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Treatment of Plague with Gentamicin or Doxycycline in a Randomized Clinical Trial in Tanzania

  1. William Mwengee1,
  2. Thomas Butler3,
  3. Samuel Mgema2,
  4. George Mhina2,
  5. Yusuf Almasi2,
  6. Charles Bradley4,
  7. James B. Formanik5, and
  8. C. George Rochester6
  1. 1Regional Medical Office, Tanga
  2. 2Lushoto District Hospital, Lushoto, Tanzania
  3. 3Departments of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas
  4. 4Departments of Pathology, Texas Tech University Health Sciences Center, Lubbock, Texas
  5. 5Departments of Ricerca Biosciences, Concord, Ohio
  6. 6Division of Biometrics III, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Maryland
  1. Reprints or correspondence: Dr. Thomas Butler, c/o William B. Greenough, III, Dept. of Geriatric Medicine, Johns Hopkins University, 5505 Hopkins Bayview Circle, Baltimore, MD 21224 (trigsby{at}jhmi.edu).
 
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Abstract

Background. Over the past 50 years, antibiotics of choice for treatment of plague, including streptomycin, chloramphenicol, and tetracycline, have mostly become outdated or unavailable. To test gentamicin in the treatment of naturally occurring plague and the implications of its use in the treatment of bioterrorist plague, a randomized, comparative, open-label, clinical trial comparing monotherapy with gentamicin or doxycycline was conducted in Tanzania.

Methods. Sixty-five adults and children with symptoms of bubonic, septicemic, or pneumonic plague of ⩽3 days duration were enrolled in the study. Bubo aspirates and blood were cultured for Yersinia pestis. Acute-phase and convalescent-phase serum samples were tested for antibody against fraction 1 antigen of Y. pestis. Thirty-five patients were randomized to receive gentamicin (2.5 mg/kg intramuscularly every 12 h for 7 days), and 30 patients were randomized to receive doxycycline (100 mg [adults] and 2.2 mg/kg [children] orally every 12 h for 7 days). Serum creatinine concentrations were measured before and after treatment, and peak and trough concentrations of antibiotics were measured.

Results. Three patients, 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, died on the first or second day of treatment, and these deaths were attributed to advanced disease and complications including pneumonia, septicemia, hemorrhage, and renal failure at the start of therapy. All other patients experienced cure or an improved condition after receiving therapy, resulting in favorable response rates of 94% for gentamicin (95% CI, 81.1%–99.0%) and 97% for doxycycline (95% CI, 83.4%–99.8%). Y. pestis isolates obtained from 30 patients belonged to biotype antigua and were susceptible to gentamicin and doxycycline, which had MICs of 0.13 mg/L and 0.25–0.5 mg/L, respectively. Serum concentrations of antibiotics were within therapeutic ranges, and adverse events were infrequent. Patients treated with gentamicin demonstrated a modest increase in the mean serum creatinine concentration after treatment (P < .05, by paired t test).

Conclusions. Both gentamicin and doxycycline were effective therapies for adult and pediatric plague, with high rates of favorable responses and low rates of adverse events.

Plague is a natural infection of rodents caused by the bacterium Yersinia pestis and is transmitted to humans by means of rodent flea bites and, less commonly, from person-to-person by means of respiratory droplets from coughing patients [1, 2]. The predominant clinical presentation is bubonic plague, which consists of fever and acute lymphadenitis (the bubo) [3]. Less common forms include pneumonia, septicemia without a bubo, and meningitis [4]. Most patients with plague who are not promptly treated with antibiotics die within a few days after the onset of symptoms. After the terrorist attacks of 2001, with the knowledge that other countries have pursued biological weapons programs, concern increased regarding the use of aerosolized Y. pestis as a potential weapon against military and civilian populations [5, 6].

In India in 1948, streptomycin was shown to be highly effective against plague by reducing mortality rates from >50% to ∼4%–15% [7–9], and it was the drug of choice for thousands of patients treated in Vietnam in the period of 1960–1975 [10–14]. Chloramphenicol and tetracyclines were also effective and widely used [15]. Of the 2 countries with the highest incidence of plague, streptomycin is used mainly in Madagascar, and tetracycline is used mainly in Tanzania [16, 17]. However, the manufacture of streptomycin and chloramphenicol has been curtailed in many countries, because of the drugs' toxicities. Although these and other antimicrobial drugs have been used, only doxycycline, demeclocycline, minocycline, tetracycline, and streptomycin are currently approved by the US Food and Drug Administration (FDA) for the treatment of plague. Several newer antimicrobial drugs, including gentamicin, are effective against Y. pestis in vitro [18–21] and in experimental animal infections [22–24]. A recent retrospective analysis of human cases has recently been reported [25], but there has not been a controlled, prospective assessment of human infection. The following clinical trial was conducted to test the efficacy and safety of gentamicin for the purpose of expanding the options of effective treatment.

