Approach
Do not wait for diagnostic test results if you suspect plague. Never delay or withhold treatment pending test results. The decision to initiate antibiotic therapy should be based on clinical signs and symptoms and the patient history (e.g., recent flea bite, exposure to areas with rodents, contact with a sick or dead animal).[26] Timely, appropriate antibiotic therapy reduces mortality.
Previous guidelines from the Centers for Disease Control and Prevention (CDC) were divided into contained casualty versus mass casualty settings. However, the current 2021 guidelines have been simplified into prophylaxis and treatment scenarios, as it may not be clear initially how large an outbreak will be. This approach provides greater flexibility for responding to uncertain scenarios. This section is predominantly based on CDC guidelines.[2] However, there is supporting guidance from the World Health Organization (WHO) in regards to antibiotic choices.[1]
This topic covers the management of plague in nonpregnant adults, pregnant women, and children. The management of neonates and special patient populations are beyond the scope of this topic. See the Prevention section for information on pre-exposure and postexposure prophylaxis.
Infection prevention and control measures for plague
Follow your local infection prevention and control guidelines.
Person-to-person transmission of plague is rare; however, patients with pneumonic plague require isolation for at least 48 hours and until their clinical condition improves.
Standard and droplet precautions are recommended when providing care to patients with suspected or confirmed pneumonic plague. Droplet precautions may be discontinued once patients have received at least 48 hours of antibiotics and have shown clinical improvement with markedly decreased sputum production.[2]
Airborne precautions are not needed. However, during procedures that are likely to generate sprays or splashes (e.g., bubo aspiration), a mask, eye protection, and face shield should be worn. Particulate-filtering facepiece respirators may be considered as an added precaution when performing aerosol-generating procedures.[2]
Antibiotic therapy for plague
Aminoglycosides (e.g., gentamicin, streptomycin) and fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin) are the mainstay of treatment for plague. Alternative antibiotics such as tetracyclines, chloramphenicol, and trimethoprim/sulfamethoxazole may be suitable depending on the clinical form of disease, and the age and pregnancy status of the patient. Specific drugs approved for plague include ciprofloxacin, levofloxacin, moxifloxacin, streptomycin, and doxycycline (licensing depends on the country). Other antibiotics may be used off-label based on clinical experience and animal data.[2]
Aminoglycosides, tetracyclines, and chloramphenicol are associated with the lowest case fatality rates of all antibiotics used for the treatment of plague. Fluoroquinolone monotherapy requires more research.[40]
Aminoglycosides have a long history of successful use for all predominant forms of plague, as well as robust human and animal data. However, their use may be limited due to their adverse effects such as ototoxicity and nephrotoxicity, the need to monitor serum drug levels, and the absence of oral formulations. Tetracyclines, sulfonamides, and chloramphenicol also have evidence to support their use. The use of fluoroquinolones has shown promising results in more recent years. Fluoroquinolones may be associated with potentially irreversible adverse effects including tendonitis, tendon rupture, arthralgia, neuropathies, and other musculoskeletal or nervous system effects. Warnings have also been issued about the increased risk of aortic dissection, significant hypoglycemia, and mental health adverse effects in patients taking fluoroquinolones.[41][42][43]
Choice of antibiotic depends on the clinical form of the disease. Recommendations for pneumonic and septicemic plague are combined because they are the most rapidly progressive forms, and patients with septicemic plague can have subclinical pneumonic infection. Recommendations for bubonic and pharyngeal plague are combined as this is a milder form of the disease. Antibiotic monotherapy is recommended in some circumstances. Dual antibiotic therapy with two antibiotics from two different classes is generally recommended in severe disease or in the event of a bioterrorist attack. Management is generally the same regardless of whether plague is naturally occurring or the result of an intentional release.[2] However, oral antibiotics are more likely to be used in a mass casualty setting.
Clinical judgment should be used to decide whether parenteral or oral (or nasogastric/gastric tube if appropriate) therapy is required. The decision is based on the severity of disease and whether the patient can tolerate oral medications. Patients who are started on parenteral therapy can be transitioned to an appropriate oral therapy when there is clinical improvement.[2]
Treatment duration for all clinical forms of plague is 10 to 14 days. Treatment can be extended for patients with ongoing fever or any other concerning clinical signs or symptoms.[2]
Some recommended antibiotics may not be available locally (e.g., streptomycin, chloramphenicol), so you should consult your local guidance. Large-scale distribution and use of these antimicrobials during a bioterrorism response might be under a Food and Drug Administration (FDA)-issued emergency use authorization (or its equivalent in other countries).
