Plague

Plague is an acute, contagious, febrile illness usually transmitted to humans by the bite of an infected flea. Plague occurs as 3 major clinical events: bubonic plague, septicemic plague, and pneumonic plague.[1]  Human-to-human transmission is ucommon except during epidemics of pneumonic plague. The disease is caused by a coccobacillus-shaped, gram negative bacterium referred to as Yersinia pestis. Yersinia is named in honor of Alexander Yersin, who successfully isolated the bacteria in 1894 during the pandemic that began in China in the 1860s. Plague is most often vector borne, transmitted by fleas, to a variety of rodent populations. The classic vector is the oriental rat flea Xenopsylla cheopis. 

Historically, plague has been known for centuries as being responsible for 3 major pandemics dating back to 430-427 BCE.[1]  The second major pandemic was the Black Death dating back to 1347-1351 which was responsible for millions of deaths across Europe. The third originated in China during the 1800’s. With the exception of Antarctica, plague is worldwide in distribution, with most of the human cases reported from developing countries with outbreaks reported regularly. 

Three studies have shown that this bacterium emerged from the gut pathogen Yersinia pseudotuberculosis shortly after the first epidemic.[2] Three biovars (with minor genetic variations) have been identified within the Y pestis clone: Antiqua, Medievalis, and Orientalis.[2] One theory is that these biovars emerged before any of the plague epidemics. In fact, as reported by Drancourt et al (2004), genotyping performed on bacteria derived from the remains of plague victims of the first two epidemics revealed sequences similar to that of Orientalis.[3]

Although plague has been considered a disease of the Middle Ages, multiple outbreaks in India and Africa during the last 20 years have stoked fears of another global pandemic. Since the number of human cases has been rising and outbreaks are reappearing in a variety of countries after years of quiescence, the plague is considered a reemerging disease.[4, 5, 6]

One reason for plague's reemergence may be global warming, which is ideal for increasing the prevalence of Y pestis in the host population. One study has estimated a more than 50% increase in the plague host prevalence with an increase of 1º C of the temperature in spring.[7]  Another reason may be the human population explosion worldwide, which is bringing humans into ever-increasing contact with wildlife. Lastly, the dramatic population increase will contribute to conditions of overcrowding and poor sanitation—conditions ripe for the flourishing of plague hosts and vectors.

Aerosolized Y pestis, causing primary pneumonic plague, has been recognized by bioterrorism experts as having one of the highest potentials as a bioterrorism agent due to its extremely high mortality, its high uptake into enzootic and epizootic animals as well as humans, and its ability to be spread over a large area. It has been classified as a Category A, or high priority, bioterrorism agent by the Centers for Disease Control and Prevention (CDC).[8]

The virulence of this bacterium results from the 32 Y pestis chromosomal genes and two Y pestis –specific plasmids, constituting the only new genetic material acquired since its evolution from its predecessor.[9] These acquired genetic changes have allowed the pathogen to colonize fleas and to use them as vectors for transmission.[4]

Plague is a zoonotic disease that primarily affects rodents; humans are incidental hosts. Dog-to-human transmission was reported in a 2014 outbreak in Colorado.[10] Survival of the bacillus in nature depends on flea-rodent interaction, and human infection does not contribute to the bacteria's persistence in nature. Of the 1500 flea species identified, only 30 of them have been shown to act as vectors of plague.[11] The most prominent of these vectors is Xenopsylla cheopis (oriental rat flea); however, Oropsylla montana has been incriminated as the primary vector for this disease in North America.[12]

Host fatality has been known to be the harbinger of an epidemic.[11] Whether susceptibility and fatality are related is unknown. However, ground squirrels and prairie dogs have been known to be highly susceptible to plague, whereas others have been known to be either moderately susceptible or absolutely resistant to infection.

 

Pathophysiology

Y pestis is a nonmotile, pleomorphic, gram-negative coccobacillus that is nonsporulating. The bacteria elaborate a lipopolysaccharide endotoxin, coagulase, and a fibrinolysin, which are the principal factors in the pathogenesis of plague. The pathophysiology of plague basically involves two phases—a cycle within the fleas and a cycle within humans.

The key to the organism’s virulence is the phenomenon of "blockage," which aids the transmission of bacteria by fleas. After ingestion of infected blood, the bacteria survive in the midgut of the flea owing to a plasmid-encoded phospholipase D that protects them from digestive enzymes.[13] The bacteria multiply uninhibited in the midgut to form a mass that extends from the stomach proximally into the esophagus through a sphincter-like structure with sharp teeth called the proventriculus.

