01Approach to the Critical Patient/attcp71

Immediate priorities

›Airway and breathing assessment

›Respiratory distress signs

›Tachypnea >= 30 per minute

›Accessory muscle use

›Secondary pneumonic plague risk

›Cough or hemoptysis present

›Bilateral crackles on auscultation

›If respiratory failure, immediate intubation preparation

›Droplet precautions mandatory

›Negative pressure room if available

›Hemodynamic status

›Septic shock features

›SBP < 90 mmHg

›MAP < 65 mmHg

›Lactate >= 2 mmol/l

›If septic shock, IV fluid resuscitation and vasopressors

›Class I recommendation

›Norepinephrine first-line vasopressor

›DIC screening

›Petechiae and purpura

›Bleeding from puncture sites

›Isolation and notification

›Droplet precautions until pneumonic plague excluded

›Standard precautions if purely bubonic and no cough

›N95 respirator if aerosolizing procedures planned

›Immediate public health notification

›Nationally notifiable disease in the US

02History/hx67

Exposure and epidemiologic history

›Flea exposure

›Residence or travel to endemic area within 14 days

›Western US Four Corners region

›Madagascar, Democratic Republic of Congo, sub-Saharan Africa

›Central Asia

›Flea-infested environments

›Hiking, camping, hunting in endemic areas

›Lack of flea control measures

›Animal contact

›Rodent or wild animal exposure

›Prairie dogs, ground squirrels

›Rabbits and hares

›Handling infected carcasses

›Hunters and trappers

›Wildlife biologists

›Domestic cat scratches or bites

›Cats can develop pneumonic plague

›Cat-to-human transmission documented

Symptom characterization

›Onset pattern

›Incubation period 2 to 8 days after flea bite or exposure

›Sudden onset fever and rigors

›Rapid progression over hours

›Bubo development

›Acutely painful swollen lymph node

›Regional to site of flea bite

›Constitutional symptoms

03Physical Exam/exam75

Vitals and general appearance

›Vital signs snapshot

›Temperature

›High fever often > 38.5 C

›Hyperthermia as severity marker

›Heart rate

›Tachycardia expected with fever and sepsis

›Bradycardia as ominous finding in severe disease

›Blood pressure

›SBP < 90 mmHg indicating septicemic progression

›MAP < 65 mmHg as resuscitation trigger

›Respiratory rate

›>= 30 per minute as severity marker

›Tachypnea suggesting pneumonic involvement

›General appearance

›Degree of prostration

›Unable to sit up

›Extreme weakness and malaise

›Diaphoresis and rigors

›Intermittent shaking chills

›Drenching sweats

Bubo examination

›Bubo characteristics

›Size

›1 to 10 cm typical range

›Rapidly enlarging over hours to days

›Tenderness

›Exquisitely tender to palpation

04Differential Diagnosis/ddx56

Life-threatening diagnoses

›Septicemic plague

›Primary septicemic without bubo

›ICD-10 A20.7

›GI symptoms dominate

›Secondary septicemic from bubonic progression

›DIC and multiorgan failure

›Purpura fulminans

›Pneumonic plague

›Secondary to bubonic or primary inhalation

›ICD-10 A20.2

›Nearly 100% fatal untreated

›Person-to-person respiratory transmission

›Droplet spread

›Tularemia

›Francisella tularensis

›Ulceroglandular form most common

›Ulcer at inoculation site distinguishes

›Similar exposure history

›Rabbit and tick exposure

›Treated with same antibiotic classes

Regional lymphadenopathy mimics

›Cat-scratch disease

›Bartonella henselae

›Regional lymphadenopathy after cat exposure

›Fluctuant and tender nodes

›Less systemic toxicity than plague

›Afebrile or low-grade fever common

05Laboratory Tests/lt65

Microbiologic diagnosis

›Blood cultures

›Before antibiotics when feasible

