Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939–2019

Abstract

Background

Plague, caused by the bacterium Yersinia pestis, has killed millions in historic pandemics and continues to cause sporadic outbreaks. Numerous antimicrobials are considered effective for treating plague; however, well-defined information on the relative efficacy of various treatments is lacking. We conducted a systematic review of published data on antimicrobial treatment of plague reported in aggregate.

Methods

We searched databases including Embase, Medline, CINAHL, Cochrane Library, and others for publications with terms related to plague and antimicrobials. Articles were included if they contained 1) a group of patients treated for plague, with outcomes reported by antimicrobial regimen, and 2) laboratory evidence of Y. pestis infection or an epidemiologic link to patients with laboratory evidence of Y. pestis. Case fatality rate by antimicrobial regimen was calculated.

Results

In total, 5837 articles were identified; among these, 26 articles published between 1939 and 2008 met inclusion criteria. A total of 2631 cases of human plague reported within these articles were included. Among cases classified by primary clinical form of plague, 93.6% were bubonic, 5.9% pneumonic, and 0.5% septicemic with associated case fatalities of 14.2%, 31.1%, and 20.0%, respectively. Case fatality rate among patients who received monotherapy with tetracyclines, chloramphenicol, aminoglycosides, or sulfonamides was 1.3%, 1.4%, 7.5%, and 20.2%, respectively. Fluoroquinolones were only given as part of combination therapy. Penicillin was associated with a case fatality rate of 75%.

Conclusions

Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague. Additional research is needed to determine the efficacy of fluoroquinolones as monotherapy.

Plague, Yersinia pestis, antimicrobials, bubonic plague, pneumonic plague

Plague, a potentially fatal disease caused by the bacterium Yersinia pestis, has a long history of causing pandemics. Progress in sanitation, diagnostic, and treatment practices have drastically decreased plague occurrences and fatalities; however, outbreaks and sporadic cases continue to occur [1–3]. The World Health Organization (WHO) reported 14 plague outbreaks worldwide since 2001 [4, 5] and an average of 650 human cases per year between 2010 and 2015 [3]. Additionally, Y. pestis has the potential to be weaponized [6, 7] and has been classified as a Tier 1 Select Agent [8].

The most common clinical forms of plague are bubonic, septicemic, and pneumonic. Bubonic plague—identified by the distinctive “bubo,” a painful lymph node swelling—is the most common form, accounting for 80–85% of cases [9]. Septicemic plague, which commonly manifests with fever, chills, and tachycardia, without localizing signs, occurs in approximately 10% of cases [9, 10]. Both bubonic and septicemic plague forms are usually transmitted to humans through the bite of an infected flea or direct contact of an open wound with infected animal tissue or fluids [9]. Primary pneumonic plague, which occurs in approximately 3% of cases [9, 10], presents with cough, dyspnea, and in severe cases, bloody sputum. Pneumonic plague is transmitted by infected droplets via inhalation [9]. It has been suggested that in a bioterrorism event, Y. pestis would likely be dispersed in aerosolized form, causing pneumonic plague [6], although Y. pestis could be disseminated in other ways, for example, by ingestion.

Fortunately, numerous antimicrobials are effective for the treatment of plague. Since antimicrobials were introduced in the late 1930s, the case fatality rate of patients treated for plague in the United States has dropped from 66% to 13% for bubonic plague, from 93% to 36% for pneumonic plague, and from 89% to 27% for septicemic plague [11]. Antimicrobials currently approved by the Food and Drug Administration (FDA) for treatment of plague include streptomycin, tetracyclines, and fluoroquinolones [12]. Additionally, gentamicin, chloramphenicol, and sulfonamides are considered effective therapies [6, 11, 13]. Penicillins, cephalosporins, and other antimicrobials are not considered effective for treatment of plague [14]. As with any antimicrobial, side effect profiles and drug-drug interactions [15–19] must also be considered when selecting a treatment regimen for patients with plague.

Plague remains a potential threat both from naturally occurring and weaponized Y. pestis; therefore, the Centers for Disease Control and Prevention (CDC) is updating clinical guidance for treatment and prophylaxis of plague. To inform this guidance, Nelson et al conducted a systematic literature review of antimicrobial treatment of plague. This review assessed individual-level patient data on antimicrobial treatment regimens with associated outcomes for each reported patient with plague [20].