It has been shown that this property requires the presence of hemin-producing genes, which are needed for the formation of a biofilm that permits colonization of the proventriculus.[14] In fact, as described by Jarrett et al (2004), this mutation in hemin genes allows colonization in the midgut without extension to the proventriculus. Consequently, the "blockage phenomenon" does not occur, thereby leading to failure of transmission.[14] This blockage causes the flea to die of starvation and dehydration.[15]

As a desperate measure, the flea then repeatedly tries to obtain a meal by biting a host, managing only to regurgitate the infected mass into host's bloodstream. However, the concept that the flea must be engorged before becoming infectious loses support when trying to explain the rapid rate of spread of disease during a plague epidemic. Studies of vectors such as O montana clearly indicate the redundancy of the aforementioned hypothesis, since this vector does not die of blockage and remains infectious for a long period, unlike its counterpart.[16]

Once the flea bites a susceptible host, the bacilli migrate to the regional lymph nodes, are phagocytosed by polymorphonuclear and mononuclear phagocytes, and multiply intracellularly. Survival and replication within macrophages are probably of greatest importance in early stages of the disease.[17] Involved lymph nodes show dense concentrations of plague bacilli, destruction of the normal architecture, and medullary necrosis. With subsequent lysis of the phagocytes, bacteremia can occur and may lead to invasion of distant organs in the absence of specific therapy.

The following are the modes of plague transmission in humans:[18]

1. Bites by fleas

2. Exposure to humans with pneumonic plague

3. Handling of infected carcasses

4. Scratches or bites from infected domestic cats

5. Exposure to aerosols containing plague-causing bacilli

Another potential mode of plague transmission in humans is contact with an infected dog. In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924.[10]

Frequency

United States

Between 2010 and 2015, 39 cases of human plague were reported in the United States, resulting in 5 deaths.[19] About half of human plague cases involve individuals aged 12-45 years, although it can affect people of all ages. The risk is slightly higher in men, probably owing to a higher likelihood of outdoor activities among males, increasing their risk of exposure to vectors.[19]

A few natural plague foci are located in the western United States. During the time period of 1970-2018, approximately 15 US states reported at least once case of bubonic plague.[19]  From the states of Arizona, California, Colorado, New Mexico, and Utah, 49 cases of plague and 3 attributed deaths were reported from 1994-1999.[20] In 2006, 13 plague cases were reported among residents of New Mexico, Colorado, California, and Texas, two of which resulted in death.[21]  The largest enzootic plague area is in North America - the southwestern United States and the Pacific coastal area. 

On average, 7 cases of human plague are reported annually in the United States, with a range of 1-17 cases per year.[19] Over time, human cases of plague have moved from crowded cities to the rural West. This has paralleled the observed patterns of introduction of exotic plants and animals.[22] The rate of plague in the United States is low, since most of the endemic areas are rural and largely uninhabited, thereby limiting human exposure. In recent years, and with the potential threat for bioterrorism, the Centers for Disease Control and Prevention (CDC) has specified Y pestis as a Category A (Tier 1) bioterrorism agent. As reviewed by Ansari et al, 2 historical events, the siege of Caffa in 1346 and the purported release of the plague bacillus in the second Sino-Japanese War and World War II, are cited examples of the effect of the deliberate release of plague into a susceptible population.[1]

Animal reservoirs in America mostly include squirrels, rabbits, and prairie dogs. However, there has been an established role of domestic cats in the transmission of plague since the late 1970s. From 1977-1998, 23 cases of human plague associated with cats were reported from the western states, representing 8% of all reported plague cases during that time.[12] In this scenario, transmission via inhalation was more common than in any other form of plague.

In a study of cat-related plague, mortality was associated with misdiagnosis or delay in treatment. Of the 23 cases from 1977-1998, 5 of 17 bubonic plague cases resulted in death.[12]

In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924.[10]

International

Most cases of plague reported outside of the United States are from developing countries in Africa and Asia. During 1990-1995, a total of 12,998 cases of plague were reported to the World Health Organization (WHO), particularly from countries such as India, Zaire, Peru, Malawi, and Mozambique. The following countries reported more than 100 cases of plague: China, Congo, India, Madagascar, Mozambique, Myanmar, Peru, Tanzania, Uganda, Vietnam, and Zimbabwe. Several foci are located in the semi-arid regions of northeastern Brazil. Outbreaks have been reported from Malawi and Zambia.

