A systematic review of the clinical profile of patients with bubonic plague and the outcome measures used in research settings.

BACKGROUND: Plague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone-no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease-how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment. METHODOLOGY/PRINCIPAL FINDINGS: This systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints-the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days. CONCLUSIONS/SIGNIFICANCE: This systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial's results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist.

In-silico approach of identifying novel therapeutic targets against Yersinia pestis using pan and subtractive genomic analysis.

The magnitude of human affliction brought about by bacterial infections has been on the rise since the mid-5th century. Yersinia pestis is one such notable, gram-negative bacterium that inflicted havoc around the globe three times throughout different millenniums by causing deadly plagues. Despite the unremitting efforts by scientists, different strains of Yersinia pestis are still affecting the populations in various parts of the world by growing resistant to existing antimicrobial agents owing to their overuse. The current scenario, therefore, calls for new therapeutics to further combat the disease. In this study, 3105 core, 387 pathogen-specific unique, 536 choke-point, 796 virulence factors, and 115 antimicrobial resistant proteins were found using a pan-genomic and subtractive genome analysis of nine Yersinia pestis strains that could be instrumental in the development of drugs against Yersinia pestis. Subsequently, 1461 and 1114 essential proteins were identified as non-homologous to human and gut microflora. 535 and 30 proteins were predicted as cytoplasmic and broad-spectrum targets respectively. Finally, four potential targets were selected for their high connectivity in protein-protein interaction network. These selected target proteins are associated with one of the major lipopolysaccharide biosynthesis pathways. Therefore, dismantling their activity might indicate a probable strategy for developing therapeutics to combat bacterial infection caused by Yersinia pestis. However, further experimental validation in the laboratory is needed to consolidate the research findings.

Gepotidacin is efficacious in a nonhuman primate model of pneumonic plague.

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode and has the potential to treat a number of bacterial diseases. Development of this new agent to treat pneumonic plague caused by Yersinia pestis depends on the U.S. Food and Drug Administration Animal Rule testing pathway, as testing in humans is not feasible. Here, preclinical studies were conducted in the African green monkey (AGM) inhalational model of pneumonic plague to test the efficacy of gepotidacin. AGMs infected with Y. pestis were dosed intravenously with gepotidacin (48, 36, or 28 milligrams/kilogram per day) for 10 days to provide a plasma concentration that would support a rationale for a 1000 mg twice or thrice daily intravenous dose in humans or saline as a control. The primary end point was AGM survival with predefined euthanasia criteria. Secondary end points included survival duration and bacterial clearance. Gepotidacin showed activity in vitro against diverse Y. pestis isolates including antibiotic-resistant strains. All control animals in the inhalational plague studies succumbed to plague and were blood culture and organ culture positive for Y. pestis. Gepotidacin provided a 75 to 100% survival benefit with all dose regimens. All surviving animals were blood culture and organ culture negative for Y. pestis. Our randomized, controlled efficacy trials in the AGM pneumonic plague nonhuman primate model together with the in vitro Y. pestis susceptibility data support the use of gepotidacin as a treatment for pneumonic plague caused by Y. pestis.

Phage Therapy Potentiates Second-Line Antibiotic Treatment against Pneumonic Plague.

Plague pandemics and outbreaks have killed millions of people during the history of humankind. The disease, caused by the bacteria Yersinia pestis, is currently treated effectively with antibiotics. However, in the case of multidrug-resistant (MDR) bacteria, alternative treatments are required. Bacteriophage (phage) therapy has shown efficient antibacterial activity in various experimental animal models and in human patients infected with different MDR pathogens. Here, we evaluated the efficiency of фA1122 and PST phage therapy, alone or in combination with second-line antibiotics, using a well-established mouse model of pneumonic plague. Phage treatment significantly delayed mortality and limited bacterial proliferation in the lungs. However, the treatment did not prevent bacteremia, suggesting that phage efficiency may decrease in the circulation. Indeed, in vitro phage proliferation assays indicated that blood exerts inhibitory effects on lytic activity, which may be the major cause of treatment inefficiency. Combining phage therapy and second-line ceftriaxone treatment, which are individually insufficient, provided protection that led to the survival of all infected animals-a synergistic protective effect that represents a proof of concept for efficient combinatorial therapy in an emergency event of a plague outbreak involving MDR Y. pestis strains.