Pneumonic or septicemic plague
Antibiotic monotherapy is recommended in patients who have mild to moderate disease (i.e., no organ dysfunction), provided that the clinical history suggests that plague is naturally occurring (i.e, close contact with a severely ill and coughing patient with known naturally acquired pneumonic plague, or close or direct contact with an animal with plague).[2]
Dual antibiotic therapy with antibiotics from two different classes is recommended in patients with severe pneumonic or septicemic disease (i.e., signs of organ dysfunction). After clinical improvement, therapy may be narrowed to a single agent. While resistance to naturally occurring plague is rare, engineered resistance has been demonstrated and remains a potential threat. Dual antibiotic therapy is recommended if there is reason to suspect engineered antimicrobial resistance as part of a bioterrorism attack.[2]
First-line options recommended by the CDC for adults include ciprofloxacin, levofloxacin, moxifloxacin, gentamicin, and streptomycin. Alternative options include other fluoroquinolones or aminoglycosides, doxycycline, chloramphenicol, and trimethoprim/sulfamethoxazole. Fluoroquinolones are a good option when the diagnosis is uncertain to include coverage for community-acquired pneumonia.[2]
First-line options recommended by the CDC for children are the same as for adults, except that moxifloxacin is not recommended as a first-line option due to it being off-label for this indication and having higher reported rates of QT interval prolongation compared with other fluoroquinolones. Alternative options include other fluoroquinolones or aminoglycosides, doxycycline, chloramphenicol, and trimethoprim/sulfamethoxazole. Data on use of fluoroquinolones and doxycycline in infants and young children are limited.[2]
The WHO supports the use of ciprofloxacin, levofloxacin, moxifloxacin, gentamicin, and streptomycin as first-line options for the treatment of pneumonic or septicemic plague.[1]
Among published cases of primary pneumonic plague, patients who received aminoglycosides, fluoroquinolones, or tetracyclines (in combination with another antibiotic) had the highest survival rates (83%, 82%, and 82%, respectively). Survival rates were similar for monotherapy with these same drugs (81%, 80%, and 83%, respectively). Survival rates were lower for chloramphenicol and sulfonamides.[44]
Among published cases of primary pneumonic and septicemic plague, patients who received sulfonamides, tetracyclines, and fluoroquinolones (either alone or in combination with another antibiotic) had the highest survival rates (100%, 93%, and 91%, respectively). Survival rates were lower for aminoglycosides and chloramphenicol.[45]
Tissue perfusion and oxygenation in septic patients should be maintained by oxygen, fluid resuscitation, and vasopressors if required. Patients with pneumonic plague may require ventilator support.
Bubonic or pharyngeal plague
Treatment is similar to pneumonic and septicemic plague, with the exception that doxycycline may be used first-line. Although some studies have demonstrated reduced efficacy for doxycycline in the treatment of pneumonic plague, it remains effective and safe for primary bubonic plague that has not progressed.[45]
Antibiotic monotherapy is recommended in patients with naturally occurring bubonic or pharyngeal plague who are stable (i.e., absence of disease progression and absence of systemic symptoms).[2]
Dual antibiotic therapy may be considered in patients with large buboes, or if there is reason to suspect engineered antimicrobial resistance as part of a bioterrorism attack.[2]
First-line options recommended by the CDC for adults include ciprofloxacin, levofloxacin, moxifloxacin, doxycycline, gentamicin, and streptomycin. Alternative options include other fluoroquinolones, aminoglycosides, or tetracyclines, chloramphenicol, and trimethoprim/sulfamethoxazole.[2]
First-line options recommended by the CDC for children are the same as for adults, except that moxifloxacin is not recommended as a first-line option. Alternative options include other fluoroquinolones, aminoglycosides, or tetracyclines, chloramphenicol, and trimethoprim/sulfamethoxazole. Tetracyclines have been associated with permanent tooth discoloration and enamel hypoplasia in children <8 years of age. However, recent evidence indicates no risk with doxycycline when used for short courses (<21 days). Other tetracyclines should only be used in children when other treatment options have been exhausted.[2]
The WHO supports the use of ciprofloxacin, levofloxacin, moxifloxacin, doxycycline, gentamicin, and streptomycin as first-line options for the treatment of bubonic plague.[1]
Patients who present with primary bubonic or pharyngeal plague that has progressed to secondary pneumonic or septicemic plague should be treated as per the recommendations for pneumonic and septicemic plague (above).[2]
Surgical incision and drainage might be necessary if the bubo becomes suppurative.[2]
Meningeal plague
Plague meningitis is uncommon with naturally occurring infection; however, it may be more prevalent in the event of an intentional release.