Many publications in the scientific literature report limited or no individual-level data on treatment of plague but nevertheless contain valuable information on groups of patients treated with various antimicrobials for plague. These include the only 2 (to our knowledge) randomized controlled trials on antimicrobial treatment of plague [21, 22]. The data on groups of patients from these articles were not included in the literature review on individual-level data. Information from these patient cohorts provides additional valuable information as it describes antimicrobial efficacy in a large number of patients. Additionally, numerous articles presenting aggregate treatment and outcome data describe patients treated with antimicrobials that are not commonly used in the United States presently, for example, sulfonamides. Data on the outcomes of patients using these treatments remain important, as these treatments could be used during a shortage of other antimicrobials or as alternatives to treatment or prophylaxis that carry fewer risks of serious adverse effects. The objective of this literature review was to summarize aggregate-level antimicrobial treatment and outcome data of patient cohorts with plague, to inform updated clinical guidelines for treatment of plague.

METHODS

Literature Search Strategy

In collaboration with CDC librarians and plague experts, we developed a search methodology that included terms related to human plague and antimicrobial treatment (Supplementary Material 1). The search strategy used for this review is identical to that described by Nelson et al [20]. In brief, we searched 9 databases and conducted hand searches of selected journal archives. We also conducted 3 rounds of systematic reference review on all articles containing information on antimicrobial treatment of human plague (individual or in aggregate) to identify additional references not captured in the database searches. This review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [23] and was registered in PROSPERO (ID: CRD42020151555) [24].

Inclusion Criteria

Articles were included if they contained 1) a group of patients treated for plague, with outcomes reported by antimicrobial regimen, and 2) patients with laboratory evidence of Y. pestis infection or an epidemiologic link to patients with laboratory evidence of Y. pestis. Aggregate data differ from the individual case-level data because it presents summarized information on patient cohorts that cannot be linked back to an individual case.

Article Review

The title and abstract of each article were screened by 2 independent reviewers; articles were divided among 4 reviewers (C.A.N., H.A.B., S.F.D., or K.M.C.) to assess whether they merited full text review. If an abstract was unavailable, authors reviewed the full text article. Foreign language articles were assessed by a fluent speaker or through Google Translate [25] to determine whether the article reported relevant data. Non-English articles meeting inclusion criteria were translated to English by a professional translation service.

Following title and abstract review, full texts of articles potentially meeting inclusion criteria were evaluated by 2 independent reviewers (K.M.C. and S.G.C.). Any discrepancies were addressed through discussion. Because some articles described the same cases, these articles were compared and the article containing the greatest detail pertaining to the cases was included in this review. Additional articles were used to supplement the selected article’s data.

Some articles reported cases with both aggregate and individual-level data; cases described both in aggregate and individually were included in this review for completeness. Some cases may be duplicative of those in the review by Nelson et al, which reported only individual-level data [20].

Data Abstraction

Following review of full-text articles, 2 abstractors (K.M.C. and S.G.C.) extracted data from each article regarding patients’ clinical forms of plague, laboratory testing, antimicrobial treatments, and outcomes (Table 1). Clinical form of plague was recorded based on reported symptoms that met criteria outlined in Supplementary Material 2. For this review we recorded primary clinical form of plague only.

Table 1.

Antimicrobial Treatment, Patient Outcome, and Laboratory Classification for Each of the 26 Articles Included in the Systematic Review