The WHO reports that, in 2003, 9 countries reported a total of 2118 plague cases and 182 deaths, 98.7% and 98.9% of which were reported from Africa, respectively. Currently, the 3 most endemic countries are Madagascar, The Democratic Republic of Congo, and Peru.[1]

Mortality/Morbidity

The risk of plague-related death depends on the type of plague and whether the infected individual receives appropriate treatment.[4]

The following are the estimated mortality rates associated with the different types of plague:

• Pneumonic plague - Untreated, 100%; treated, 50%
• Bubonic plague - Untreated, up to 60%; treated, < 5% when appropriate antibiotics are used
• Septicemic plague - 20%-25%

Race

In the United States, most cases of plague occur in whites. Native Americans living in endemic areas of Arizona, New Mexico, and Utah have a 10-fold greater risk of acquiring the disease than non–Native Americans.

Humans are exposed in the domestic or outdoor environment. Infections in the wild are usually isolated or sporadic, causing infections in Indians, hunters, miners, and tourists in the United States and Brazil.

Sex

Plague has no sexual predilection.

Age

Most cases of plague occur in persons younger than 20 years.

Travel to endemic areas within and outside the United States, history of a flea bite, close contact with a potential host, or exposure to dead rodents or rabbits should raise suspicion for plague.

Bubonic plague

This is the most common presentation of naturally occurring plague.

Disease follows the bite of a flea infected with Y pestis. Bacteria deposit in the area of the bite and disseminate to regional lymph nodes. 

The incubation period varies but usually ranges 2-6 days.

There is a sudden onset of high fever, chills, and headache associated with the development of swollen and painful lymph nodes.

Patients with this type experience body aches, extreme exhaustion, weakness, abdominal pain, and/or diarrhea.

Painful, swollen lymph glands (buboes) arise, usually in the groin (most common site), axilla, or neck.

Axillary, cervical, and epitrochlear buboes are almost always seen in cat-associated plague.[23]  Occasionally, the infection can involve mesenteric or retroperitoneal lymph nodes mimicking a surgical abdomen. 

Without intervention, this stage may lead to secondary pneumonic plague or meningitis or may disseminate and manifest as sepsis.

Meningeal plague

This is characterized by fever, headache, and nuchal rigidity.

Buboes are common in meningeal plague.

Axillary buboes are associated with an increased incidence of meningeal plague.

Pharyngeal plague

Pharyngeal plague results from ingestion of the plague bacilli.

Patients experience sore throat, fever, and painful cervical lymph nodes.[24]

Marshall et al (1967) has described an asymptomatic pharyngeal carrier state of Y pestis infection in patients with bubonic plague.[25]

Pneumonic plague

Pneumonic plague is highly contagious and transmitted by aerosol droplets. It is less common than either bubonic or septicemic plague, but can be most severe. It can be classified as either primary occurring with the inhalation of respiratory droplets containing the organism or secondary in which the lungs are involved following hematogenous spread. The latter may occur with bubonic or septicemic plague. 

Primary pneumonic plague may be seen in laboratory workers, individuals exposed to an infected person, or those who have been exposed to a cat with pneumonic plague.[26]

There is an abrupt onset of fever and chills, accompanied by cough, chest pain, dyspnea, purulent sputum, or hemoptysis. The usual incubation period is 1-4 days. The onset may appear like an influenza-like illness that progresses rapidly to include lower respiratory tract symptoms and findings. 

Buboes may or may not be associated with pneumonic plague.

Pneumonic plague may spread from human to human by aerosols making Y pestis a potential agent of bioterrorism. The average secondary infection rate (R0) is approximately 1.3.[1]

Septicemic plague

This occurs when the flea bite injects the bacteria directly into the vasculature or when they bypass regional lymph nodes (primary septicemic plague) or when the bacteria hematogenously spread from a bubo. This is the second most common manifestation of plague in which the infection rapidly progresses to sepsis, multiorgan failure, and possibly death, if not successfully treated.    

Septicemic plague is observed in elderly patients and causes a rapid onset of symptoms.

Patients experience nausea, vomiting, abdominal pain, and diarrhea. (Diarrhea may be the predominant symptom.)

Patients exhibit a toxic appearance and soon become moribund.

Buboes may not be observed in septicemic plague, making the diagnosis elusive.

Septicemic plague carries a high mortality rate and is associated with disseminated intravascular coagulation (DIC), multiorgan failure, peripheral gangrene, and profound hypotension.

Plague initially occurred as a flea-borne septicemic disease. However, over its evolutionary course, it acquired the plasminogen activator gene, giving rise to the bubonic form of disease.[27]

Genitourinary/gastrointestinal plague

This was reported as the sole presentation of Y pestis infection in 4 of 27 patients in a case series published in 1992.[18]

Cutaneous plague

This manifests as purpura.[24]

Bubonic plague

Vesicles may be observed at the site of the infected flea bite. With advanced disease, papules, pustules, carbuncles, or an eschar may be observed in areas of the skin drained by the involved lymph nodes. A generalized papular rash of the hands and feet may be observed.