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Methods

Study design and sample size. The study intended to compare gentamicin and the standard drug, doxycycline, as monotherapy for plague. The design was a randomized, controlled, comparative, superiority, open-label trial. The sample size was calculated to show a difference in response rates, with respect to prompt cure or improvement of condition among febrile patients with less tender buboes within 3 days, of 50%. If we assume that standard therapy (given to the control group) will result in a 60% rate of prompt cure or improvement of condition (the other 40% being a result of receiving delayed treatment and/or having a complicated or fatal course, as occurred in Madagascar in 1997) [26], then ∼30 patients in each treatment group will be required to reach a significance level of .05 (α; 2-sided) and .20 (β; 1-sided) [27]. The method of randomization included the use of random number tables with variable permuted block sizes. Each patient's treatment group assignment was sealed in an envelope that was opened after the patient was selected and gave consent to enter the trial [28–30].

Informed consent and entry criteria. The study was approved by the Tanzanian National Institute for Medical Research. Informed consent was obtained from all eligible patients or their legal guardians. The consent form explained the purpose of the trial, procedures, risks (allergic reactions, renal failure, deafness, vertigo, or worsening of clinical condition), and voluntary participation. Before enrolling the patient, the investigator explained verbally in the patient's own language the content of the consent form. Inclusion criteria included persons of all ages and both sexes who lived in regions where plague is endemic and who presented with histories of ⩽3 days of fever and bubo (enlarged tender lymph nodes), pneumonia, or septicemia. Excluded subjects included pregnant or nursing women, persons who received >2 doses of pretreatment with an effective antimicrobial drug during the previous 3 days, persons who had an allergic reaction to either of the study drugs, and persons who had a significant underlying disease.

Procedures. Bubo aspiration was performed by inserting a 10-ml syringe with a 21-gauge needle containing 1 cc of sterile saline, through the skin, into the bubo. The saline was injected and reaspirated until blood-tinged fluid appeared in the syringe. Drops were placed on slides for Gram staining and fluorescent antibody staining, and the remaining fluid was cultured on MacConkey agar and in trypticase soy broth. Blood samples used for culture were placed into trypticase soy broth. Bubo aspirate specimens were incubated at 25°C for 48 h or until characteristic colonies were visible for placement onto nutrient agar slants for transport to the reference laboratory. Blood cultures were incubated for 48 h and subcultured on MacConkey agar, and characteristic colonies were placed on nutrient agar slants. Venous blood was drawn at the time of admission and on day 8 after the start of therapy, allowed to clot in a glass tube at room temperature for 30 min, and centrifuged at 1500 g for 10 min, and serum was removed and frozen for serologic testing and serum chemistry analysis. Serum creatinine concentration was observed to assess any renal effects caused by gentamicin during the course of therapy.

Venous blood samples were also drawn for serum antibiotic measurements at peak times of 1 h after gentamicin injections and 2 h after receipt of doxycycline and at trough times of 12 h after receipt of antibiotics. Temperature, pulse, respirations, and blood pressure were measured twice daily for 7 days. Bubo length was measured, and severity of tenderness (mild, moderate, or severe) was assessed daily. Other symptoms and adverse effects of study drugs were elicited daily by means of follow-up systems review and physical examination. Because gentamicin can cause injury to the eighth nerve, ototoxicity was measured by equilibrium in the standing position and by changes in hearing acuity. One to 2 weeks after the end of therapy, patients were asked to return to the clinic for follow-up examination of symptoms and examination of the bubo.

Antimicrobial treatment. Immediately after specimens were obtained for culture and patients were randomized, treatment was started and administered twice daily for 7 days. Gentamicin (Garamycin; Schering-Plough) was administered intramuscularly in 2.5-mg/kg doses. One hundred—mg capsules of doxycycline (Vibramycin; Pfizer) were administered by mouth to adults, and children received powder from capsules suspended in 100 mL of water in 2.2-mg/kg doses, which they drank.

Definitions of outcomes. Cure was defined as resolution of fever and painful bubo swelling, and, if initially present, recovery from pneumonia or any other symptoms of plague. Improvement of condition was defined as the persistence of any sign or symptom in a milder degree. Treatment failure was defined as a lack of improvement in condition, relapse, or death. Relapse was defined as the return of bubo tenderness, fever, or other symptoms within 1–2 weeks after the end of therapy. A confirmed microbiological diagnosis was based on positive culture results and/or results of serological tests of the clinical samples sent to a reference laboratory. If the clinical sample only tested positive at the local laboratory, a presumptive microbiological diagnosis was assigned.