Article Title, Author, and Year of Publication (Listed in Reverse Chronological Order)	Antimicrobial Treatment	Outcome (Deaths/Total Patients Treated)	Laboratory Classificationa
Analysis of diagnosis and treatment of 14 pneumonic plague cases in Qinghai Province, Jiao Batai, 2008	Streptomycin, ciprofloxacin, and sulfamethoxazole	6/14	Confirmed
Treatment of plague with gentamicin or doxycycline in a randomized clinical trial in Tanzania, Mwengee, 2006	Gentamicin	1/34	Confirmed
	Doxycycline	1/30	Confirmed
	Gentamicin and tetracycline	1/1	Confirmed
Gentamicin and tetracyclines for the treatment of human plague: review of 75 cases in New Mexico, 1985–1999, Boulanger, 2004	Streptomycin	0/14b	Confirmed
	Gentamicin	0/18c	Confirmed
	Gentamicin and tetracycline	0/10d	Confirmed
	Tetracycline	0/8c	Confirmed
	Penicillin	3/3	Confirmed
	Chloramphenicol	1/1	Confirmed
	Tetracycline, gentamicin, and chloramphenicol	0/1	Confirmed
A report on 42 cases of epidemic fulminant human plague in Guangxi Providence, China, Haijian, 2002	Streptomycin or gentamicin (unclear)	0/30	Confirmed
	Cephalosporins	0/10	Confirmed
	Tetracycline	0/1	Confirmed
Resurgence of the plague in the district of Ikongo in Madagascar in 1998, Migliani, 2001	Streptomycin	1/13	Probable
Urban epidemic of bubonic plague in Majunga, Madagascar: epidemiological aspects (cases from 1995 to 1998, annual outbreaks), Boisier, 1997	Streptomycin and sulfonamides	9/103	Probable
Bubonic plague outbreak in Mozambique 1994, Barreto, 1995	Chloramphenicol	3/226	Suspect
Plague, a clinical review of 27 cases, Crook, 1992	Penicillin	3/5	Probable
Yersinia pestis infection in Vietnam II. Quantitative blood cultures and detection of endotoxin in the cerebrospinal fluid of patients with meningitis, Butler, 1976	Streptomycin	0/18	Confirmed
	Bactrim	0/5	Confirmed
	Streptomycin and chloramphenicol	0/15	Confirmed
	Streptomycin with or without chloramphenicol	4/4	Confirmed
Plague in Vietnam clinical observations and treatment with Kanamycin, Cantey, 1974	Kanamycin	3/18	Confirmed
	Tetracycline, ampicillin, and kanamycin	0/1	Confirmed
	Kanamycin and ampicillin	1/1	Confirmed
Plague as seen in South Vietnamese children, Burkle, 1973	Tetracycline	0/16	Suspect
	Chloramphenicol	0/59	Suspect
	Chloramphenicol and streptomycin	1/1	Suspect
	Chloramphenicol and tetracycline	1/1	Suspect
The Luangwa valley plague outbreaks and their significance to savannah plague in central Africa, Davis, 1960	Sulfadiazine	0/4	Suspect
	Streptomycin	0/2	Suspect
	Tetracycline	0/21	Suspect
	Streptomycin and tetracycline	0/1	Suspect
Treatment of bubonic plague with sulfonamides and antibiotics, Sokhey and Wagle, 1953	Sulfapyridine	33/122	Suspect
	Sulfathiazole	59/274	Suspect
	Streptomycin	6/148	Suspect
	Sulfadiazine	16/180	Suspect
	Sulfamerazine	9/113	Suspect
An outbreak of plague in Nanded with particular reference to treatment with sulpha drugs and streptomycin, Rao, 1952	Sulfonamides (sulfadiazine, cibazol, thiazamide)	3/91	Suspect
	Sulfonamides (sulfadiazine, cibazol, thiazamide) and streptomycin	12/316	Suspect
Streptomycin in bubonic plague, Chen, 1949	Sulfadiazine	11/40	Suspect
	Sulfadiazine and streptomycin	0/3	Suspect
Plague controlled in Haifa by the use of DDT alone, Pollock, 1948	Sulfadiazine	1/16	Suspect
	Sulfadiazine and streptomycin	0/3	Suspect
A short note on plague cases treated in Campbell hospital, Datt Gupta, 1948	Streptomycin	7/24	Probable
	Sulfadiazine	7/71	Probable
	Sulfamezathine	4/37	Probable
Pneumonic plague and its treatment, Wagle, 1948	Streptomycin	0/2	Suspect
	Streptomycin and sulfamerazine	1/4	Suspect
Some clinical impressions of a plague epidemic, Shamanna, 1946	Sulfathiazole	6/26	Suspect
Bubonic plague outbreak in Ferryville (Tunisia), Magrou, 1945	Sulfadiazine	2/28	Suspect
The plague epidemic in Nairobi, with special reference to place incidence and treatment, Plum, 1942	Sulfapyridine (dagenan)	61/162	Suspect
On the epidemiology and treatment of plague in Egypt, Kamal, 1941	Sulfapyridine (dagenan)	22/91	Suspect
	Sulfanilamide	23/65	Suspect
Sobre el ultimo brote de pest, Villfane Lastra, 1941	Sulfanilamide thiazole (cibazol)	6/24	Suspect
Treatment of plague by sulphonamides-experimental and human, Girard, 1941	M&B 693 PO soludagenan IM (sulfapyradine)	4/19	Suspect
	1162 F (sulfonamide)	2/11	Suspect
	M&B 693 (sulfapyridine) and 1162F (sulfonamide) (sometimes together, other times one or the other)	9/37	Suspect
The treatment of plague by fungal antibiotics, Girard, 1941–1946 (exact year of publication unclear)	Streptomycin	4/20	Suspect
	Streptomycin, penicillin, thiazomide, and aureomycin	1/1	Suspect
Examen critique de la pathologie du Congo-Belge en 1939, Van Hoof, 1939	Astreptine (sulfanilamide)	11/14	Suspect

^aLaboratory classification was based on the highest laboratory classification of a case within the article.