Buboes are unilateral, oval, extremely tender lymph nodes and can vary from 2-10 cm in size. Femoral lymph nodes are most commonly involved. Patients with an inguinal bubo walk with a limp, and the affected limb may be in a position of flexion, abduction, and external rotation. Patients resist any attempt to examine the involved lymph nodes. Enlargement of the buboes leads to rupture and discharge of malodorous pus.

Hepatomegaly and splenomegaly often occur and may be tender.

Pharyngeal plague

Pharyngeal plague causes pharyngeal erythema and painful and tender anterior cervical nodes.

Pneumonic plague

Pneumonic plague causes fever, lymphadenopathy, productive sputum, and/or hemoptysis.

Septicemic plague

Because of an overwhelming infection with the plague bacillus, patients with septicemic plague have a toxic appearance and may present with tachycardia, tachypnea, and hypotension. Hypothermia is common.

Generalized purpura may be observed and can progress to necrosis and gangrene of the distal extremities.

No evidence of lymphadenitis or bubo formation is apparent. Patients may die of a high-grade bacteremia.

Y pestis is the cause of plague.

Risk factors include the following:

• Flea bite

• Contact with a patient or a potential host

• Contact with sick animals or rodents

• Residence in an endemic area of plague (eg, southwestern United States)

• Presence of a food source for rodents in the immediate vicinity of the home

• Camping, hiking, hunting, or fishing

• Occupational exposure (eg, researchers, veterinarians)

• Direct handling or inhalation of contaminated tissue or tissue fluids

• Contact with a dog infected with Y pestis[10]

The possibility of plague should be strongly considered in febrile patients from endemic areas who have history of exposure to rodents. Rapid recognition of the classic symptoms of this disease and laboratory confirmation are essential to instituting lifesaving therapy.

Expertise in testing for plague bacilli is limited to reference laboratories in plague-endemic states and the CDC.

Leukocytosis with a predominance of neutrophils is observed, and the degree of leukocytosis is proportional to the severity of illness.

Peripheral blood smear shows toxic granulations and Dӧhle bodies.

Thrombocytopenia is common, and fibrin degradation product levels may be elevated.

Serum transaminases and bilirubin levels may be elevated.

Proteinuria may be present, and abnormalities in renal function have been associated.

Hypoglycemia may be observed.

Twenty-seven percent to 96% of blood cultures are positive for Y pestis in patients with bubonic plague and septicemic plague.[26] Microbiology staff should be informed of the possibility of Y pestis agents in samples so that they can take adequate precautions when handling specimens.

Y pestis may be observed on a peripheral blood smear. Smear stained with Wright-Giemsa reveals rod-shaped bacteria. A Wayson stain demonstrates the typical "safety pin" appearance (bipolar staining) of the bacterium. Gram stain shows small gram-negative coccobacilli.

Lymph node aspirates often demonstrate Y pestis. In patients with pharyngeal plague, Y pestis is cultured from throat swabs.

Cerebrospinal fluid (CSF) analysis in meningeal plague may show pleocytosis with a predominance of polymorphonuclear leukocytes.[29] Gram stain of CSF may show plague bacilli.

Gram stain of sputum often reveals Y pestis.

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[30]

Chest radiography reveals patchy infiltrates, consolidation, or a persistent cavity in patients with pneumonic plague.

ECG reveals sinus tachycardia and ST-T changes.

Nuclear imaging may help localize areas of lymphadenitis and meningeal inflammation.

Direct immunofluorescence testing of fluid or cultures may aid in rapid diagnosis. A novel rapid diagnostic test capable of detecting miniscule amounts of Y pestis F1 antigen within 15 minutes has been developed and field tested in Madagascar.[31] This test yields 100% sensitivity and specificity for Y pestis and other Yersinia species.

A passive hemagglutination test (performed on serum from a patient in acute or convalescent stages) with a 16-fold or greater increase in titer (single titer) suggests plague infection.[24]

A 4-fold rise in antibody titers to the F-1 antigen of Y pestis also confirms infection.[21]

A polymerase chain reaction (PCR) using primers derived from Y pestis plasminogen activator gene has been used to detect the pathogen in fleas, but the application of this method in humans is still a matter of speculation.[32]

Aspiration of lymph node (bubo)

Inject 1 mL of sterile saline into the bubo with a 20-gauge needle; after withdrawing several times, aspirate the fluid. Gram stain of the aspirate reveals gram-negative coccobacilli and polymorphonuclear leucocytes.

