Bacteremia, Septicemia and Sepsis

Terminology

Bacteremia: bacteria in blood, NO multiplication. Septicemia: bacteria circulate + MULTIPLY, produce toxins. Viremia/parasitemia/fungemia = same concept, other organisms.

Patterns

Transient: spontaneous/minor event (brushing, chewing, instrumentation, non-sterile surgery). Usually cleared, can seed septicemia/IE. Continuous: constant release. Septic shock, endocarditis, endovascular infection; early enteric fever/brucellosis/leptospirosis. Intermittent: most infections. Undrained abscess (release ~45min before fever spike), early meningitis/pneumonia/septic arthritis/osteomyelitis.

Etiology

Bacterial (majority): Primary — typhoidal Salmonella, Brucella, spirochetes (Leptospira, Borrelia), HACEK, viridans strep, rickettsiae (endothelium). Secondary spillover — Gram+cocci (staph, beta-strep, enterococci, pneumococci), Gram-cocci (meningococci), Gram+bacilli (B. anthracis, Listeria), Gram-bacilli (E. coli, Klebsiella, Enterobacter, non-fermenters, Haemophilus, Aeromonas), anaerobes (Bacteroides).

Viral: HIV/retroviruses (CD4+macrophage), VHF agents (dengue/chikungunya/Ebola/Marburg/Lassa/yellow fever — endothelial cells), EBV (lymphocytes), CMV (monocytes/PMN/lymphocytes).

Parasitic: Direct RBC infection (Plasmodium, Babesia). Transient blood phase before tissue migration (Toxoplasma tachyzoite, Leishmania amastigote, Trypanosoma trypomastigote). Lymphatic-transient (microfilariae).

Fungal: Candida = leading fungemia cause (8-10% nosocomial BSI). C. albicans + non-albicans (tropicalis, parapsilosis, auris). Immunosuppressed/malignancy/chemo/terminal illness. Systemic mycosis agents disseminate from lung. Cryptococcus — fungemia possible but mainly meningitis.

Intravascular vs Extravascular

Intravascular: originates in CVS (endocarditis, myocarditis, pericarditis, vascular infection). Extravascular: MOST clinically significant bacteremia. Primary site → lymphatics → blood → RE clearance OR further multiplication (septicemia).

Contributing factors: immunosuppression, broad-spectrum antibiotics (kills normal flora, resistant strains emerge), invasive procedures/surgery, prolonged survival of debilitated patients.

Portal of entry: GU tract (25%, commonest) > Respiratory (20%) > Abscess (10%) > Surgical site (5%) > Biliary (5%). ~25% uncertain.

Organism-portal link: E. coli/GNB = urinary tract (most common)/intestine. H. influenzae b = meninges/epiglottis/lungs. Pneumococcus = meninges/lungs. Brucella = RE system. S. Typhi = small intestine/lymph nodes/RE system. Listeria = intestine/meninges. S. aureus/CoNS = surgical site.

Sepsis and Septic Shock

Bacteremia stage (usually silent) → Septicemic stage (symptoms from multiplication+toxin release).

Sepsis: fever/hypothermia ± chills/rigors, hyperventilation (resp alkalosis), skin lesions, altered mentation, diarrhea. Definition: life-threatening organ dysfunction from dysregulated host response to infection.

SOFA score (6 parameters): Respiratory (PaO2/FiO2), Coagulation (platelets), Liver (bilirubin), Cardiovascular (MAP), CNS (GCS), Renal (creatinine, urine output). Acute rise ≥2 points = organ dysfunction.

qSOFA (bedside, rapid): RR≥22/min, altered mentation, SBP≤100mmHg.

Septic shock: subset of sepsis, profound circulatory/metabolic abnormality. GRAVEST late complication — hypotension, DIC, multi-organ failure. Gram-negative ENDOTOXIN drives pathogenesis (“endotoxic shock”). Criteria: sepsis + persisting hypotension needing vasopressors (MAP≥65) + lactate >2mmol/L (18mg/dL) despite fluid resuscitation. Mortality: septic shock >40% vs sepsis 10%.

Laboratory Diagnosis

Specimen Collection

Site: PAIRS, 2 separate venipuncture sites + 2 separate decontaminations. Central line present → 1 sample from line + 1 venipuncture. Skin decon: 2-step — 70% isopropyl alcohol THEN povidone iodine/chlorhexidine, circular motion (5cm dia) center→periphery, air-dry before puncture. Timing: before antibiotics; if started, just before next dose. Volume: ↑volume=↑yield (+3.2%/mL). Adult 8-10mL/bottle, pediatric 1-3mL/bottle. Number: ≥2-3 sets (1 aerobic+1 anaerobic each) — 65%/80%/95% isolation with 1/2/3 sets. More for endocarditis. Dispensing/transport: no needle change (old practice, not recommended). Never refrigerate — 35°C incubator or room temp if delayed.

