01Approach to the Critical Patient/attcp66

Immediate stabilization

›Airway and respiratory threats

›Airway protection status

›Altered mental status or obtundation requiring definitive airway

›If unable to protect airway, proceed to rapid sequence intubation

›Oxygenation failure

›SpO2 target >= 94%

›Supplemental oxygen escalation to high-flow if needed

›Secondary pneumonic plague

›New cough or hemoptysis in septicemic patient

›Upgrade to airborne precautions immediately

›Circulatory resuscitation

›Septic shock identification

›MAP < 65 mmHg

›SBP < 90 mmHg

›Tachycardia with poor perfusion

›IV crystalloid resuscitation

›30 ml/kg IV bolus as initial target

›Reassess for fluid responsiveness at 500 ml increments

›Vasopressor initiation

›Norepinephrine 0.01–0.5 mcg/kg/min IV for persistent hypotension

›Target MAP >= 65 mmHg

›Antibiotics within minutes of diagnosis

›Do not delay for confirmatory microbiology

›Delay > 24 hours dramatically increases mortality

›Blood cultures before antibiotics when feasible but must not delay treatment

Isolation and public health

›Infection control escalation

02History/hx59

Exposure and epidemiologic history

›Geographic and environmental exposures

›Endemic area residence or recent travel

›Southwestern US: New Mexico, Arizona, Colorado, California

›Madagascar, Democratic Republic of Congo

›Parts of Central and East Asia

›Animal contact

›Flea bites

›Direct contact with rodents, prairie dogs, rabbits

›Domestic cat scratch or bite

›Handling infected animal carcasses

›Occupational exposures

›Hunters, trappers, veterinarians

›Hikers and campers in endemic rural areas

Symptom onset and presentation

›Timeline

›Incubation period 2–8 days after exposure

›Abrupt onset high fever

›Rigors and chills

›Rapid progression

›Prostration within hours to days

›Altered mental status

›Hemodynamic deterioration

›Core symptoms

›Constitutional symptoms

›High fever

›Rigors, chills, malaise, headache

›Gastrointestinal symptoms

03Physical Exam/exam60

Vital signs

›Hemodynamic instability pattern

›Temperature

›High fever often > 39 C

›Hypothermia as marker of severe sepsis

›Blood pressure

›SBP < 90 mmHg or MAP < 65 mmHg indicating septic shock

›Orthostatic changes if not yet in frank shock

›Heart rate and respiratory rate

›Tachycardia with poor perfusion

›Tachypnea as respiratory compensation for metabolic acidosis

Skin examination

›Hemorrhagic manifestations

›Petechiae distribution

›Early and widespread distribution

›Herald sign of DIC

›Purpura and ecchymoses

›Progressive coagulopathy marker

›Differentiate from meningococcemia (very similar appearance)

›Acral findings

›Acral cyanosis and digital ischemia

›Frank gangrene of digits and nose (late finding; historical Black Death appearance)

›Mottling of extremities indicating microvascular failure

Lymph node and abdominal exam

›Lymph node examination

›Notably absent lymphadenopathy

›Distinguishes primary septicemic from bubonic plague

›Any lymphadenopathy suggests bubonic co-presentation

04Differential Diagnosis/ddx47

Life-threatening mimics

›Gram-negative sepsis syndromes

›Meningococcemia

›ICD-10 A39.2

›Purpura fulminans, identical skin findings

›No exposure history to rodents or endemic area

›Other gram-negative bacteremia

›E. coli, Klebsiella, Pseudomonas

›Most common misdiagnosis for septicemic plague

›ICD-10 A41.9 (sepsis unspecified)

›Rocky Mountain Spotted Fever

›ICD-10 A77.0

›Endemic overlap in southwestern US

›Tick exposure, petechial rash often begins peripherally

Bioterrorism and zoonotic differentials

›Bioterrorism agents with similar presentation

›Tularemia (typhoidal form)

›ICD-10 A21.7

›Similar exposure history (rabbits, ticks)