^b2 of these cases (from Boulanger et al. 2004) may have also been treated with a sulfonamide or beta-lactam.

^c4 of these cases (from Boulanger et al. 2004) may have also been treated with a sulfonamide or beta-lactam.

^d3 of these cases (from Boulanger et al. 2004) may have also been treated with a sulfonamide or beta-lactam.

Laboratory Classification

Classification of laboratory evidence of infection was based in part on the 1999 World Health Organization case definition [26]. The 1999 WHO plague case definition was used rather than more recent case definitions, which were broadened and permitted a positive rapid diagnostic test (using immunochromatography to detect F1 antigen) to be confirmatory in certain endemic areas. Laboratory classification was recorded as confirmed, probable, or suspect based on criteria documented in Supplementary Material 3.

After at least 1 case in each article was identified as having laboratory evidence of Y. pestis infection, additional cases were included if an epidemiologic link to the initial case was reported. The overall laboratory classification of each article was assigned based on the case(s) with the highest level of laboratory classification.

Antimicrobial Analysis

Cases were categorized by reported antimicrobial medication or class of medication. Sulfonamides were grouped as a class (rather than by individual antimicrobial name) due to the numerous sulfonamides reported and the lack of specificity about which sulfonamide was used in several articles. Case fatality rates, or the proportion of deaths within each treatment group, were calculated for each antimicrobial regimen.

Subset Analysis

Timeliness of antimicrobial treatment improves survival in patients with plague [6, 27, 28]. To account for treatment delays, we conducted a subset analysis in which we excluded patients who were moribund at time of treatment initiation. Moribund patients were defined as those who (a) died within 24 hours of beginning antimicrobial treatment; (b) were described as septic or moribund by the authors; or (c) were classified as unconscious, semiconscious, toxemic, or “in shock” at time of presentation for medical treatment.

Completeness and Quality of Included Studies

We assessed validity and quality of included studies using the US Preventive Services Task Force (USPSTF) framework [29, 30]. Two reviewers (K.M.C. and Z.R.) assessed each article independently using 7 different criteria, which varied slightly depending on study design (see Supplementary Material 4). Articles were rated as good, fair, or poor quality based on alignment with USPSTF criteria. Discrepancies were resolved by a third reviewer (S.G.C.).

RESULTS

The search identified 5837 articles; 101 articles merited full text review, 30 of which met inclusion criteria. Four articles were excluded because they contained duplicate reports from other articles. Pertinent data from the 26 articles that met final inclusion criteria are summarized in Table 1. Two articles reported the findings of randomized controlled trials (RCT), and 2 reported data from a combination of a clinical trial and cohort study. The remaining 22 articles were cohort studies (see Supplementary Material 5). A total of 2631 patients with plague were included (Figure 1).

Figure 1.

PRISMA flow diagram of search results and articles selected. Abbreviations: EID, Emerging Infectious Diseases; MMWR, Morbidity and Mortality Weekly Report; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; WHO, World Health Organization.

Demographics

Publication years of included articles ranged from 1939 to 2008. Patients included were from 14 countries; over 50% were from India (Table 2). Among 78.2% (n = 2058) of patients with documented primary clinical form of plague, 93.6% (n = 1926) were classified as bubonic, 5.9% (n = 122) as pneumonic, and 0.5% (n = 10) as septicemic plague. Primary clinical form of plague was not documented for 21.8% (n = 573) of patients. No other specific forms of plague such as pharyngeal or meningitic were documented.

Table 2.