Culture Media

Conventional: Monophasic (BHI broth 50-100mL) or Castaneda’s biphasic (BHI agar slope+broth). 1:5 dilution (dilutes serum antibacterial factors). SPS = anticoagulant + neutralizes blood bactericidal activity. 37°C upright, up to 7 days. Monophasic: subculture when turbid or blind periodic — contamination risk each cap-opening. Biphasic: tilt bottle (broth over agar slope), NO cap opening — lower contamination risk.

Automated: BACTEC, BacT/ALERT (latest = Virtuo). Continuous monitoring, reads q15-20min. Faster, more sensitive. Diagnoses CRBSI via differential time to positivity.

Identification: colony morphology, Gram stain, biochemical or MALDI-TOF/VITEK.

AST: MIC-based (VITEK) PREFERRED over disk diffusion for blood isolates (esp. penicillin reporting in IE). De-escalation approach: broad empirical (e.g. meropenem+vancomycin) → narrow per culture sensitivity.

Fever of Unknown Origin (FUO)

Original definition (Petersdorf-Beeson 1961): fever >38.3°C ×2 occasions, >3 weeks, undiagnosed after 1 week INPATIENT workup.

Modified because: inpatient requirement dropped (outpatient workup now thorough), immunocompromised excluded (different workup needed), vague “1 week” → SPECIFIC qualitative investigation list (enables cross-center comparison).

Current definition:

1. Fever ≥38.3°C ×2 occasions
2. Duration ≥3 weeks
3. No known immunocompromised state
4. Uncertain diagnosis after thorough history+exam+obligatory investigations: ESR/CRP, CBC, electrolytes/creatinine/protein/ferritin/electrophoresis, liver+muscle enzymes, ANA+RA factor, urinalysis, blood culture(3 negative)+urine culture, CXR+abdominal USG, tuberculin/IGRA.

Etiology:

• Infections (36%, LARGEST): localized pyogenic (appendicitis, cholangitis, cholecystitis, abscess, osteomyelitis, PID, sinusitis, suppurative thrombophlebitis, intravascular); systemic bacterial (mycobacterial, typhoid, rickettsial, Mycoplasma, chlamydial, brucellosis, melioidosis, listeriosis, bartonellosis, actinomycosis/nocardiosis, spirochetes); viral/parasitic/fungal (broad list)
• Neoplasms (19%): lymphoma, leukemia, myeloma, renal/colon/liver cancer
• Non-infectious inflammatory (19%): RA, SLE
• Miscellaneous (19%): granulomatous disease, inherited/metabolic disease, thermoregulatory disorders
• Undiagnosed (7%)

Lab approach: History+exam guide specimen choice. Microscopy: blood film (malaria, microfilariae, LD bodies, Toxoplasma, trypanosomes), stool wet mount, Gram stain, ZN (TB), PAS/GMS (fungal). Culture: blood (typhoid, brucellosis), LJ medium (TB), pus/exudate, SDA (fungal), cell line (viral, e.g. CMV on human diploid cells). Serology: agglutination (brucellosis), microscopic agglutination (leptospirosis), cold agglutinin (Mycoplasma), Weil-Felix (rickettsial), Paul-Bunnell (IM), Widal (typhoid), microIF (chlamydial), RA factor, ANA. Molecular: PCR/multiplex PCR (low organism load). Other: CBC (neutrophilia=pyogenic), ESR, biopsy histopath, imaging (CXR-TB, CT/MRI-malignancy), ECG/echo (RF/IE).

Infections Causing Anemia

Iron deficiency (blood loss, microcytic hypochromic): Hookworm (Necator, Ancylostoma), Trichuris trichiura, Schistosoma.

Hemolytic (RBC destruction): P. falciparum, Babesia microti, Bartonella bacilliformis, C. perfringens sepsis, Mycoplasma pneumoniae, EBV (IM), Hepatitis A.

Megaloblastic: Diphyllobothrium latum — dissociates B12-intrinsic factor complex in gut → ↓B12 absorption (ileum).

Aplastic (bone marrow dysfunction, normocytic normochromic): M. tuberculosis, rickettsial infections, Leishmania donovani, CMV, EBV, VZV, Parvovirus B19 (aplastic crisis in chronic hemolytic anemia patients), HIV, HHV-6, Hepatitis C, rarely dengue.

