What comes to mind when you think of the plague? Perhaps you’re thinking of Middle Ages Europe, where masked plague doctors walked from home to home. However, this disease, caused by the bacterium Yersinia pestis, remains a public health concern today. Luckily, early treatment using antibiotics has reduced the death rate of the bubonic plague by 40-50%.¹

Bubonic plague is the most common form of this disease, accounting for 70-90% of global cases, with pneumonic plague (lung infection) and septicaemic plague (blood infection) making up the remaining cases. This disease is transmitted from rodent fleas carrying the Y. pestis bacteria. Once bitten by a flea, the bacteria enter the human body and grow and multiply in the lymph nodes. This causes the appearance of swollen lymph nodes, also known as buboes, in the neck, groin, and armpits. 

So, what should you do if you suspect you may have a case of the bubonic plague? We’ll be discussing some key symptoms and treatment options in this article.

Transmission, signs and symptoms 

According to the World Health Organisation, most reported cases of plague have been in Peru, Madagascar, and the Democratic Republic of the Congo (DRC). Transmission of the bubonic plague can occur from:

• Bites of infected fleas - these fleas may be found on rodents, and in rare cases, house cats 
• Direct contact with bodily fluids containing Y. pestis
• Contact with surfaces containing the bacteria
• Rarely, from person to person 

Once the bacteria enter the body, disease onset is often sudden and rapid. The time between the bacteria entering the body and the appearance of signs and symptoms (incubation period) is usually 1-7 days. Symptoms include:

• Fever
• Body chills and aches
• Nausea and vomiting
• Headaches 
• General weakness
• Meningitis, if the bacteria infect the membranes around the brain and/or spinal cord
• Buboes in the neck, groin, and armpits that may develop into sores containing pus 
• Red skin surrounding the buboes

If this disease progresses without treatment, pneumonic plague may follow, due to bacteria spreading to the lungs. This form of plague can be spread via the inhalation of infectious droplets. Without treatment, pneumonic plague causes death in 100% of cases. 

Speak with a healthcare provider if you: 

• Have symptoms
• Have travelled to a high-risk area within the last 8 days
• Have been in close contact with an infected person in the last 8 days

Diagnosis

Diagnosis typically involves:

• Antigen tests to detect the Y. pestis bacteria. In Africa and South America, a dipstick test, where the patient sample is added to a special plastic stick and the results are read within a few minutes, can be used for rapid identification of the bacteria
• Samples of pus, sputum (thick mucus produced in the lungs), or blood from the buboes may be sent to a lab to be cultured (grown in special containers and then seen under a microscope) and for PCR testing, that detect the bacteria’s DNA, to confirm plague¹ 

Treatment with antibiotics

Antibiotics are drugs that can be used to kill (bactericidal antibiotics) or inhibit the growth of bacteria (bacteriostatic antibiotics) within the body. When used early, these drugs can be highly effective against bubonic plague. Antibiotics may also be used as a preventative measure for those at high risk (e.g. people who had close contact with an infected person or animal).¹

In the late stages of the disease, antibiotics are often injected into the veins as they reach affected lymph nodes much faster than if they are ingested as pills.² Usually, antibiotics must be taken for 10 days but they might be prescribed for longer in some cases.¹ 

Antibiotics used to treat bubonic plague include:

• Aminoglycosides (e.g. streptomycin and gentamicin)
• Fluoroquinolones (e.g. ciprofloxacin, levofloxacin)
• Tetracyclines (e.g. doxycycline)

Aminoglycosides

These drugs are bactericidal, meaning they kill bacteria. They show poor oral absorption and therefore require intravenous or intramuscular injection. These drugs work in 3 main steps:

• Damaging the membrane structure of the Y. pestis cell. Normally, this membrane keeps everything together within the cell and controls the passage of contents in and out. A weakened membrane can be deadly for the microorganism
• Binding to the ribosome (the ‘protein factory’ of the cell). This prevents the production of proteins required for bacterial survival and growth
• The antibiotic results in bacterial cell death, with increasing drug concentrations further preventing Y. pestis protein production

Streptomycin

This has been used as a drug to treat plague cases since 1948.³ However, this drug has a low therapeutic index, meaning that the dosage required for effective treatment and the toxic dosage are very similar. As such, care must be taken to prevent overdose which can cause hearing loss and loss of balance (vestibular dysfunction). 