Wayson stain (basic fuchsin-methylene blue, ethyl alcohol-phenol stain) of the aspirate shows plague bacilli as light-blue bacilli with dark-blue polar bodies.

Examination of the aspirate of the fluid from the inguinal lymph nodes shows a characteristic bipolar appearance that resembles a closed safety pin.

Lumbar puncture

Lumbar puncture is strongly recommended when meningeal plague is suspected.

Guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[30, 33]

Precautions

All patients with suspected plague and signs of pneumonia should be placed in strict respiratory isolation for 48-72 hours after antibiotic therapy is initiated and kept there until pneumonia has been ruled out or until sputum culture have shown negative findings.

Report patients thought to have plague to the local health department and to the WHO.

Alert laboratory personnel to the possibility of the diagnosis of plague. All fluid specimens must be handled with care to prevent aerosolization of the infected fluids. Gowns, gloves, and masks should be worn at all times, and strict infection control is of utmost importance.

Supportive therapy

Hemodynamic monitoring and ventilatory support are performed as appropriate.

Management of sepsis associated with plague requires aggressive intravenous hydration. Norepinephrine and other vasopressors may be required to manage hypotension and to improve hemodynamic status.

Postexposure prophylaxis and treatment guidelines

Both the prevention of symptomatic plague and treatment of plague have been recently reviewed.[1]  In adults, first line treatment is usually streptomycin or gentamicin plus doxycycline with ciprofloxacin, levofloxacin, moxifloxacin or chloramphenicol as secondary choices. In children, streptomycin or gentamicin are the primary choices for treatment with doxycycline, ciprofloxacin or chloramphenicol as secondary choices. Consultation with an infectious diseases specialist for either prophylaxis or treatment antibiotic choices is strongly recommended.  

Presumptive therapy (post-exposure prophylaxis) consists of a 7-day course of oral doxycycline and ciprofloxacin as first line treatment in adults. Treatment of an established case is usually for 10-14 days. 

In a community experiencing a pneumonic plague epidemic, individuals with a temperature of 38.5°C or higher or newly onset cough should promptly receive parenteral antimicrobial therapy.[34]

Enlarging or fluctuant buboes require incision and drainage.

The following specialists may be consulted:

• Infectious disease specialist

• Pulmonary and critical care specialist

• General surgeon

• Neurologist

The Centers for Disease Control and Prevention (CDC) published clinical practice guidelines on the treatment of plague in July 2021 in the Morbidity and Mortality Weekly Report.[35, 36]  These are some of the highlights of the guidelines.

Plague is treatable with antimicrobials and supportive care. Early recognition and administration of effective antimicrobials are key to saving lives. Persons exposed to Yersinia pestis can avoid illness if given effective antimicrobial prophylaxis.

Aminoglycosides and fluoroquinolones are the mainstays of treatment for plague. Tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole might also be suitable treatment, depending on the type of disease and the age and pregnancy status of the patient. Dual therapy with distinct classes of antimicrobials is recommended in the case of a bioterrorist attack with Y. pestis engineered for resistance to treatment.

FDA-approved antimicrobials for plague include streptomycin, ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline. Although not approved for plague, gentamicin, chloramphenicol, and trimethoprim-sulfamethoxazole are considered effective.

Patients initially treated with parenteral antimicrobials can be transitioned to oral administration when they are improving clinically.

All of the recommended oral antimicrobials except for ciprofloxacin recommended by the CDC can be given by enteral routes such as nasogastric tube and gastric tube. All clinical forms of plague require 10-14 days of treatment in total. The duration of treatment can be extended for those with continuing fever or other worrisome signs or symptoms.

Treatment recommendations for those who are elderly or immunocompromised ar the same as those for adults; however, these patients may experience decreased glomerular filtration rate or polypharmacy, and clinicians should adjust treatment as necessary.

Pneumonic plague or septicemic plague in adults aged ≥ 18 years

For naturally occurring pneumonic plague, the CDC recommends levofloxacin or moxifloxacin. Because plague is life threatening, doxycycline is not considered contraindicated in children and has not been shown to cause tooth staining, unlike other tetracyclines, which should be avoided if possible.

Pneumonic and septicemic plague are the most severe and quickly progressive forms of plague. Subclinical pneumonic infection has been seen in patients with septicemic plague.

Ciprofloxacin is now a first-line agent instead of an alternative agent. Levofloxacin and moxifloxacin (recommended for naturally-occurring plague) have been added as first-line or alternative agents for treatment and prophylaxis.

Institute dual therapy with 2 distinct antimicrobial classes for patients with severe septicemic or pneumonic disease, and narrow therapy to a single antimicrobial after the patient improves clinically.