Terminology

Bloodstream infections are among the most serious presentations in infectious disease, since microbial invasion of the blood can rapidly threaten every organ in the body — shock, multi-organ failure, and disseminated intravascular coagulation are all real possibilities, which is why timely detection of the causative agent is a priority laboratory goal.

The “-emia” suffix (Greek, “blood”) describes presence of a substance in blood, and the precise term used matters clinically:

• Bacteremia — bacteria present in blood without multiplication.
• Septicemia — bacteria actively circulating and multiplying in blood, producing harmful products (toxins).
• The same logic gives viremia, parasitemia, and fungemia for the corresponding organism classes.

Patterns of Bacteremia

• Transient — spontaneous or minor-event-triggered (tooth brushing, chewing, instrumentation of a contaminated mucosal site, surgery at a non-sterile site); usually cleared by host defences without progressing, though it can occasionally seed septicemia or a distant site (as in infective endocarditis).
• Continuous — organisms released at a fairly constant rate: septic shock, endocarditis, other endovascular infections, or the early stage of enteric fever, brucellosis, and leptospirosis.
• Intermittent — most other infections: a sequestered undrained abscess (bacteria released roughly 45 minutes before a febrile spike), or the early course of meningitis, pneumonia, septic arthritis, and osteomyelitis.

Etiological Agents

All four major microbial groups cause bloodstream infection, though bacteria account for the majority.

Bacterial: primary bloodstream pathogens include typhoidal salmonellae, Brucella, spirochetes (Leptospira, Borrelia), HACEK organisms, viridans streptococci, and rickettsiae (which specifically infect vascular endothelium) — each covered in its own topic. Beyond these, a wide range of organisms that primarily infect another site can secondarily spill into blood: Gram-positive cocci (staphylococci, beta-hemolytic streptococci, enterococci, pneumococci), Gram-negative cocci (meningococci), Gram-positive bacilli (Bacillus anthracis, Listeria), Gram-negative bacilli (E. coli, Klebsiella, Enterobacter, non-fermenters like Pseudomonas/Acinetobacter/Burkholderia/Stenotrophomonas, Haemophilus, Aeromonas), and anaerobes (Bacteroides).

Viral: HIV and other retroviruses (attack CD4 T cells and macrophages); viral haemorrhagic fever agents (dengue, chikungunya, Ebola, Marburg, Lassa, yellow fever — infect endothelial cells); EBV (invades lymphocytes); CMV (invades monocytes, PMNs, lymphocytes).

Parasitic: those directly infecting blood cells (Plasmodium, Babesia — RBCs); those transiently passing through blood before migrating to tissue (Toxoplasma tachyzoites, Leishmania amastigotes, Trypanosoma trypomastigotes); and those present transiently from lymphatics (microfilariae).

Fungal: Candida species are the leading cause of fungemia (8–10% of all nosocomial bloodstream infections — both C. albicans and non-albicans species like C. tropicalis, C. parapsilosis, C. auris), typically in immunosuppressed, malignancy, chemotherapy, or terminally ill patients. Systemic mycosis agents (Histoplasma, Blastomyces, Coccidioides, Paracoccidioides) can disseminate from an initial pulmonary focus into blood. Cryptococcus causes fungemia too but predominantly presents as meningitis.

Intravascular versus Extravascular Bloodstream Infection

Two major categories exist. Intravascular infections originate within the cardiovascular system itself (endocarditis, myocarditis, pericarditis, vascular infections — covered under Infective Endocarditis). Extravascular infections account for most clinically significant bacteremia: organisms multiply at a primary site (e.g. lungs), drain via lymphatics into the blood, and are either cleared by the reticuloendothelial system or multiply further, causing septicemia.

Contributing factors to BSI initiation: immunosuppression, broad-spectrum antimicrobial use (suppresses normal flora, letting resistant strains emerge), invasive procedures/extensive surgery (breach the blood barrier), and prolonged survival of debilitated patients.

Portal of entry for extravascular BSI: genitourinary tract (25%, the commonest), respiratory tract (20%), abscesses (10%), surgical site infections (5%), biliary tract (5%) — with up to 25% remaining uncertain. The likely organism tracks the portal: E. coli and other Gram-negative rods from the urinary tract (most common) or intestine; H. influenzae type b from meninges/epiglottis/lungs; pneumococcus from meninges/lungs; Brucella from the reticuloendothelial system; Salmonella Typhi from small intestine/lymph nodes/RE system; Listeria from intestine/meninges; S. aureus/CoNS from surgical site infections.