Comparison between physiologically based pharmacokinetic and population pharmacokinetic modelling to select paediatric doses of gepotidacin in plague.

AIMS: To develop physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models to predict effective doses of gepotidacin in paediatrics for the treatment of pneumonic plague (Yersinia pestis). METHODS: A gepotidacin PBPK model was constructed using a population-based absorption, distribution, metabolism and excretion simulator, Simcyp®, with physicochemical and in vitro data, optimized with clinical data from a dose-escalation intravenous (IV) study and a human mass balance study. A PopPK model was developed with pooled PK data from phase 1 studies with IV gepotidacin in healthy adults. RESULTS: For both the PopPK and PBPK models, body weight was found to be a key covariate affecting gepotidacin clearance. With PBPK, ~90% of the predicted PK for paediatrics fell between the 5th and 95th percentiles of adult values except for subjects weighing ≤5 kg. PopPK-simulated paediatric means for Cmax and AUC(0-τ) were similar to adult exposures across various weight brackets. The proposed dosing regimens were weight-based for subjects ≤40 kg and fixed-dose for subjects >40 kg. Comparison of observed and predicted exposures in adults indicated that both PBPK and PopPK models achieved similar AUC and Cmax for a given dose, but the Cmax predictions with PopPK were slightly higher than with PBPK. The two models differed on dose predictions in children <3 months old. The PopPK model may be suboptimal for low age groups due to the absence of maturation characterization of drug-metabolizing enzymes involved with clearance in adults. CONCLUSIONS: Both PBPK and PopPK approaches can reasonably predict gepotidacin exposures in children.

Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak.

BACKGROUND: Pneumonic plague (PP), caused by Yersinia pestis, is the most feared clinical form of plague due to its rapid lethality and potential to cause outbreaks. PP outbreaks are now rare due to antimicrobial therapy. METHODS: A PP outbreak in Madagascar involving transmission of a Y. pestis strain resistant to streptomycin, the current recommended first-line treatment in Madagascar, was retrospectively characterized using epidemiology, clinical diagnostics, molecular characterization, and animal studies. RESULTS: The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including 3 untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. This same mutation causes streptomycin resistance in 2 unrelated Y. pestis strains, one isolated from a fatal PP case in a different region of Madagascar in 1987 and another isolated from a fatal PP case in China in 1996, documenting this mutation has occurred independently at least 3 times in Y. pestis. Laboratory experiments revealed this mutation has no detectable impact on fitness or virulence, and revertants to wild-type are rare in other species containing it, suggesting Y. pestis strains containing it could persist in the environment. CONCLUSIONS: Unique antimicrobial resistant (AMR) strains of Y. pestis continue to arise in Madagascar and can be transmitted during PP outbreaks.

Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague.

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis, is a fatal disease that causes death within 6 days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 h after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased the efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of interleukin-6 (IL-6) and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

The impact of COVID-19 on clinical research for Neglected Tropical Diseases (NTDs): A case study of bubonic plague.

BACKGROUND: Among the many collaterals of the COVID-19 pandemic is the disruption of health services and vital clinical research. COVID-19 has magnified the challenges faced in research and threatens to slow research for urgently needed therapeutics for Neglected Tropical Diseases (NTDs) and diseases affecting the most vulnerable populations. Here we explore the impact of the pandemic on a clinical trial for plague therapeutics and strategies that have been considered to ensure research efforts continue. METHODS: To understand the impact of the COVID-19 pandemic on the trial accrual rate, we documented changes in patterns of all-cause consultations that took place before and during the pandemic at health centres in two districts of the Amoron'I Mania region of Madagascar where the trial is underway. We also considered trends in plague reporting and other external factors that may have contributed to slow recruitment. RESULTS: During the pandemic, we found a 27% decrease in consultations at the referral hospital, compared to an 11% increase at peripheral health centres, as well as an overall drop during the months of lockdown. We also found a nation-wide trend towards reduced number of reported plague cases. DISCUSSION: COVID-19 outbreaks are unlikely to dissipate in the near future. Declining NTD case numbers recorded during the pandemic period should not be viewed in isolation or taken as a marker of things to come. It is vitally important that researchers are prepared for a rebound in cases and, most importantly, that research continues to avoid NTDs becoming even more neglected.