›Ulceroglandular or systemic forms

›Inhalational anthrax

›ICD-10 A22.1

›Bioterrorism differential in cluster presentations

›Mediastinal widening on CXR distinguishes

›Smallpox

›Historical bioterrorism concern

›Vesicular-pustular rash progression

›Other zoonoses

05Laboratory Tests/lt60

Blood cultures and microbiologic studies

›Blood cultures

›Two sets before antibiotics when feasible

›Y. pestis grows on standard media within 24–48 hours

›Automated systems may misidentify Y. pestis; alert lab explicitly

›Specimen labeling

›Label all specimens as BSL-3 high-risk pathogen

›Y. pestis poses significant laboratory infection risk

›Gram stain of blood

›Gram-negative coccobacilli

›Bipolar "safety pin" staining with Wright-Giemsa or Wayson stain

Hematologic and coagulation labs

›Complete blood count

›Leukocytosis with marked left shift

›Bandemia prominent finding

›Leukopenia in fulminant cases

›Thrombocytopenia

›Early DIC marker

›Progressive with coagulopathy

›Coagulation studies for DIC

›PT/INR and aPTT

›Elevated in DIC

›Monitor serially

›Fibrinogen

›Falling fibrinogen confirms consumptive coagulopathy

›Threshold < 1.5 g/L clinically significant

›D-dimer

›Markedly elevated in DIC

06Diagnostic Tests/dt60

Scoring Systems

›Sepsis severity tools applicable to plague

›SOFA score (Sequential Organ Failure Assessment)

›Respiratory, coagulation, hepatic, cardiovascular, CNS, renal components

›SOFA >= 2 meets sepsis definition

›Increasing SOFA score correlates with mortality

›qSOFA

›Respiratory rate >= 22/min

›Altered mentation

›Systolic BP <= 100 mmHg

›Score >= 2 predicts poor outcome outside ICU

›DIC scoring (ISTH criteria)

›Platelet count (< 50 = 2 points, < 100 = 1 point)

›Elevated fibrin degradation products (D-dimer moderate = 2, strong = 3)

›Prolonged PT (> 6 sec = 2, 3–6 sec = 1)

›Fibrinogen < 1 g/L = 1 point

›Score >= 5 indicates overt DIC

MRI

›MRI in plague complications

›Plague meningitis evaluation

›MRI brain with contrast for encephalopathy workup

›Leptomeningeal enhancement pattern

›Diffuse cerebral edema in severe cases

›Limitations in acute septicemic plague

›No role in primary diagnosis

›Logistical barriers in unstable patients

›CT preferred for rapid assessment in hemodynamically unstable patients

07Disposition/dispo34

ICU admission

›All septicemic plague patients require ICU admission

›No role for observation or outpatient management

›Case fatality rate 20–38% even with treatment

›Nearly 100% fatality untreated

›Delay > 24 hours in antibiotics dramatically increases mortality

›ICU care requirements

›Vasopressor capability

›Continuous hemodynamic monitoring

›Mechanical ventilation availability for ARDS

Isolation and infection control

›Isolation level

›Droplet isolation as minimum standard

›Standard plus droplet precautions for all septicemic plague cases

›Private room mandatory

›Airborne precautions upgrade

›Upgrade immediately if secondary pneumonic plague suspected

›N95 respirator, negative pressure room

›All close contacts within 2 meters require evaluation

Transfer criteria

›Transfer considerations

›Facility capability assessment

›Transfer to tertiary center if ICU or infectious disease support unavailable

›Do not delay antibiotics pending transfer

›Transfer team precautions

›Full droplet or airborne precautions during transport

›Pre-notify receiving facility and public health before transfer

08Treatment/t84

Antibiotic therapy: first-line regimens

›Preferred regimen (CDC 2021 guidelines)

›Gentamicin plus ciprofloxacin combination

›Gentamicin 5 mg/kg IV/IM every 24 hours

›Renal function monitoring mandatory

›Aminoglycoside levels: trough < 1 mcg/ml

›Ciprofloxacin 400 mg IV every 8 hours

›Baseline QTc before initiation

›Maximum QTc 500 ms before dose adjustment

›Gentamicin plus levofloxacin alternative

›Gentamicin 5 mg/kg IV/IM every 24 hours

›Levofloxacin 750 mg IV every 24 hours

›Renal dose adjustment required if CrCl < 50 ml/min

Antibiotic therapy: alternative regimens

›Streptomycin (historical gold standard)

›Streptomycin 1 g IV/IM every 12 hours

›First antibiotic proven effective against plague

›Limited availability in many settings

›Nephrotoxicity and ototoxicity monitoring

›Fluoroquinolone monotherapy

›Ciprofloxacin 400 mg IV every 8 hours

›NEJM 2025 (IMASOY trial): ciprofloxacin monotherapy non-inferior to combination for bubonic plague