Potential side effects of streptomycin also include kidney damage and nausea. Although the kidney damage is typically not long-lasting, effects on hearing are usually irreversible.⁴

Streptomycin is often limited in supply, and thus, other antibiotics may be used.^1,5

Gentamicin

In the UK, gentamicin is often the first-choice drug (alongside doxycycline).¹ This drug is preferred over doxycycline in pregnancy as the latter may affect foetal bone and tooth development. A study in 2004 found that gentamicin is just as effective as streptomycin in treating bubonic plague.⁶ Additionally, this drug is used in place of streptomycin in the US and France.² Similar to streptomycin, side effects of this drug include:

• Hearing loss
• Damage to kidneys
• Nausea
• Tinnitus (buzzing/ringing in the ears)
• Difficulties balancing

Fluoroquinolones

The fluoroquinolones are bactericidal antibiotics which prevent the bacterial cell from duplicating its DNA. As a result, cells are unable to replicate and eventually die. These are available as oral pills, but can be injected if required.

Ciprofloxacin

In a study performed on mice with advanced cases of bubonic plague, ciprofloxacin was found to have a higher efficacy than gentamicin.⁷ This is supported by data in human plague cases analysed by the WHO.³ However, it is difficult to draw definitive conclusions due to the small sample size used in the latter. Side effects of this drug include:

• Nausea
• Vomiting
• Diarrhoea
• Stomach aches
• Kidney damage
• Tendonitis (the inflammation of the tissue connecting muscles to bones)

When taking this drug, dairy products should be avoided as calcium can decrease drug absorption. Caffeinated beverages should be limited as these may worsen the effects of anxiety and sleeplessness from caffeine.⁸ 

Levofloxacin

This drug shows relatively low toxicity. However, side effects such as diarrhoea may be experienced. Less common side effects include:⁹

• Blisters 
• Stomach aches
• Confusion
• Skin itching and rash
• Fever

In a study where a single high dose was given to animals, the following were reported:⁹

• Reduced ability to move
• Tremors
• Convulsions
• Ataxia (loss of muscle control)

Tetracyclines

Doxycycline

This is a bacteriostatic drug which can be provided as an oral pill. It works by: 

• Binding to the ribosome in the bacterial cell, preventing proteins essential for survival from being made
• This antibiotic also helps reduce inflammation in the lymph nodes, by slowing the movement of white blood cells through the blood¹⁰ 

It has also been suggested that this class of antibiotics may target key aspects of the plague more efficiently than aminoglycosides.⁵ This might be because aminoglycosides are less effective in acidic environments, like inside buboes.^11,12 As such, this drug may be given to those who cannot tolerate aminoglycosides. Common side effects include:

• Headaches
• Nausea
• Vomiting
• Skin becoming sensitive to the sun

Chloramphenicol

This is often used to treat plague meningitis as it can cross the blood-brain barrier, enabling the drug to reach the brain.³ It works by preventing the production of key bacterial proteins. This is not used as a front-line drug due to the risk of bone marrow toxicity, increasing the risk for diseases such as anaemia. Attempts have been made to use aminoglycosides as an alternative, but they do not travel through the cerebrospinal fluid very well.³ 

Generally, only one antibiotic is used at a time. Studies combining these drugs have shown either minimal or no improvement in patient outcomes.^2,3,7 Furthermore, combining antibiotics may worsen the side effects and reduce the efficacy of one or both drugs.²

Antibiotic resistance

Antibiotic resistance (when the drug cannot affect the bacteria anymore) is quite rare among Y. pestis.^1,5 However, Y. pestis strains have been identified which are resistant to antibiotics such as streptomycin and chloramphenicol. An antibiotic sensitivity test will often be performed from the pus or blood samples provided to identify appropriate antibiotics.¹ To prevent further antibiotic resistance, you should complete the full course of antibiotics, even if your symptoms go away early on. Stopping early can allow remaining bacteria to survive and develop resistance.

Luckily, new classes of antibiotics that can target drug-resistant bacteria are being developed been developed.² These include: 

• LpxC inhibitors: LpxC is an enzyme that is important for making bacteria membranes. Inhibiting it (and stopping it from working) prevents the production of Y. pestis membranes, causing cell death. This drug has shown efficacy against multi-drug resistant forms of the bacteria in vitro
• Antivirulence drugs: these drugs target mechanisms in Y. pestis that allow it to infect and harm human cells (e.g. its ability to make and release certain toxins)

Summary

The bubonic plague, caused by Yersinia pestis, remains a public health concern. It is primarily transmitted by fleas on rodents or by contact with infected materials or individuals. Symptoms include fever, chills, nausea, headaches, weakness, and buboes. Without treatment, it can progress to the highly contagious and fatal pneumonic plague.

Effective antibiotics include streptomycin, ciprofloxacin, levofloxacin, doxycycline, gentamicin, and chloramphenicol. These can all be used to treat the same disease, but are suitable for different patients. New treatments targeting resistant strains are being developed, such as LpxC inhibitors and antivirulence drugs. However, early detection and antibiotic treatment remain crucial for managing the disease.