Dual antibiotic therapy with chloramphenicol plus either levofloxacin or moxifloxacin is recommended by the CDC for the initial treatment of patients with plague who present with signs of meningitis, when possible.[2] The antibiotics selected must cross the blood-brain barrier. Chloramphenicol has a long history of successful use in plague meningitis. However, there are no data available on the use of levofloxacin and moxifloxacin in plague meningitis. If chloramphenicol is not available, a nonfluoroquinolone first-line antibiotic (or alternative) for septicemic plague may be used (see above).[2]
The WHO supports the use of chloramphenicol plus an intravenous fluoroquinolone such as moxifloxacin for the treatment of meningeal plague.[1]
For patients who develop secondary meningitis while already receiving antibiotic therapy for plague, chloramphenicol should be added to the existing regimen. Levofloxacin or moxifloxacin may be added instead if chloramphenicol is not available or there is concern over its adverse effects, provided the patient is not already on these agents. The entire combination regimen should be continued for an additional 10 days.[2]
Treatment of plague in pregnant and breastfeeding women
Data on plague during pregnancy are limited. Untreated infection during pregnancy is associated with a high risk of maternal mortality and pregnancy loss, as well as preterm birth and hemorrhage. While antibiotic therapy can improve maternal survival, there is still a high risk of pregnancy loss. Limited evidence suggests that perinatal transmission is possible, particularly in the absence of antibiotic therapy.[46]
Antibiotic therapy is recommended in pregnant women when indicated, even if its use carries some risks for adverse events to the fetus. While available safety data related to use during pregnancy should be considered when selecting an appropriate antibiotic, fetal safety concerns should not prevent access to rapid treatment for pregnant women during a plague outbreak. Efficacy should be the main factor contributing to antibiotic choice in pregnant women.[2]
Dual antibiotic therapy is recommended in pregnant women with infection caused by either naturally occurring infection or intentional release. Parenteral administration is preferred, when possible, as pregnant women may be less able to tolerate oral medications and there may be decreased gastrointestinal absorption during pregnancy.[2]
First-line options recommended by the CDC in pregnant women with pneumonic, septicemic, bubonic, or pharyngeal plague include ciprofloxacin, levofloxacin, or gentamicin. Alternatives include other fluoroquinolones or aminoglycosides, doxycycline, chloramphenicol, or trimethoprim/sulfamethoxazole. For women with plague meningitis, treat as per nonpregnant adults (see above).[2]
Gentamicin, amikacin, tobramycin, and sulfadiazine during pregnancy were not associated with adverse maternal, fetal, or neonatal outcomes. However, the limited number of prenatal exposures may affect the ability to detect rare associations. Prenatal exposure to streptomycin and trimethoprim/sulfamethoxazole may be associated with birth defects in some studies. Streptomycin has been associated with maternal and neonatal ototoxicity and/or vestibular deficits, especially with longer duration of exposure. Trimethoprim/sulfamethoxazole increases the risk of neural tube defects with first-trimester exposure and hyperbilirubinemia in the third trimester; however, the risk-benefit profile for the treatment of plague favors its use during any trimester with appropriate monitoring. The risks associated with chloramphenicol and doxycycline are less clear. These agents may be associated with adverse pregnancy and neonatal outcomes (e.g., undescended testis, cardiovascular birth defects, spontaneous abortion); however, data are limited to single studies.[47] A review of the safety of fluoroquinolones during pregnancy did not find evidence of an association between maternal exposure and pregnancy loss or birth defects; however, they are generally not recommended in the first trimester.[48]
Consider hospitalization, particularly for those with pneumonic plague or those who are in their second or third trimester, to facilitate parenteral administration of antibiotics and monitoring for preterm labor and maternal hemorrhage. Follow standard guidelines for maternal sepsis and corticosteroid administration for fetal lung maturity.[2]
Transmission via breast milk has not been reported, but data are limited. The majority of antibiotics recommended for the treatment of plague produce low concentrations in breast milk and have an acceptable safety profile, except for chloramphenicol.[2]
Yersiniosis
Yersiniosis is generally self-limiting but invasive disease may occur. Oral rehydration fluids or intravenous fluids are recommended in patients who are dehydrated.
Antibiotic therapy does not seem to reduce illness severity and is generally not recommended.[49] However, for invasive disease, treatment with antibiotics is usually effective.[50] The Infectious Diseases Society of America recommends trimethoprim/sulfamethoxazole or ciprofloxacin for Yersinia enterocolitica infection.[51] Other options may include third-generation cephalosporins, aminoglycosides, and tetracyclines.[38]
Antibiotics have not been shown to alter the likelihood of postinfectious sequelae, such as reactive arthritis.[38]
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