Please see the Pediatric Plague article for clinical guidelines for infants, breastfeeding infants and mothers, and children aged 17 years and younger.

First-line

• Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 750 mg every 12 hrs PO
• Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO
• Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO
• Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM
• Streptomycin (Aminoglycoside) - 1 g every 12 hrs IV or IM

Alternatives

• Doxycycline (Tetracycline) - 200 mg  loading dose ,  then 100 mg every 12 hrs IV or PO
• Chloramphenicol (Amphenicol) - 12.5–25 mg/kg every 6 hrs IV (maximum 1 g/dose)
• Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO
• Gemifloxacin (Fluoroquinolone) - 320 mg every 24 hrs PO
• Amikacin (Aminoglycoside) - 15–20 mg/kg every 24 hrs IV or IM
• Tobramycin (Aminoglycoside) - 5–7 mg/kg every 24 hrs IV or IM
• Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV
• Trimethoprim-sulfamethoxazole (Sulfonamide) - 5 mg/kg (trimethoprim component) every 8 hrs IV or PO

Gentamicin, chloramphenicol, and trimethoprim-sulfamethoxazole are not approved by the FDA but are considered to be effective.

Because of the potential for adverse effects including nephrotoxicity and ototoxicity, when treating with aminoglycosides, check drug concentrations as indicated based on dosing strategy (eg, extended interval or traditional dosing) and adjust dose and dosing interval as appropriate. Aminoglycosides lack oral formulations; therefore other medications may be preferable.

Please see the Pediatric Plague article for pediatric guidelines. 

Pharyngeal plague or bubonic plague

Pharyngeal and bubonic plague are milder forms of illness and often occur along with focal lymphadenopathy.

Gentamicin or streptomycin are first-line agents for bubonic plague; they must be given parenterally and are associated with nephrotoxicity and ototoxicity. Alternative first-line agents include high-dose ciprofloxacin, levofloxacin, moxifloxacin, and doxycycline, administered intravenously or orally. Consider dual therapy and drainage for patients with large buboes. Treatment is for 10-14 days.

It may be necessary to perform surgical incision and drainage if the bubo becomes suppurative.

Please see Pediatric Plague article for pediatric guidelines. 

First-line

Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 750 mg every 12 hrs PO

Levofloxacin (Fluoroquinolone) 750 mg every 24 hrs IV or PO

Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO

Doxycycline (Tetracycline) - 200 mg loading dose, then 100 mg every 12 hrs IV or PO

Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM

Streptomycin (Aminoglycoside) - 1 gm every 12 hrs IV or IM

Alternatives

Chloramphenicol (Amphenicol) 12.5-25 mg/kg every 6 hrs IV (maximum 1 g/dose)

Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO

Gemifloxacin (Fluoroquinolone) - 320 mg every 24 hrs PO

Amikacin (Aminoglycoside) - 15-20 mg/kg every 24 hrs IV or IM

Tobramycin (Aminoglycoside) - 5-7 mg/kg every 24 hrs IV or IM

Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV

Tetracycline (Tetracycline) - 500 mg every 6 hrs PO

Omadacycline (Tetracycline) - 200 mg loading dose on day 1, then 100 mg every 24 hrs IV or 450 mg loading dose every 24 hrs on days 1 and 2, then 300 mg every 24 hrs PO

Minocycline (Tetracycline) - 200 mg loading dose, then 100 mg every 12 hrs IV or PO

Eravacycline (Tetracycline) - 1 mg/kg every 12 hrs IV

Trimethoprim-sulfamethoxazole -  5 mg/kg (trimethoprim component) every 8 hrs IV or PO

Plague meningitis

Moxifloxacin and levofloxacin have robust activity against Yersinia pestis and excellent CNS penetration; therefore, they should be effective for plague meningitis. Quinolones, however, can cause seizures. When possible, dual therapy with chloramphenicol and moxifloxacin or levofloxacin should be used as initial treatment in patients with plague and signs of meningitis, such as nuchal rigidity. If chloramphenicol is not available, a non-fluoroquinolone first-line antimicrobial or an alternative antimicrobial for septicemic plague can be used.

Because plague has a high case-fatality rate, the CDC recommends antimicrobial treatment and prophylaxis for affected pregnant women even if antimicrobial treatment carries risk to the fetus. Fetal safety concerns should not prevent access to rapid treatment or prophylaxis for pregnant women during a plague outbreak. Antimicrobial safety profiles can help the clinician select the antimicrobial treatment that maximizes benefit to the pregnant woman while minimizing potential risk. In pregnant women with secondary plague meningitis, chloramphenicol should be added to the antimicrobial treatment regimen for all trimesters.