›Septicemic plague data extrapolated; combination preferred pending further evidence

›Moxifloxacin 400 mg IV every 24 hours

›Alternative when other fluoroquinolones contraindicated

›QTc prolongation risk higher than ciprofloxacin

›Doxycycline

›Loading dose 200 mg IV, then 100 mg IV every 12 hours

›Listed as alternative per CDC 2021 guidelines

›Less robust evidence for septicemic form; supported by animal data

›Acceptable when aminoglycosides and fluoroquinolones contraindicated

Antibiotic therapy: meningitis add-on

›Chloramphenicol for plague meningitis

›Chloramphenicol 12.5–25 mg/kg IV every 6 hours

›Maximum 1 g per dose

›Add to primary regimen when meningeal involvement suspected or confirmed

›Good CNS penetration (aminoglycosides and fluoroquinolones have poor CNS entry)

›Monitor for bone marrow suppression with prolonged use

Treatment duration and transition

›Duration of therapy

›Total 10–14 days

›Extend if persistent fever or ongoing concern

›Full course mandatory regardless of clinical improvement timing

›IV to oral transition

›When clinically improving and tolerating oral intake

›Ciprofloxacin 500–750 mg orally every 12 hours

›Doxycycline 100 mg orally every 12 hours

Sepsis and shock management

›Fluid resuscitation

›Initial crystalloid bolus

›30 ml/kg IV crystalloid as initial target per Surviving Sepsis Campaign

›Reassess fluid responsiveness after each 500 ml increment

›Balanced crystalloid (lactated Ringer) preferred over normal saline

›Vasopressor therapy

›Norepinephrine first-line

›Start 0.01 mcg/kg/min IV

›Titrate to MAP >= 65 mmHg

›Maximum 0.5 mcg/kg/min before adding second agent

›Vasopressin adjunct

›0.03 units/min IV fixed dose

›Add when norepinephrine dose > 0.25 mcg/kg/min

›Norepinephrine-sparing effect

›DIC management

›Platelet transfusion

›Target platelet count >= 50 x 10^9/L if active bleeding or invasive procedure

›Consider >= 20 x 10^9/L for prophylactic threshold

›Fresh frozen plasma

›PT/INR > 1.5 with active bleeding

›Dose 10–15 ml/kg IV

›Cryoprecipitate

›Fibrinogen < 1.5 g/L with active bleeding

›Target fibrinogen >= 1.5 g/L

Contraindicated agents

›Ineffective antibiotics

›Penicillins

›75% case fatality rate with penicillin monotherapy

›Not effective against Y. pestis; avoid

›Beta-lactams and cephalosporins

›Not recommended by CDC 2021 guidelines

›Natural resistance mechanisms present

Post-exposure prophylaxis for contacts

›Close contact prophylaxis

›Doxycycline 100 mg orally twice daily for 7 days

›Preferred first-line post-exposure prophylaxis

›For household contacts and healthcare workers with unprotected exposure

›Ciprofloxacin 500 mg orally twice daily for 7 days

›Alternative to doxycycline

›Used when doxycycline contraindicated

›Monitoring of contacts

›Monitor for 7 days for fever or symptoms

›Immediate evaluation if symptoms develop

09Special Populations/sp73

Pregnancy

›Antibiotic considerations in pregnancy

›Gentamicin safety in pregnancy

›Category D (risk of fetal toxicity)

›Benefits outweigh risks in life-threatening plague

›Monitor fetal well-being and renal function closely

›Fluoroquinolone use in pregnancy

›Generally avoided; CDC guidelines accept use when benefit outweighs risk

›Ciprofloxacin: risk of arthropathy (animal data); use if alternative unavailable

›Doxycycline avoidance

›Contraindicated in pregnancy (fetal bone and tooth development)