In vitro and in vivo activity of GT-1, a novel siderophore cephalosporin, and GT-055, a broad-spectrum ß-lactamase inhibitor, against biothreat and ESKAPE pathogens.

Antimicrobial-resistance (AMR) has become an increasingly difficult issue to overcome for bacteria associated with both community- and hospital-acquired infections as well as potential biodefense threats. The need to identify new therapeutics of novel classes and/or with unique mechanisms is critical to combatting AMR in the coming years. GT-1 (LCB10-0200), a siderophore-linked cephalosporin, is one such novel option and is formulated to be used either alone or in combination with a novel broad-spectrum ß-lactamase inhibitor, GT-055 (LCB18-055). This study assessed the in vitro and in vivo efficacy of GT-1 and GT-055 against a broad array of multi-drug resistant and biothreat pathogens. Here, we demonstrated sub-4 µg ml-1 efficacy against a number of pathogens in vitro. We further determined that in mice infected via aerosol route with Yersinia pestis, efficacy of GT-1/GT-055 treatment is at least equivalent to the comparator antibiotic, ciprofloxacin.

Antibiotic Therapy of Plague: A Review.

Plague-a deadly disease caused by the bacterium Yersinia pestis-is still an international public health concern. There are three main clinical forms: bubonic plague, septicemic plague, and pulmonary plague. In all three forms, the symptoms appear suddenly and progress very rapidly. Early antibiotic therapy is essential for countering the disease. Several classes of antibiotics (e.g., tetracyclines, fluoroquinolones, aminoglycosides, sulfonamides, chloramphenicol, rifamycin, and ß-lactams) are active in vitro against the majority of Y. pestis strains and have demonstrated efficacy in various animal models. However, some discrepancies have been reported. Hence, health authorities have approved and recommended several drugs for prophylactic or curative use. Only monotherapy is currently recommended; combination therapy has not shown any benefits in preclinical studies or case reports. Concerns about the emergence of multidrug-resistant strains of Y. pestis have led to the development of new classes of antibiotics and other therapeutics (e.g., LpxC inhibitors, cationic peptides, antivirulence drugs, predatory bacteria, phages, immunotherapy, host-directed therapy, and nutritional immunity). It is difficult to know which of the currently available treatments or therapeutics in development will be most effective for a given form of plague. This is due to the lack of standardization in preclinical studies, conflicting data from case reports, and the small number of clinical trials performed to date.

Finafloxacin Is an Effective Treatment for Inhalational Tularemia and Plague in Mouse Models of Infection.

Infection with aerosolized Francisella tularensis or Yersinia pestis can lead to lethal disease in humans if treatment is not initiated promptly. Finafloxacin is a novel fluoroquinolone which has demonstrated broad-spectrum activity against a range of bacterial species in vitro, in vivo, and in humans, activity which is superior in acidic, infection-relevant conditions. Human-equivalent doses of finafloxacin or ciprofloxacin were delivered at 24 h (representing prophylaxis) or at 72 or 38 h (representing treatment) postchallenge with F. tularensis or Y. pestis, respectively, in BALB/c mouse models. In addition, a short course of therapy (3 days) was compared to a longer course (7 days). Both therapies provided a high level of protection against both infections when administered at 24 h postchallenge, irrespective of the length of the dosing regimen; however, differences were observed when therapy was delayed. A benefit was demonstrated with finafloxacin compared to ciprofloxacin in both models when therapy was delivered later in the infection. These studies suggest that finafloxacin is an effective alternative therapeutic for the prophylaxis and treatment of inhalational infections with F. tularensis or Y. pestis.