Gentamicin is preferred over streptomycin because streptomycin has been shown to have the greater risk of irreversible fetal ototoxicity. Both ciprofloxacin and levofloxacin are preferred over moxifloxacin because of the lack of safety and efficacy data for moxifloxacin in pregnant women.

Please see the Pediatric Plague article for pediatric guidelines. 

First-line

Chloramphenicol (Amphenicol) - 25 mg/kg every 6 hrs IV (maximum 1 g/dose)

Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO

Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO

Treatment of pregnant women with pneumonic, septicemic, bubonic, or pharyngeal plague

Because plague has a high case-fatality rate, the CDC recommends antimicrobial treatment and prophylaxis for affected pregnant women even if antimicrobial treatment carries risk to the fetus. Fetal safety concerns should not prevent access to rapid treatment or prophylaxis for pregnant women during a plague outbreak.

Antimicrobial safety profiles can help the clinician select the antimicrobial treatment that maximizes benefit to the pregnant woman while minimizing potential risk. In pregnant women with secondary plague meningitis, chloramphenicol should be added to the antimicrobial treatment regimen for all trimesters.

First-line: Gentamicin plus either ciprofloxacin or levofloxacin

Ciprofloxacin (Fluoroquinolone) - 400 mg every 8 hrs IV or 500 mg every 8 hrs PO

Levofloxacin (Fluoroquinolone) - 750 mg every 24 hrs IV or PO

Gentamicin (Aminoglycoside) - 5 mg/kg every 24 hrs IV or IM

Alternatives

Moxifloxacin (Fluoroquinolone) - 400 mg every 24 hrs IV or PO

Ofloxacin (Fluoroquinolone) - 400 mg every 12 hrs PO

Streptomycin (Aminoglycoside) - 1 g every 12 hrs IV or IM

Amikacin (Aminoglycoside) - 15-20 mg/kg every 24 hrs IV or IM

Tobramycin (Aminoglycoside) - 5-7 mg/kg every 24 hrs IV or IM

Plazomicin (Aminoglycoside) - 15 mg/kg every 24 hrs IV

Doxycycline (Tetracycline) - 200 mg loading dose IV, then 100 mg every 12 hrs IV or PO or 200 mg every 24 hrs IV

Chloramphenicol (Amphenicol) - 12.5- 25 mg/kg every 6 hrs IV (maximum 1 g/dose)

Trimethoprim-sulfamethoxazole (Sulfonamide) - 5 mg/kg (trimethoprim component) every 8 hrs IV or PO

Personal protective equipment

Caretakers should wear a mask in addition to taking standard precautions, as well as wear eye protection and a face shield if splashing is likely.

Pre-and post-exposure prophylaxis

The CDC’s clinical guidelines include information on pre- and post-exposure prophylaxis for adults (including pregnant patients) and children.

Untreated plague can progress to a fulminant illness with a high risk of mortality. Thus, early and appropriate antibiotic treatment is essential.

Historically, streptomycin (15 mg/kg, up to 1 g intramuscularly every 12 h) has been the drug of choice[34] ; however, in the United States, supplies of streptomycin are scarce.

An in vitro comparison[37] and a murine model[38] demonstrated that gentamicin (5 mg/kg intravenously or intramuscularly once daily) is comparable to or superior than streptomycin. Gentamicin has been used successfully in the treatment of human plague,[18] is inexpensive, and can be dosed once daily.

Doxycycline (as dosed for anthrax) is a recommended alternative in patients who cannot take aminoglycosides or in the event of a mass casualty scenario, making parenteral therapy unachievable.[34]

Because chloramphenicol attains high CSF concentrations,[34] it has been used to treat meningeal plague, although no studies have been conducted for substantiation.[39]  Chloramphenicol may be challenging to obtain.

Studies in murine models have shown that fluoroquinolones demonstrate efficacy similar to that of the aminoglycosides.[38] Fluoroquinolones are a reasonable alternative therapy.[39]

The FDA has approved levofloxacin and moxifloxacin for the treatment of plague. These have also been approved for use as prophylaxis following exposure to Yersinia pestis.

Trimethoprim-sulfamethoxazole has been used to treat bubonic plague; however, it is not considered first-line therapy.

Beta-lactam antibiotics and macrolides should not be used.

Patients with advanced plague have a presentation of typical gram-negative sepsis and need antibiotic treatment for 10-14 days, along with other supportive measures.[39]

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

Levofloxacin (Levaquin)

Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerases type II), enzymes required for DNA replication, transcription, repair, and recombination. It is indicated for treatment and prophylaxis of plague, including pneumonic and septicemic plague, caused by Yersinia pestis in adults and pediatric patients, aged 6 months or older.