›Avoid unless all alternatives exhausted

›Chloramphenicol in pregnancy

›Gray baby syndrome risk in third trimester

›Avoid near term; use with caution if meningitis benefit required

›Obstetric management

›Fetal monitoring

›Continuous fetal monitoring in septic shock

›Placental abruption risk with DIC

›Delivery planning

›Multidisciplinary team including obstetrics and critical care

›Preterm delivery may be required based on maternal condition

›Post-exposure prophylaxis in pregnancy

›Ciprofloxacin preferred over doxycycline

›500 mg orally twice daily for 7 days

›Shared decision-making with patient and obstetrics

Geriatric

›Physiologic considerations

›Altered pharmacokinetics

›Reduced creatinine clearance affects aminoglycoside dosing

›Extended interval dosing with careful monitoring

›Lower volume of distribution for gentamicin

›Atypical presentation risks

›Hypothermia instead of fever in severe sepsis

›Baseline cognitive impairment masking encephalopathy

›Reduced tachycardic response on beta-blockers

›Frailty and resuscitation

›Aggressive fluid resuscitation risks

›Higher risk of fluid overload and pulmonary edema

›Smaller fluid boluses with frequent reassessment

›Earlier vasopressor use may be preferred

›Goals of care assessment

›Early goals of care discussion given high mortality

›Frailty scales (CFS) to guide resuscitation intensity

›Aminoglycoside monitoring

›Enhanced nephrotoxicity risk in elderly

›Daily renal function monitoring

›Drug level monitoring: trough < 1 mcg/ml

›Consider shorter duration or alternative if toxicity develops

Pediatrics

›Antibiotic dosing in children

›Gentamicin pediatric dosing

›2.5 mg/kg IV/IM every 8 hours

›Neonates: 2.5 mg/kg every 12–18 hours depending on gestational age

›Therapeutic drug monitoring required

›Ciprofloxacin in children

›CDC guidelines accept ciprofloxacin use in children for plague

›15 mg/kg IV every 12 hours (maximum 400 mg per dose)

›10–15 mg/kg orally every 12 hours for oral transition (max 500 mg per dose)

›Doxycycline in children

›Avoid in children < 8 years due to dental staining

›Children >= 8 years: 2.2 mg/kg orally twice daily (max 100 mg per dose)

›Streptomycin in children

›15 mg/kg IV/IM every 12 hours (maximum 2 g per day)

›Pediatric-specific clinical features

›Higher prevalence of bubonic form in children

›Septicemic presentation less common than adults

›Abdominal pain common presenting complaint

›DIC manifestations

›Purpura fulminans pattern

›Urgent FFP and platelet support

›Post-exposure prophylaxis in children

›Doxycycline for children >= 8 years

›2.2 mg/kg orally twice daily for 7 days (max 100 mg per dose)

›Ciprofloxacin for children of any age

›15 mg/kg orally twice daily for 7 days (max 500 mg per dose)

10Background/b65

Epidemiology

›Global burden and distribution

›Worldwide incidence

›Approximately 1,000–2,000 reported cases per year globally

›WHO estimated 3,248 cases and 584 deaths reported 2010–2015

›Madagascar accounts for > 75% of global cases

›US epidemiology

›Average 7 human cases per year in the United States

›Predominantly southwestern states: New Mexico, Arizona, Colorado, California

›Most recent US cases concentrated in rural high-altitude regions

›Plague form distribution

›Septicemic plague proportion

›Accounts for approximately 10–25% of plague cases

›May occur as primary form or secondary to bubonic plague

›Highest case fatality rate among plague forms: 38% even with treatment

›Nearly universally fatal if untreated

›Animal reservoir

›Sylvatic plague maintained in rodent populations (ground squirrels, prairie dogs, rats)

›Flea vector: Xenopsylla cheopis (oriental rat flea) primary vector

›Domestic cats at high risk and transmit to humans via bite or scratch

Pathophysiology

›Y. pestis virulence mechanisms

›Organism characteristics

›Gram-negative, facultative anaerobic coccobacillus

›Grows at 28 C in flea vector; shifts virulence factor expression at 37 C in mammalian host

›F1 (fraction 1) antigen: antiphagocytic capsular antigen; basis of rapid diagnostic test

›Immune evasion

›Yops (Yersinia outer proteins): injected into host cells via type III secretion system

›Suppress inflammatory cytokine production early

›Allow silent bacteremia before immune activation

›Invasive cascade

›Pla protease: plasminogen activator enabling dissemination from infection site

›Facilitates direct bloodstream invasion without bubo formation (primary septicemic form)

›Septicemic complications

›DIC mechanism

›LPS (endotoxin) triggers systemic inflammatory cascade

›Activation of coagulation cascade and fibrinolysis

›Microthrombi causing end-organ damage and acral gangrene

›Secondary pneumonic plague

›Hematogenous seeding of lungs from bacteremia

›Y. pestis replicates in alveolar macrophages

›Subsequent aerosol transmission person-to-person (pneumonic form)