Country of Origin of 2631 Cases of Plague Reported in Aggregate and Included in the Systematic Literature Review

Country	Number of Cases	Percent of Total Cases
India	1408	53.5%
Mozambique	226	8.6%
Madagascar	204	7.8%
Kenya	162	6.1%
Egypt	156	5.9%
Vietnam	139	5.3%
China	98	3.7%
Tanzania	65	2.5%
United States	60	2.3%
Zambia	28	1.1%
Tunisia	28	1.1%
Spain	24	0.9%
Israel	19	0.7%
Democratic Republic of the Congo	14	0.5%
Total	2631	100%

Antimicrobial Treatment and Outcome

Case fatality rate for patients treated with any antimicrobial(s) was 13.6%. Case fatality rates for patients with reported primary clinical form of plague were 14.2% for bubonic, 31.1% for pneumonic, and 20.0% for septicemic plague forms.

A total of 31.8% (n = 837) of patients, 157 of whom died, met criteria to be considered moribund and were removed for the subset analysis of patients who were nonmoribund at initiation of treatment.

Antimicrobial Monotherapy

Monotherapy was used for 81.9% (n = 2155) of patients with a case fatality rate of 15.1%. Of those patients, 77.3% (n = 1666) were nonmoribund at initiation of treatment and were therefore included in the subset analysis, yielding an overall case fatality rate of 11.5%. Among patients who received antimicrobial monotherapy with an antimicrobial considered effective for plague, associated case fatality rates ranged from 0% for patients who received tetracycline to 20.2% for patients who received sulfonamides (Table 3).

Table 3.

Case Fatality Rate of Patients Treated for Plague, by Antimicrobial Regimen Before and After Removal of Moribund^a Patients

Antimicrobial(s)	Total Patients Treated	Number of Deaths Among Treated Patients	Case Fatality Rate of Treated Patients
Monotherapy
Aminoglycosides
Streptomycinb	245	22	9.0%
Streptomycin (nonmoribund)	187	8	4.3%
Gentamicin	52	1	1.9%
Gentamicin (nonmoribund)	51	0	0%
Kanamycin	18	3	16.7%
Kanamycin (nonmoribund)	17	2	11.8%
Total aminoglycosidesc	345	26	7.5%
Total aminoglycosides (nonmoribund)	255	10	3.9%
Tetracyclines
Tetracycline	46	0	0%
Doxycycline	30	1	3.3%
Doxycycline (nonmoribund)	29	0	0%
Total tetracyclines	76	1	1.3%
Sulfonamides
Sulfonamides	1430	289	20.2%
Sulfonamides (nonmoribund)	1094	176	16.1%
Chloramphenicol
Chloramphenicol	286	4	1.4%
Chloramphenicol (nonmoribund)	283	3	1.1%
Other Antimicrobial
Cephalosporins	10	0	0%
Penicillin	8	6	75.0%
Penicillin (nonmoribund)	5	3	60.0%
Combination Therapy
Dual Therapy
Streptomycin and sulfonamide	429	22	5.1%
Streptomycin and sulfonamide (nonmoribund)	104	9	8.7%
Streptomycin and chloramphenicol	16	1	6.3%
Streptomycin and chloramphenicol (nonmoribund)	15	0	0%
Gentamicin and tetracycline	11	1	9.1%
Streptomycin and tetracycline	1	0	0%
Kanamycin and ampicillin	1	1	100%
Kanamycin and ampicillin (nonmoribund)	1	1	100%
Chloramphenicol and tetracycline	1	1	100%
Multiple therapy (≥3 antimicrobial)
Streptomycin, ciprofloxacin, and sulfonamide	14	6	42.9%
Aminoglycoside, tetracycline, and penicillin	1	0	0%
Streptomycin, Penicillin, thiazomide, and aureomycin	1	1	100%

^aMoribund patients were defined as those who (a) died within 24 hours of beginning antimicrobial treatment; (b) were described as septic by the authors; or (c) were classified as unconscious, semiconscious, toxemic, or “in shock” at the time of presentation for medical treatment.

^bFour fatal cases (from Butler et al) were documented as receiving streptomycin with or without chloramphenicol.

^cThirty cases (from Haijian et al) were treated with either streptomycin or gentamicin; all survived.

Aminoglycosides were used as monotherapy for 13.1% (n = 345) of patients. (Table 1). Patients were treated with streptomycin, (9.3%, n = 245), gentamicin, (2.0%, n = 52), and kanamycin (0.7%, n = 18) (Table 3). Additionally, 1 article reported patients (1.1%, n = 30) who received either streptomycin or gentamicin; however, it did not provide further clarification [31].

Tetracyclines were used as monotherapy in 2.9% (n = 76) of patients. Tetracyclines included doxycycline (1.1.%, n = 30) and tetracycline (1.7%, n = 46) (Table 1).