Reference laboratories. At Texas Tech University Health Sciences Center (Lubbock), NCCLS-approved standard assays were used to determine antimicrobial susceptibility using disk diffusion on Mueller-Hinton agar (Difco Detroit) in 150 × 15—mm petri dishes and using Escherichia coli ATCC 25922 as a control. Paper disks (Becton Dickinson) were used with the following drugs, with zone diameters to define susceptibility: 10 µg of ampicillin (zone diameter, ⩾14 mm), 30 µg of chloramphenicol (zone diameter, ⩾18 mm), 5 µg of ciprofloxacin (zone diameter, ⩾21 mm), 30 µg of doxycycline (zone diameter, ⩾16 mm), 10 µg of gentamicin (zone diameter, ⩾15 mm), 10 µg of streptomycin (zone diameter, ⩾10 mm), 30 µg of tetracycline (zone diameter, ⩾19 mm), and 1.25/23.7 µg of trimethoprim-sulfamethoxazole (zone diameter, ⩾16 mm) [31, 32]. MICs were determined in a tube dilution assay using Mueller-Hinton II broth containing gentamicin sulfate and doxycycline hydrochloride (Sigma-Aldrich). Serum creatinine concentrations were measured by an enzymatic slide method using a Vitros 950 analyzer (Ortho-Clinical Diagnostics). The reference interval for creatinine level in healthy control subjects was 0.7–1.5 mg/dL. Gentamicin concentrations in serum were measured by fluorescence polarization immunoassay (AxSYM; Abbott Laboratories). At the Fort Collins Laboratories of Centers for Disease Control and Prevention (CDC), cultures were confirmed as Y. pestis using phage lysis, and biotype was determined using nitrate reduction and glycerol fermentation [32]. Serological testing included passive hemagglutination and inhibition tests to detect antibodies against fraction 1 antigen of Y. pestis, with a diagnostic titer defined as ⩾1:16 and capture of IgM and IgG against fraction 1 antigen of Y. pestis in ELISAs. The direct fluorescent antibody test for fraction 1 of Y. pestis was applied to slides of bubo aspirates and, if the result was positive, allowed for a presumptive diagnosis of plague. At Ricerca Biosciences (Concord, OH), doxycycline concentrations in serum were measured by liquid chromatography—mass spectroscopy/mass spectroscopy.

Data analysis. Outcomes in the treatment groups were compared by means of an intent-to-treat analysis for incidences of cures, condition improvements, and treatment failures and for incidences of adverse events by binomial 95% CIs [33, 34], using statistical software StatXact, version 5.0 (Cytel Software) and the χ2 test. Means of continuous variables, such as creatinine concentration, were compared with student's t test.

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Results

Patients

Sixty-five patients were enrolled between January and April 2002 from the plague-endemic area. Thirty-five patients were randomized to receive gentamicin, and 30 were randomized to receive doxycycline (table 1). All patients had bubonic plague, with symptoms of fever and acute lymphadenitis, except for 1 patient who presented with septicemia 1 week after a bubo had been treated and had resolved, prior to entry into the study, and 1 patient with pneumonia and a bubo. Ages ranged from 7 months to 65 years, and younger children were, by chance, assigned to the gentamicin group, resulting in a younger median age for the gentamicin group. Men were predominant in both groups. Locations and sizes of buboes were similar for both groups. Temperatures increased to higher levels in the gentamicin group, resulting in a median temperature at the time of admission that was 0.5°C higher than that in the doxycycline group. Serum creatinine concentrations were >1.5 mg/dL in only 2 patients in each treatment group, and the mean concentrations were similar for both treatment groups. The majority of patients in both groups (89% of the gentamicin group and 84% of the doxycycline group) had the diagnosis of plague confirmed by culture or serologic testing. Other patients had presumptive diagnoses confirmed by fluorescent antibody applied to bubo aspirates or by culture in the local laboratory. Only 2 patients, both in the gentamicin group, had no laboratory diagnosis of plague, and neither of them had convalescent-phase serum samples available for serologic testing.

Table 1
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Table 1

Characteristics of patients with plague before gentamicin or doxycycline treatment.