Clinical Manifestations: Sepsis and Septic Shock

Bloodstream infection runs through a bacteremia stage (usually asymptomatic) into a septicemic stage, where organism multiplication and toxin release produce systemic manifestations, graded by severity into sepsis and septic shock.

Sepsis presents with fever or hypothermia (with or without chills/rigors), hyperventilation (from CO₂ loss, causing respiratory alkalosis), skin lesions, altered mental status, and diarrhoea. It is formally defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

Severity and organ failure are assessed by the SOFA (Sepsis-related Organ Failure Assessment) score, based on six parameters: respiratory system (PaO₂/FiO₂), coagulation (platelet count), liver (bilirubin), cardiovascular (mean arterial pressure), CNS (Glasgow coma scale), and renal (creatinine, urine output). An acute rise in total SOFA score ≥2 points following infection identifies organ dysfunction.

Because full SOFA calculation takes time (multiple lab parameters), the qSOFA (quick SOFA) score allows rapid bedside identification: respiratory rate ≥22/min, altered mentation, systolic BP ≤100 mmHg.

Septic shock is a subset of sepsis with profound circulatory and cellular/metabolic abnormality — the gravest late-stage complication, manifesting as hypotension, DIC, and multi-organ failure (acute respiratory distress, renal failure, tissue destruction). Gram-negative endotoxin directly drives the pathogenesis of this “endotoxic shock.” Clinically, septic shock is identified by sepsis plus persisting hypotension requiring vasopressors to maintain MAP ≥65 mmHg and serum lactate >2 mmol/L (18 mg/dL) despite adequate volume resuscitation. Mortality: >40% for septic shock versus 10% for sepsis alone.

Laboratory Diagnosis

Diagnosis rests on isolating the causative agent by blood culture.

Specimen Collection

Extreme care is needed given the high risk of skin-flora contamination:

• Site and pairing: always collected in pairs, from two separate venipuncture sites with two separate skin-decontamination procedures. If a central line is present, one sample comes from the line and one from venipuncture.
• Skin decontamination: a two-step procedure — 70% isopropyl alcohol first, then a second antiseptic (povidone iodine or chlorhexidine), applied in a circular motion (5 cm diameter) from centre to periphery, allowed to air-dry before puncture.
• Timing: collected before antimicrobial therapy; if already started, just before the next dose.
• Volume: higher blood volume increases yield (isolation chance rises ~3.2% per mL cultured); at least 8–10 mL per bottle for adults, 1–3 mL for paediatric bottles.
• Number of sets: at least 2–3 sets (each set = one aerobic + one anaerobic bottle) for good isolation rate — roughly 65%, 80%, and 95% with one, two, and three sets respectively. More cultures are collected for suspected endocarditis.
• Dispensing and transport: dispensed directly into the culture bottle at the bedside without changing the needle (an older practice no longer recommended); transported immediately, never refrigerated — kept at 35°C incubator if delayed, or at room temperature.

Culture Media and Methods

Conventional media: monophasic (50–100 mL brain heart infusion broth) or Castaneda’s biphasic (BHI agar slope + BHI broth). Blood is diluted 1:5 in the medium to dilute any antibacterial serum components; sodium polyanethol sulfonate (SPS) is added as anticoagulant, which also neutralizes blood’s natural bactericidal activity. Bottles incubate upright at 37°C for up to 7 days. In monophasic medium, subcultures are made when the broth turns turbid or periodically (“blind” subcultures) — with real contamination risk each time the cap is opened; biphasic medium avoids this, since tilting the bottle lets broth flow over the agar slope without opening the cap.

Automated systems (BACTEC, BacT/ALERT, the latest being BacT/ALERT Virtuo) continuously monitor growth, reading every 15–20 minutes and flagging positivity automatically — faster, more sensitive than conventional media, and able to diagnose CRBSI via differential time to positivity.

Identification proceeds by colony morphology, Gram stain, and either conventional biochemical tests or automated systems (MALDI-TOF, VITEK).

AST: MIC-based methods (e.g. VITEK) are preferred over disk diffusion for blood isolates, especially for reporting penicillin susceptibility in endocarditis isolates. Given high MDRO prevalence and sepsis mortality, empirical antibiotics should start as soon as sepsis is clinically suspected, following a de-escalation approach: broad empirical coverage first (e.g. meropenem plus vancomycin, covering both Gram-negative and Gram-positive organisms), narrowed once culture sensitivity results return.