Moxifloxacin (Avelox)

Moxifloxacin is a fluoroquinolone antibiotic that inhibits A subunits of DNA gyrase (topoisomerase type II) and topoisomerase IV, resulting in inhibition of bacterial DNA replication and transcription. It is indicated in adults for treatment and prophylaxis of pneumonic or septicemic plague caused by Yersinia pestis.

Streptomycin

Aminoglycoside antibiotic recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Gentamicin (Garamycin)

Aminoglycoside antibiotic for gram-negative coverage.

Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Ciprofloxacin (Cipro, Cipro XR, ProQuin XR)

Patients with plague who are critically ill and require transfer to another facility should be transported under strict isolation precautions.

Prophylactic antibiotic therapy

The CDC recommends short-term prophylactic antibiotic therapy in people who have been bitten by potentially infected rodent fleas during a plague outbreak.

Prophylactic antibiotic therapy is recommended in persons who have handled an animal known to be infected with the plague bacterium.

Choice of agent should be based on established recommendations and usually utilize doxycycline or ciprofloxacin. 

Prophylactic antibiotic therapy is recommended in persons who have had close exposure to a person or an animal thought to have pneumonic plague. Sulfadoxine prophylaxis has been effective in outbreaks of pneumonic plague.[40] The infection rate in contacts was 8.4% with this strategy. Recent studies have shown that doxycycline can be used as an alternative for sulfadoxine.[39]

Preferred antibiotics for prophylaxis against plague include doxycycline 100 mg PO q12h for 14-21 days (for patients >8 y) or full-dose ciprofloxacin for 7 days.[41] Chloramphenicol may be used as an alternative. To be effective, chemoprophylaxis must be initiated within 7 days of exposure.

Plague vaccine

A recent review by Sun and Singh provides an excellent review of current efforts to produce safe and effective anti-plague vaccines.[42]  The hope of vaccination strategies is to provide long-term prevention against the acquisition of the disease. 

Historically, plague vaccination is of limited use[43] and has not been mandatory for entry into any country. The vaccine is not effective against the pneumonic form of plague. Plague vaccine is recommended for field workers in endemic areas and for scientists and laboratory personnel who routinely work with the plague bacterium. The vaccine is composed of killed whole cells. It needs to be taken as 2 injections 1-3 months apart followed by the booster every 6 months until the patient is no longer considered to be at risk.[24] Live vaccines are in development.[44]

Animal studies have conclusively established that certain antibodies are protective against plague.[45] Murine antibodies to fraction (FI) protein and/or fraction V antigen have been shown to be protective against bubonic and pneumonic plague in murine models.[46]

The F1-V (fusion protein) vaccine protected mice for a year against an inhalation challenge and is now being tested in primates.[41]

An oral vaccine with an attenuated strain of Y pseudotuberculosis named VTNF1 has been reported to provide highly efficient and long-lasting protection against both bubonic and pneumonic plague after a single oral vaccine dose. It confers full protection against the two forms of plague. This may offer an option for mass vaccination in tropical endemic areas, as well as for populations exposed to bioterrorism.[47]

Multiple other vaccine constructs are being tested, but so far none are ready for routine use in humans or are licensed in the western world.[42]

Environmental sanitation

Efforts to control the animal reservoir and flea population may be effective in reducing transmission of plague bacteria.

Remove food sources used by rodents.

Rodent-proof homes, buildings, and warehouses.

Trained professionals should apply chemicals to kill fleas and rodents.

Trained professionals should fumigate cargo areas of ships and docks.

Potential complications of plague include the following:

• Acute respiratory distress syndrome

• Chronic lymphedema from lymphatic scarring

• DIC

• Septic shock

• Superinfections of the buboes by Staphylococcus and Pseudomonas species

Untreated plague carries a mortality rate of approximately 50%; however, with appropriate therapy, the mortality rate drops dramatically.[48]

Report sick or dead animals to the local health department or law enforcement officials and wear gloves when handling potentially infected animals.

Eliminate food sources and nesting places for rodents around homes, workplaces, and recreation areas and make homes rodent-proof.

Personal protective measures include wearing protective clothing and applying insect repellents to clothing and skin to prevent flea bites.

Restrain pet dogs and cats in areas endemic to plague and regularly treat pets to control fleas.

Spraying of appropriate chemicals by health authorities may be necessary to kill fleas at selected sites during animal plague outbreaks.

For patient education information, see Plague Disease (Black Death). For additional information, visit the Centers for Disease Control and Prevention Web page on Plague.