›Usually positive in septicemic plague

›Notify lab of plague suspicion before sending

›Y. pestis identification

›Gram-negative coccobacillus

›Bipolar staining safety pin appearance on Wayson stain

›Bubo aspirate

›Gram stain

›Gram-negative coccobacilli with bipolar staining

›Wright-Giemsa or Wayson stain for bipolar appearance

›Culture

›BSL-3 handling required

›Reference laboratory confirmation

›Molecular and antigen testing

›PCR targeting pla and caf1 genes

›Available at CDC and reference labs

›Remains positive even after antibiotics started

›F1 antigen rapid diagnostic test

›Point-of-care dipstick test

›Results in 15 minutes

›Validated in Madagascar field conditions

›Direct fluorescent antibody testing

›Clinical specimens from bubo, blood, sputum

›Reference laboratory method

›Serology

›Anti-F1 IgG antibody

06Diagnostic Tests/dt76

Scoring Systems

›Sepsis severity tools

›qSOFA

›Respiratory rate >= 22 per minute

›SBP <= 100 mmHg

›Altered mental status

›Score >= 2 indicating high sepsis risk

›SOFA score

›Multi-organ dysfunction quantification

›Serial assessment for ICU triage

›SIRS criteria

›Temperature < 36 or > 38 C

›Heart rate > 90 per minute

›Respiratory rate > 20 per minute

›WBC < 4 or > 12 x10^9/l

›Plague-specific severity stratification

›Uncomplicated bubonic

›Fever plus bubo, hemodynamically stable

›No respiratory symptoms

›Oral monotherapy candidate

›Complicated plague

›Secondary septicemic, pneumonic, or meningeal involvement

›Parenteral therapy and ICU level care required

MRI

›MRI role in plague

›Limited role in acute management

›Not primary imaging modality

›Availability and time constraints

07Disposition/dispo54

Admission indications

›All suspected plague cases require hospitalization

›Medical emergency with high case fatality rate

›Class I recommendation for immediate admission

›Observe minimum 48 to 72 hours after starting antibiotics

›Isolation requirements

›Droplet precautions until pneumonic plague excluded

›Contact precautions for draining bubo

›ICU indications

›Septic shock

›Vasopressor requirement

›Rising lactate despite resuscitation

›Secondary pneumonic plague

›Respiratory failure

›Bilateral infiltrates with hypoxemia

›DIC

›Active bleeding

›Severe thrombocytopenia

›Altered mental status or meningitis

›Neurologic compromise

›Seizures

Transfer considerations

›Transfer to tertiary center

›If BSL-3 laboratory capacity not available locally

›CDC laboratory network referral

›Subspecialty consultation needs

›Infectious disease

›Critical care

08Treatment/t112

Initial stabilization

›Sepsis resuscitation

›IV fluid resuscitation

›30 ml/kg crystalloid bolus for hypotension

›Reassess after each bolus

›Vasopressors for refractory hypotension

›Norepinephrine 0.01 to 3 mcg/kg/min IV

›Titrate to MAP >= 65 mmHg

›Supplemental oxygen

›Titrate to SpO2 >= 94%

›High flow nasal cannula for moderate hypoxemia

›Infection control measures

›Droplet precautions immediately

›Surgical mask on patient

›Healthcare worker N95 if aerosolizing procedures

›Obtain specimens before antibiotics when possible

›Blood cultures

›Bubo aspirate for gram stain and culture

›Immediate empiric antibiotics without delay

›Do not wait for culture results

First-line antibiotics

›Uncomplicated bubonic plague oral therapy

›Doxycycline PO

›100 mg PO twice daily

›Duration 10 to 14 days

›First-line for uncomplicated bubonic plague per CDC 2021 guidelines

›Ciprofloxacin PO

›500 mg PO twice daily

›Duration 10 days

›Shown noninferior to aminoglycoside-ciprofloxacin combination in IMASOY trial NEJM 2025