Sulfonamides, the most frequently administered antimicrobial for monotherapy, were used to treat 54.2% (n = 1425) of patients. Nonmoribund patients made up 76.5% (n = 1094) of those treated with sulfonamides. (Table 1, Figure 2).

* These case fatality rates were based on data from 10 or fewer cases. € Some of the cases from Boulanger et al, 2004 may have also been treated with a sulfonamide or beta-lactam.Figure 2.

Case fatality rate of patients with plague who received antimicrobial monotherapy, by decade.

Chloramphenicol was used to treat 10.8% (n = 286) of patients and was only recorded as monotherapy in three articles containing aggregate treatment data (Table 1). Chloramphenicol was associated with a low case fatality rate that decreased marginally following removal of 3 moribund patients including 1 death (Table 3).

The remaining antimicrobials used in monotherapy included cephalosporins and penicillin (Table 3), although both were used in treatment of only 10 or fewer patients. Penicillins, although used to treat a small number of patients, had the highest associated case fatality rate of all monotherapies (Table 3, Figure 2).

Combination Therapy

Combinations of multiple antimicrobial classes were used in 18.1% (n = 476) of patients’ treatment regimens. Case fatality rate of all patients treated with multiple antimicrobials was 6.9%; for nonmoribund patients treated with combination therapy case fatality rate was 8.4%.

The most common antimicrobial combination was streptomycin and sulfonamides (16.3%, n = 429). Of patients who received streptomycin and sulfonamides, 73.4% (n = 315) were moribund, including 13 deaths. The next most common combination of antimicrobials was streptomycin and chloramphenicol (0.6%, n = 16). One death occurred, in a moribund patient [32], yielding a case fatality rate of 6.3% overall and 0% for nonmoribund patients. The combination of streptomycin, ciprofloxacin and sulfonamides, was reported in only 1 article and was associated with a case fatality rate of 42.9% (n = 14) [33]. Numerous combinations of antimicrobials were used to treat only 1 patient with plague (Table 3).

Completeness and Quality of Included Studies

The 26 articles included were assessed using USPSTF criteria; 23.1% (n = 6) met the majority of criteria and received a good rating, 11.5% (n = 3) met some criteria and received a fair rating, and 65.4% (n = 17) had at least 1 important flaw causing the article to receive a poor rating (Supplementary Material 5). Important flaws found in those 17 articles were commonly lack of consideration of potential confounders and little information on laboratory testing.

DISCUSSION

This systematic review captures aggregate-level antimicrobial treatment and outcome data for patients grouped by antimicrobial treatment regimen and provides data on mortality associated with antimicrobial treatments for plague. This analysis includes data from over 2500 globally distributed patients treated with 18 different antimicrobial treatment regimens. Tetracyclines, chloramphenicol, and aminoglycosides displayed the lowest associated case fatality rates; among nonmoribund cases, these results were even more pronounced.

In contrast, sulfonamides and penicillins had high associated case fatality rates both overall and for nonmoribund patients. Sulfonamides, the most commonly used monotherapy, had the highest associated case fatality rate of all monotherapies used to treat more than 10 patients. Although the number of treated patients was small, penicillin had the highest associated case fatality rate of all monotherapy regimens [14, 27], confirming previous recommendations that this antimicrobial should not be used for treatment of plague [14]. Penicillins with enhanced activity against gram-negative organisms (eg, ampicillin, amoxicillin) may display higher efficacy [34]; however, this review found no reports of patients treated with aminopenicillins as monotherapy. We cannot draw conclusions on monotherapy with cephalosporins due to the small number of patients treated with this antimicrobial.

Nearly a quarter of patients who received streptomycin monotherapy were considered moribund. Because streptomycin proved to be highly effective against plague very early in records of antimicrobial use [22], it is possible that clinicians reserved streptomycin for severely ill patients. In fact, in some publications authors clearly stated that severely ill patients were treated with streptomycin preferentially [35–37]. For this reason, the case fatality rate associated with streptomycin, although <10%, was likely artificially elevated.

Monotherapy was associated with a higher case fatality rate than combination therapy, both overall and in the subset analysis. This finding may indicate that combination therapy is more effective than monotherapy; however, these data are not sufficient to draw firm conclusions. The elevated case fatality rate of monotherapy is likely distorted by sulfonamides, which were used in over half of the monotherapy regimens and had the highest case fatality rate of all monotherapy treatment regimens with a sample size >10 patients. Additionally, the relatively high case fatality rate associated with all monotherapies is likely skewed by early era of monotherapy treatments and associated lack of diagnostic testing, hospital care, and sanitation standards that are currently in place today [22].