WHO guidelines for plague management: revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission

Plague has killed millions of people during the past 25 centuries, and the disease reappeared in several countries during the 1990s. Consequently, plague was categorized as a re-emerging disease. Human plague outbreaks continue to be reported, including an outbreak of pneumonic plague in Madagascar in 2017. Plague is an acute bacterial infection caused by Yersinia pestis. Although effective antimicrobials are available, plague still has high mortality because most outbreaks take place in remote places, where proper diagnosis and treatment remain challenging. Early identification of the disease is crucial to ensure prompt treatment and better outcomes. Pneumonic plague is highly contagious and of particular concern because of the high risk of triggering epidemics. Thus, plague is both a medical and a public health emergency. These guidelines were developed in accordance with the WHO handbook for guideline development. A WHO Steering Group, led by the responsible technical officer, developed the draft scope of the guidelines and the key questions to be addressed. The Steering Group selected the members of the Guideline Development Group (GDG) to ensure diverse areas of expertise were represented, including clinicians, microbiologists, public health professionals, researchers and an anthropologist. The Steering Group also commissioned technical advisers to lead the Evidence Review Team and provide methodological support. The GDG assisted with developing the final scope of the guideline and defining the key areas to be addressed, and also formulated the recommendations. Three key areas were selected to be addressed: (i) the use of rapid diagnostic tests (RDTs) for diagnosing plague in different contexts; (ii) the choice of antimicrobials for treating the different forms of plague, including whether fluoroquinolones should be introduced as a first-line medicine of choice; and (iii) the use of personal protective equipment in case of exposure to the dead body of a person who was infected with plague. The Evidence Review Team conducted systematic reviews to address each of the three key areas. At a meeting in Antananarivo, Madagascar, on 20­21 September 2019, the GDG interpreted the main findings of the systematic reviews as they applied to each key question and formulated evidence-based recommendations following the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. For each key question, there was discussion about the certainty of the evidence, desirable and undesirable effects, values and preferences, cost, acceptability, equity, feasibility and barriers to implementation. The GRADE evidence-to-decision tables were used to facilitate consensus and record the decision of the GDG. The GDG developed final recommendations where possible and graded each of them as strong or conditional. The final guidelines were written by the Evidence Review Team.

Influenza virus infection augments susceptibility to respiratory Yersinia pestis exposure and impacts the efficacy of antiplague antibiotic treatments.

Various respiratory viral infections in general and seasonal influenza in particular may increase the susceptibility to bacterial infections. Plague caused by Yersinia pestis endangers large populations during outbreaks or bioterrorism attacks. Recommended antibiotic countermeasures include well-established protocols based on animal studies and corroborated by effective treatment of human cases. Until now, prior exposure to viral respiratory infections was not taken into consideration when selecting the appropriate treatment for plague. Here, we show that as late as 25 days after exposure to influenza virus, convalescent mice still exhibited an increased susceptibility to sublethal doses of Y. pestis, presented with aberrant cytokine expression, and impaired neutrophil infiltration in the lungs. Increased levels of M2 alveolar macrophages and type II epithelial cells, as well as induction in metalloproteases expression and collagen and laminin degradation, suggested that the previous viral infection was under resolution, correlating with enhanced susceptibility to plague. Surprisingly, postexposure prophylaxis treatment with the recommended drugs revealed that ciprofloxacin was superior to doxycycline in mice recovering from influenza infection. These results suggest that after an influenza infection, the consequences, such as impaired immunity and lung tissue remodeling and damage, should be considered when treating subsequent Y. pestis exposure.

Techniques and Strategies for Potential Protein Target Discovery and Active Pharmaceutical Molecule Screening in a Pandemic.

Viruses remain a major challenge in the fierce fight against diseases. There have been many pandemics caused by various viruses throughout the world over the years. Recently, the global outbreak of COVID-19 has had a catastrophic impact on human health and the world economy. Antiviral drug treatment has become another essential means to overcome pandemics in addition to vaccine development. How to quickly find effective drugs that can control the development of a pandemic is a hot issue that still needs to be resolved in medical research today. To accelerate the development of drugs, it is necessary to target the key target proteins in the development of the pandemic, screen active molecules, and develop reliable methods for the identification and characterization of target proteins based on the active ingredients of drugs. This article discusses key target proteins and their biological mechanisms in the progression of COVID-19 and other major epidemics. We propose a model based on these foundations, which includes identifying potential core targets, screening potential active molecules of core targets, and verifying active molecules. This article summarizes the related innovative technologies and methods. We hope to provide a reference for the screening of drugs related to pandemics and the development of new drugs.