›Moderate to severe or unable to take oral therapy

›Gentamicin IV or IM

›5 mg/kg IV or IM every 24 hours

›Duration 10 to 14 days

›Adjust for renal impairment

›Monitor levels to prevent nephrotoxicity and ototoxicity

›Streptomycin IM

›15 mg/kg IM every 12 hours

›Duration 10 to 14 days

›Adjust for renal impairment

›Audiologic monitoring with prolonged use

›Progression to pneumonic or septicemic plague

›Dual therapy gentamicin plus ciprofloxacin or levofloxacin

›Gentamicin 5 mg/kg IV every 24 hours

›Ciprofloxacin 400 mg IV every 8 hours or levofloxacin 750 mg IV every 24 hours

›Parenteral route mandatory

›ICU level care

Alternative antibiotics

›Fluoroquinolone alternatives

›Levofloxacin IV or PO

›750 mg every 24 hours

›Duration 10 to 14 days

›Moxifloxacin IV or PO

›400 mg every 24 hours

›QT prolongation monitoring required

›Other alternatives

›Chloramphenicol

›25 mg/kg IV every 6 hours

›Preferred for plague meningitis due to CNS penetration

›Monitor for aplastic anemia

›Trimethoprim-sulfamethoxazole

›Second-line option for less severe disease

›Limited clinical evidence compared to primary agents

›Penicillins are contraindicated

›Associated with 75% case fatality rate

›Y. pestis resistant via intrinsic beta-lactamase

›Do not use amoxicillin, ampicillin, or piperacillin

Procedural management

›Bubo aspiration and incision and drainage

›Bubo aspiration for diagnostic purposes

›Narrow gauge needle into fluctuant area

›Send for gram stain, culture, F1 antigen testing

›Surgical incision and drainage when suppurative

›Fluctuant bubo with liquefaction

›Reduces bacterial burden and pain

›Post-procedure wound care

›Standard wound dressings

›Contact precautions for wound drainage

›Lumbar puncture for meningitis

›If meningeal plague suspected

›After CT head if focal neurologic signs

›CSF analysis for cell count, protein, glucose, culture

›Chloramphenicol preferred antibiotic for meningeal involvement

›Superior CNS penetration

›25 mg/kg IV every 6 hours

Post-exposure prophylaxis

›Close contacts of pneumonic plague cases

›Doxycycline PO

›100 mg PO twice daily

›Duration 7 days

›Ciprofloxacin PO

›500 mg PO twice daily

›Duration 7 days

›Monitor contacts for 7 days after last exposure

›Quarantine if symptomatic

›Temperature monitoring twice daily

Supportive care

›Fever and pain management

›Acetaminophen for fever and analgesic effect

›1000 mg PO or IV every 6 to 8 hours

›Preferred over NSAIDs in sepsis

›Opioid analgesia for bubo pain

›Morphine or hydromorphone IV for severe pain

›Titrate to comfort

›Nutritional support

›Adequate hydration maintenance

›Oral fluids when tolerated

›IV maintenance when oral not feasible

›NPO if bubo surgical drainage planned

›Resume as soon as tolerated post-procedure

›DIC management

›Treat underlying infection aggressively

›DIC resolves with source control

›Blood product support for active bleeding

›Fresh frozen plasma for coagulopathy

›Platelet transfusion threshold < 10 to 20 x10^9/l or active bleeding

›Hematology consultation

›Anticoagulation decisions complex in DIC

09Special Populations/sp73

Pregnancy

›Pregnancy considerations

›High-risk condition for both mother and fetus

›Maternal sepsis associated with preterm labor

›Placental involvement possible

›Antibiotic selection in pregnancy

›Gentamicin generally preferred for moderate to severe disease

›5 mg/kg IV every 24 hours

›Aminoglycoside category D; benefit outweighs risk in life-threatening infection

›Ciprofloxacin as alternative

›Category C

›Avoid in first trimester when possible

›Doxycycline

›Avoid in pregnancy particularly after 20 weeks

›Dental and bone effects in fetus

›Dual therapy recommended for complicated plague in pregnancy

›Gentamicin plus fluoroquinolone

›Infectious disease consultation mandatory

›Obstetric monitoring

›Fetal monitoring when viable gestation

›Continuous fetal heart monitoring if septic

›Maternal oxygenation target SpO2 >= 95%

›Fetal oxygen delivery dependent on maternal SpO2

›Neonatology consultation for preterm risk

Geriatric

›Older adult presentation

›Atypical fever response

›Blunted fever despite serious infection

10Background/b90

Epidemiology

›Global burden and distribution

›1000 to 3000 cases reported to WHO annually

›Most cases in Africa particularly Madagascar and DRC

›Sub-Saharan Africa accounts for over 95% of global cases

›Endemic regions

›Madagascar: highest annual case burden worldwide

›Western United States: Four Corners region

›Central Africa, parts of Asia and South America

›Seasonality

›Flea activity peaks in warm months

›Madagascar epidemic season August to November

›US epidemiology

›Average 7 cases per year reported in the US

›New Mexico, Colorado, Arizona, California most common states

›2015 outbreak included 16 cases

›Case fatality rate in US approximately 11%

›Higher in primary septicemic and pneumonic forms

›Clinical form distribution

›Bubonic plague 80 to 95% of cases

›Most common presentation worldwide

›Secondary septicemic plague approximately 10 to 20%

›Progression from untreated or delayed bubonic

›Pneumonic plague approximately 1 to 4% of cases

›Develops in approximately 12% of US cases from bubonic form

Pathophysiology

›Organism and transmission

›Yersinia pestis

›Gram-negative coccobacillus

›Facultative intracellular pathogen

›Transmission routes

›Flea bite from infected rodent flea (Xenopsylla cheopis)

›Direct contact with infected tissue or fluids

›Respiratory droplets from pneumonic plague patient

›Laboratory exposure

›Reservoir hosts

›Wild rodents: ground squirrels, prairie dogs, rats

›Domestic cats serve as amplifying hosts

›Disease mechanism

›Flea bite inoculation into dermis

›Y. pestis travels to regional lymph node via lymphatics

›Replication within lymph node macrophages

›Bubo formation

›Massive lymph node enlargement from bacterial replication

›Surrounding tissue edema and hemorrhagic necrosis

›Systemic dissemination

›Bacteremia from overwhelmed lymph node barrier

›Septicemic plague with endotoxin release

›Cytokine storm driving shock and DIC

›Pneumonic form

›Hematogenous seeding of lungs from bacteremia

›Highly infectious respiratory secretions produced

›Virulence factors

›F1 capsular antigen

›Anti-phagocytic properties

›Target of rapid diagnostic tests

›pla (plasminogen activator)