Fluoroquinolones have been FDA approved for treatment of plague since 2012 [38]; however, articles in this review only reported treatment using this class of antimicrobials in combination with streptomycin and sulfonamides. This triple antimicrobial treatment was provided to 14 moribund patients, 6 of whom died [33], preventing assessment of the efficacy of this antimicrobial as monotherapy. Fluoroquinolones have been demonstrated to be effective during in vitro and animal studies [6, 39–42] and in several human cases [43, 44]. Further research on these antimicrobials for treatment of human plague will be important to delineate their relative efficacy compared with other antimicrobial treatments for plague.

Interestingly, the case fatality rate for patients receiving combination therapy increased following removal of moribund patients, specifically for patients who received dual therapy with streptomycin and sulfonamides. There is no clear explanation for this, although possible reasons include that our definition of “moribund” may not have captured all patients who were legitimately moribund, skewing the case fatality rate. Furthermore, streptomycin was described in some articles as the best treatment option for patients who were severely ill and was preferentially used for patients who failed monotherapy treatment, particularly by sulfonamides [45–47]. It is also possible that nonmoribund patients may not have received complete antimicrobial courses. For these reasons, the case fatality rate of patients treated with combination therapy even after removal of patients identified as moribund may have been artificially elevated.

This review has several key limitations. First, the majority of included articles were case series and thus low-quality data by definition. Second, our inclusion criteria were limited to only human cases that demonstrated laboratory evidence of infection or that had an epidemiological link to a case with laboratory evidence. This may have resulted in inclusion of nonplague cases, as well as exclusion of true cases of plague. Third, publication bias is likely for case series and associated outcomes included in this review. For example, the percentage of cases reported with each clinical form of plague differed from previously observed percentages among cases identified through national surveillance [10, 11]. This may have been due to publication bias as cases with uncommon clinical manifestations, human-to-human transmission of pneumonic plague during outbreaks, or unexpected clinical outcomes are more likely to be described. Finally, this review describes published reports of plague from a range of 80 years and 14 countries and thus presents heterogeneous data representing only a portion of total cases during that time period.

This review comprehensively describes aggregate-level data reported in the literature of patients treated with various antimicrobial regimens and their outcomes. The findings of this review complement those published in the summaries of individual-level data by Nelson et al and Kugeler et al, which showed that patients with plague can be effectively treated with numerous antimicrobial classes, including aminoglycosides and tetracyclines. Together, this review and other research on antimicrobial efficacy in treatment of plague can inform clinical guidelines for treatment and prophylaxis.

Further research on antimicrobial efficacy for plague is warranted. When outbreaks and sporadic cases of plague do occur, detailed reporting of patients’ treatment regimens, timing of antimicrobial administration, and patient outcomes would serve to inform clinicians and public health practitioners of treatment options for future patients with plague. Furthermore, implementation of RCTs with antimicrobials effective for plague in endemic areas that could be used in the event of an outbreak would provide valuable information on plague treatment and outcomes.

CONCLUSIONS

Antimicrobial treatment and outcome data for patients infected with Y. pestis and reported in aggregate revealed that patients who received tetracyclines, chloramphenicol, and aminoglycosides had the lowest case fatality rates. This result was similar for nonmoribund patients. Fluoroquinolones, FDA approved for treatment of plague, require more research as human antimicrobial monotherapy. As expected, penicillin was not found to be effective for treatment of plague.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. All authors provided critical revisions to the paper for intellectual content and approved the final version for publication.

Acknowledgments. We wish to thank Joanna Taliano, CDC Librarian; DeAnna Howell, DVM, MPH, DACVPM, Colorado School of Public Health and US Army Veterinary Corps; and Helen Talley-McRae, CDC National Center for Emerging and Zoonotic Diseases, Office of the Director.

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Financial support. This project was supported by the CDC and the Office of the Assistant Secretary for Preparedness and Response. The project was also supported in part by an appointment to the CDC Fellowship Program, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and CDC.

Supplement sponsorship. This article appears as part of the supplement “Plague and Bioterrorism Preparedness,” sponsored by the Centers for Disease Control and Prevention.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.