Two fatal cases of plague after consumption of raw marmot organs.

Marmots are an important reservoir of Yersinia pestis and a source of human plague in Mongolia. We present two fatal cases of plague after consumption of raw marmot organs and discuss the distribution of natural foci of Y. pestis in Mongolia.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Immunotropic Properties of an Experimental Synthetic Selenium-Organic Compound.

We studied immunotropic properties of synthetic selenium-organic preparation 2,6-dipyridinium-9-selenabicyclo[3.3.1]nonyl dibromide (974zh). The experimental preparation reduced the cAMP/cGMP ratio, which indicated an increase in proliferative activity of cells of immunocompetent organs (thymus and spleen) in experimental animals. It was shown that 974zh intensified the immune response to Yersinia pestis EV thereby increasing the resistance to the plague agent.

Dapsone is not a Pharmacodynamic Lead Compound for its Aryl Derivatives.

BACKGROUND: The relatedness between the linear equations of thermodynamics and QSAR was studied thanks to the recently elucidated crystal structure complexes between sulfonamide pterin conjugates and dihydropteroate synthase (DHPS) together with a published set of thirty- six synthetic dapsone derivatives with their reported entropy-driven activity data. Only a few congeners were slightly better than dapsone. OBJECTIVE: Our study aimed at demonstrating the applicability of thermodynamic QSAR and to shed light on the mechanistic aspects of sulfone binding to DHPS. METHODS: To this end ligand docking to DHPS, quantum mechanical properties, 2D- and 3D-QSAR as well as Principle Component Analysis (PCA) were carried out. RESULTS: The short aryl substituents of the docked pterin-sulfa conjugates were outward oriented into the solvent space without interacting with target residues which explains why binding enthalpy (ΔH) did not correlate with potency. PCA revealed how chemically informative descriptors are evenly loaded on the first three PCs (interpreted as ΔG, ΔH and ΔS), while chemically cryptic ones reflected higher dimensional (complex) loadings. CONCLUSION: It is safe to utter that synthesis efforts to introduce short side chains for aryl derivatization of the dapsone scaffold have failed in the past. On theoretical grounds we provide computed evidence why dapsone is not a pharmacodynamic lead for drug profiling because enthalpic terms do not change significantly at the moment of ligand binding to target.

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

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.

Antimicrobial Treatment Patterns and Illness Outcome Among United States Patients With Plague, 1942-2018.

BACKGROUND: Plague is a rare and severe zoonotic illness with limited empiric evidence to support treatment recommendations. We summarize treatment information for all patients with plague in the United States (US) as collected under the auspices of public health surveillance. METHODS: We reviewed use of specific antimicrobials and illness outcome among cases of plague reported from 1942-2018. Antimicrobials were a priori classified into high-efficacy (aminoglycosides, tetracyclines, fluoroquinolones, sulfonamides, and chloramphenicol) and limited-efficacy classes (all others). Logistic regression models were created to describe associations between use of specific antimicrobial classes and illness outcome while controlling for potential confounding factors. RESULTS: Among 533 total reported plague cases during 1942-2018, 426 (80%) received high-efficacy antimicrobial therapy. Mortality differed significantly among those receiving high-efficacy therapy (9%) and only limited-efficacy therapy (51%). Aminoglycosides and tetracyclines were used more commonly than other classes, and their use was associated with increased odds of survival of plague. Gentamicin use was associated with higher mortality than streptomycin, and aminoglycoside use was linked to higher mortality than for tetracyclines. Fluoroquinolones have been used in treatment of >30% of patients in recent years and limited data suggest clinical effectiveness. CONCLUSIONS: Most US patients with plague have received effective antimicrobials. Aminoglycosides and tetracyclines substantially improve survival of plague, and fluoroquinolones may be equally as effective, yet lack sufficient data. Early recognition and early treatment with any of these antimicrobial classes remain the most important steps to improving survival of plague.