›Meningeal spread

›Bacteremia with CNS seeding

›Plague meningitis occurs 9–14 days after onset (particularly younger patients)

Therapeutic Considerations

›Antibiotic evidence base

›Historical perspective

›Streptomycin established 1940s as first effective treatment

›Chloramphenicol added for CNS penetration

›Fluoroquinolones accepted 1990s–2000s based on in vitro data and animal models

›Current evidence

›CDC 2021 MMWR guidelines: most comprehensive current reference

›Systematic review (Nelson et al., Clin Infect Dis 2020): individual case analysis 1937–2019

›NEJM 2025 IMASOY trial: ciprofloxacin non-inferior to aminoglycoside-ciprofloxacin for bubonic plague

›Septicemic plague evidence extrapolated; combination preferred for severe disease

›Antibiotic resistance

›Naturally susceptible; acquired resistance rare but documented

›Multidrug-resistant Y. pestis reported in Madagascar (1997): resistance to all first-line agents

›Bioterrorism concern: engineered resistance possible

›Supportive care considerations

›Surviving Sepsis Campaign applicability

›Hour-1 bundle: lactate, blood cultures, broad-spectrum antibiotics, IV fluids, vasopressors

›Class I recommendation for septic shock resuscitation

›DIC management principles

›Treat underlying cause (antibiotics) as primary DIC intervention

›Transfusion support for active bleeding

›Heparin not routinely recommended in plague-associated DIC

11Patient Discharge Instructions/pdi30

copy discharge instructions

›Discharge instructions for Plague (Septicemic)

›About your condition

›You were treated for septicemic plague, a severe bloodstream infection caused by the bacterium Yersinia pestis

›Plague is a serious infection requiring full completion of your antibiotic course

›Early follow-up is essential to monitor for late complications

›Medications

›Complete the full course of antibiotics prescribed even if you feel better

›Do not skip doses or stop antibiotics early

›Take oral antibiotics at evenly spaced intervals as directed

›Activity and diet

›Rest and gradually increase activity as strength returns

›Maintain good hydration: at least 2 litres of fluid daily unless restricted

›No specific dietary restrictions unless advised

›Wound and skin care

›Monitor any skin lesions, blackened areas, or digit color changes closely

›Return to emergency department immediately if skin lesions worsen or spread

›Hearing and kidney monitoring

›If you received aminoglycoside antibiotics, follow up for hearing test and kidney function within 2–4 weeks

›Return to emergency department immediately for

›Recurrent fever or chills

›New or worsening cough or coughing up blood

›Confusion, severe headache, or stiff neck

›Worsening skin lesions, new black areas, or digit color changes

›Sudden severe abdominal pain

›Decreased urine output or dark urine

›Any new bleeding or bruising

›Public health

12References/r37

Guidelines and key sources

›CDC 2021 MMWR guidelines (primary reference)

›Nelson CA, Meaney-Delman D, Fleck-Derderian S, et al. Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response

›MMWR Recommendations and Reports 2021

›PMID 34264565

›Primary authority for antibiotic selection, dosing, duration, and post-exposure prophylaxis

›Systematic review of individual cases

›Nelson CA, Fleck-Derderian S, Cooley KM, et al. Antimicrobial Treatment of Human Plague: A Systematic Review of the Literature on Individual Cases, 1937–2019

›Clinical Infectious Diseases 2020

›PMID 32435802

›Grounding for case fatality rates and treatment outcomes

›Aggregate data systematic review

›Godfred-Cato S, Cooley KM, Fleck-Derderian S, et al. Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939–2019

›Clinical Infectious Diseases 2020

›PMID 32435800

Clinical and epidemiologic references

›NEJM 2025 IMASOY trial

›Randremanana RV, Raberahona M, Bourner J, et al. Ciprofloxacin versus Aminoglycoside-Ciprofloxacin for Bubonic Plague

›New England Journal of Medicine 2025

›Ciprofloxacin monotherapy non-inferior to combination for bubonic plague

›Prentice and Rahalison landmark review

›Prentice MB, Rahalison L. Plague. Lancet 2007

›PMID 17416264

›Comprehensive pathophysiology and epidemiology reference

›Bioterrorism management

›Inglesby TV, Dennis DT, Henderson DA, et al. Plague as a Biological Weapon: Medical and Public Health Management

›JAMA 2000

›Working Group on Civilian Biodefense consensus statement

Evidence & Review

Evidence & Review