Fever of Unknown Origin (FUO)

FUO is not any unexplained fever — most febrile illness resolves or declares itself before this label applies. The term is reserved for prolonged fever that resists diagnosis despite intensive, specifically defined evaluation.

The original Petersdorf and Beeson definition (1961) required fever >38.3°C on ≥2 occasions, duration >3 weeks, and failure to diagnose despite one week of inpatient investigation. This has been substantially revised as diagnostics evolved: the inpatient requirement has been dropped (modern outpatient workup can be just as thorough), immunocompromised patients are now excluded (they need an entirely different, more extensive workup), and the vague “1 week of evaluation” criterion has been replaced by a specific, qualitative list of required investigations — allowing meaningful comparison of FUO cases across different centres and countries.

Current definition: (1) fever ≥38.3°C on at least two occasions; (2) duration ≥3 weeks; (3) no known immunocompromised state; (4) diagnosis remaining uncertain after thorough history, examination, and a defined set of obligatory investigations — ESR/CRP, complete blood count, electrolytes/creatinine/total protein/ferritin/protein electrophoresis, liver and muscle enzymes, ANA and rheumatoid factor, urinalysis, blood cultures (3 negative) and urine culture, chest X-ray and abdominal ultrasound, and tuberculin skin test or IGRA.

Etiology: infections account for the largest share (36%) — spanning localized pyogenic infection (appendicitis, cholangitis, cholecystitis, abscess, osteomyelitis, PID, sinusitis, suppurative thrombophlebitis, intravascular infection), systemic bacterial infection (mycobacterial disease, typhoid, rickettsial/Mycoplasma/chlamydial infection, brucellosis, melioidosis, listeriosis, bartonellosis, actinomycosis/nocardiosis, spirochete disease), and a broad range of viral, parasitic, and fungal causes. Non-infectious causes make up the rest in roughly equal shares: neoplasms (19% — lymphoma, leukaemia, myeloma, renal/colon/liver cancer), non-infectious inflammatory disease (19% — rheumatoid arthritis, SLE), miscellaneous causes (19% — granulomatous disease, inherited/metabolic disease, thermoregulatory disorders), and cases that remain undiagnosed even after full workup (7%).

Laboratory approach: guided by a detailed history (travel, immunization, exposure) and physical exam that points toward the right specimen — blood, urine, bone marrow aspirate, pus. Microscopy covers blood films (malaria, microfilariae, LD bodies, Toxoplasma, trypanosomes), stool wet mounts (parasitic cysts/trophozoites), Gram stain, Ziehl-Neelsen (TB), and PAS/GMS (fungal morphology). Culture spans blood (typhoid, brucellosis), Löwenstein-Jensen (TB), pus/exudate, SDA (fungal), and cell-line culture (viral, e.g. CMV on human diploid cells). Serology is extensive — agglutination tests for brucellosis, microscopic agglutination for leptospirosis, cold agglutinin for Mycoplasma, Weil-Felix for rickettsial disease, Paul-Bunnell for infectious mononucleosis, Widal for typhoid, microimmunofluorescence for chlamydial infection, RA factor, and ANA. Molecular methods (PCR, multiplex PCR) help when organism load is very low. Additional tests: CBC (neutrophilia suggests pyogenic infection), ESR, biopsy histopathology (for suspected tumour), imaging (chest X-ray for TB, CT/MRI for malignancy), and ECG/echocardiography (for rheumatic fever or endocarditis).

Infections Causing Anaemia

Several infections cause anaemia through distinct mechanisms, and recognizing which mechanism is in play narrows the likely cause considerably:

• Iron deficiency anaemia (from blood loss, microcytic hypochromic): hookworm (Necator, Ancylostoma), Trichuris trichiura, Schistosoma species.
• Haemolytic anaemia (RBC destruction): Plasmodium falciparum, Babesia microti, Bartonella bacilliformis, Clostridium perfringens sepsis, Mycoplasma pneumoniae, EBV (infectious mononucleosis), hepatitis A virus.
• Megaloblastic anaemia: caused specifically by Diphyllobothrium latum, which dissociates the vitamin B12-intrinsic factor complex within the gut lumen, blocking B12 absorption in the ileum.
• Aplastic anaemia (bone marrow dysfunction, normocytic normochromic): M. tuberculosis, rickettsial infections, Leishmania donovani, CMV, EBV, varicella-zoster virus, parvovirus B19 (specifically triggers aplastic crisis in patients with existing chronic haemolytic anaemia), HIV, HHV-6, hepatitis C virus, and rarely dengue.

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