiella, Proteus) is a classic cause, especially with obstruction or catheters. - Biliary (ascending cholangitis) and intra-abdominal sources (E. coli, Bacteroides). - Neutropenic patients: Pseudomonas, so need an antipseudomonal agent (cefepime). - Asplenia: encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) causing overwhelming post-splenectomy sepsis. - Waterhouse-Friderichsen: bilateral adrenal hemorrhage due to meningococcemia with DIC, leading to adrenal insufficiency. - Pseudomonas: oxidase positive, produces exotoxin A (inhibits EF-2), pyocyanin; treat with antipseudomonal agents. - Endotoxin is heat stable and not destroyed by autoclaving; assayed with Limulus lysate test. - Complications: DIC, ARDS, AKI, adrenal insufficiency, multiorgan failure; mortality is high in septic shock (about 30-40%).