›Facilitates tissue invasion

›PCR target for molecular diagnosis

›Yersiniabactin iron acquisition system

›Essential for survival in iron-limiting host environment

Therapeutic Considerations

›Antibiotic mechanism and resistance

›Aminoglycosides target 30S ribosomal subunit

›Bactericidal activity against Y. pestis

›Streptomycin historical gold standard

›Gentamicin practical substitute given availability

›Fluoroquinolones target DNA gyrase and topoisomerase IV

›IMASOY trial 2025 NEJM demonstrated ciprofloxacin noninferior to combination therapy

›Emerging evidence supports oral monotherapy for uncomplicated disease

›Tetracyclines bacteriostatic at usual doses

›Doxycycline first-line oral agent per CDC 2021 guidelines

›Penicillin class contraindicated

›Intrinsic resistance with 75% case fatality in historical data

›Acquired antibiotic resistance rare but documented

›MDR Y. pestis isolates reported from Madagascar

›Fluoroquinolone resistance surveillance important

›Bioterrorism considerations

›Y. pestis listed as CDC Category A bioterrorism agent

›Highest priority pathogens for public health preparedness

›Engineered antibiotic-resistant strains possible threat

›Mass casualty event protocols

›Strategic national stockpile antibiotics available

›Public health emergency declaration criteria

›Post-exposure prophylaxis at scale

›Doxycycline or ciprofloxacin for close contacts

›Coordinated with public health authorities

›Vaccine status

›No licensed vaccine currently available in US or most countries

›Previously available killed whole-cell vaccine discontinued

›Subunit F1-V vaccines in development

›Pre-exposure prophylaxis not available for general population

›Recommended flea and rodent control for endemic area residents

11Patient Discharge Instructions/pdi36

copy discharge instructions

›Plague home care instructions

›Take all antibiotics exactly as prescribed until finished

›Do not stop early even if feeling better

›Duration typically 10 to 14 days total

›Adequate rest during recovery

›Fever and weakness may persist several days

›Stay well hydrated

›Fluids to replace losses from fever and sweating

›Bubo care

›Keep wound clean and dry if drainage was performed

›Change dressings as instructed

›Bubo swelling may take weeks to fully resolve

›Warning signs to return to ER immediately

›New or worsening cough or coughing up blood

›May indicate spread of infection to lungs

›Difficulty breathing or shortness of breath

›High fever not improving after 48 hours of antibiotics

›Confusion, severe headache, or stiff neck

›Skin bruising, bleeding, or purple spots

›Fainting or severe lightheadedness

›Rapid bubo enlargement after starting antibiotics

›Unable to keep antibiotics or fluids down

›Contact tracing and prevention

›Report all household close contacts to public health

›Contacts may need preventive antibiotics

›Flea prevention measures

›Treat pets with veterinarian-approved flea products

12References/r39

Guidelines and key sources

›Primary guidelines

›CDC MMWR 2021 Nelson et al. Antimicrobial Treatment and Prophylaxis of Plague

›Recommendations for naturally acquired infections and bioterrorism response

›MMWR Recommendations and Reports 2021

›JAMA 2000 Inglesby et al. Plague as a Biological Weapon

›Medical and public health management

›Working Group on Civilian Biodefense consensus statement

›Landmark trials and systematic reviews

›IMASOY Trial NEJM 2025 Randremanana et al.

›Ciprofloxacin versus aminoglycoside-ciprofloxacin for bubonic plague

›Demonstrated noninferior outcomes with ciprofloxacin monotherapy

›Godfred-Cato et al. Clinical Infectious Diseases 2020

›Treatment of human plague systematic review

›Antimicrobial efficacy data 1939 to 2019

›Jullien et al. Cochrane Database of Systematic Reviews 2020

›Rapid diagnostic tests for plague

›F1 antigen RDT validation evidence

›Epidemiology and outbreak reports

›Randremanana et al. Lancet Infectious Diseases 2019

›Madagascar urban plague epidemic August to November 2017

›Epidemiological characteristics report

›Prentice and Rahalison Lancet 2007

›Comprehensive plague review

›Global epidemiology and clinical management

›Bioterrorism and special topics

›Adalja Toner Inglesby NEJM 2015

›Clinical management of potential bioterrorism-related conditions

Evidence & Review