Identification and Susceptibilities of Y. pestis

Y. pestis was isolated from 30 patients and confirmed by phage lysis at the CDC (Fort Collins, CO). These isolates had been obtained from bubo aspirates of 29 patients and from a culture of blood obtained from 1 septicemic patient; the 30 confirmed isolates belonged to biotype antigua. All isolates were susceptible by disc diffusion to ampicillin, chloramphenicol, ciprofloxacin, doxycycline, gentamicin, streptomycin, tetracycline, and trimethoprim-sulfamethoxazole. The median MIC for each isolate tested, using the 2–3 results for each isolate, were 0.13 mg/L of gentamicin (range, 0.06–0.25 mg/L) for 30 isolates, and 0.25 mg/L of doxycycline for 18 isolates, and 0.50 mg/L of doxycycline for 12 isolates (range for both median values, 0.13–0.5). All isolates were susceptible to all tested antimicrobial drugs by disk diffusion. MICs of gentamicin and doxycycline that were low (in the range of 0.06–0.5 mg/L) confirmed that all isolates were susceptible to the study drugs.

Response to Treatment and Adverse Events

Three patients died on days 1 and 2 after the start of therapy (table 2), 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, and these deaths were attributed to advanced disease and complications at the time therapy was initiated. All other patients had favorable responses to treatment and were considered to be cured or to have had an improved condition after 7 days of treatment. The rates of favorable outcome were 94% (95% CI, 81.1%–99.0%) for gentamicin and 97% (95% CI, 83.4%–99.8%) for doxycycline. The estimated difference of response rates (gentamicin-doxycycline) was -3% (95% CI for true difference in response rates, -16.1% to 12.1%; P > .05). When patients returned for follow-up visits 1–2 weeks after the end of therapy, no relapses had occurred. Four patients failed to return for follow-up visits; 3 of these had received gentamicin, and 1 had received doxycycline. The patients who died are described as brief case reports.

Table 2
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Table 2

Clinical responses to gentamicin or doxycycline treatment.

Case Reports

Patient 1. One day before admission, a 10-year-old girl suddenly developed fever, headache, submandibular swelling, and cough. On the same day, she experienced chills and myalgias and was observed to be delirious. She took a tablet of acetaminophen. On admission, she had a temperature of 41°C, a pulse rate of 88 beats per min, and respirations of 24 per min. There was a submandibular lymph node that measured 2 × 2 cm. The chest exam showed coarse rales. No radiographic examination was available. She received 1 dose of gentamicin 40 mg intramuscularly. Three hours later, she was noted to have had a seizure, and she died. The bubo aspirate obtained before treatment tested positive for Y. pestis. This simultaneous presentation of pneumonia and submandibular bubo suggests that the patient was exposed to an aerosol of Y. pestis from another person with pneumonic plague and that the inoculum reached the lungs by inhalation at the same time as it did the submandibular lymph nodes through the oral mucosa.

Patient 2. A 65-year-old woman developed a painful swelling in the right groin 7 days before admission. She treated herself with 8 tablets of tetracycline, and the swelling subsided. On the day of admission, she developed chills and myalgia. She did not have a bubo, her temperature was 38.5°C, her pulse rate was 78 per min, she had respirations of 24 per min, and she had systolic/diastolic blood pressure of 110/70 mm Hg. She received gentamicin (80 mg intramuscularly), and she died 4 h later. Results of a blood culture performed before treatment were positive for Y. pestis. This patient with bubonic plague was partially treated with tetracycline, and the patient's condition improved clinically, but regrowth of residual bacteria in the blood caused fatal septicemia before the immune response was protective.

Patient 3. A 34-year-old woman pregnant for 24 weeks developed fever, chills, headache, myalgias, and left inguinal swelling 2 days before admission. She aborted a dead fetus on the morning of admission. Her temperature was 38.8°C, her pulse rate was 100 beats per min, she had respirations of 20 per min, and her systolic/diastolic blood pressure was 120/80 mm Hg. She had a tender left inguinal bubo that measured 5 × 2 cm. She was confused and had vaginal bleeding. She received doxycycline (100 mg orally) twice on the day of admission. She continued to have vaginal bleeding and received ergotamine injections. She died the next morning. A bubo aspirate obtained before treatment grew presumptive Y. pestis. Her serum creatinine concentration at admission was 3.0 mg/dL. This pregnant patient with presumptive bubonic plague died after an abortion, with complications of hemorrhage and prerandomization renal failure.

Among the surviving patients, buboes responded with reduced tenderness and, in most patients, were smaller or had disappeared after 7 days of treatment. In 2 patients treated with gentamicin, buboes suppurated and spontaneously drained pus. Temperatures of most patients in both treatment groups, which were measured daily, promptly decreased to <38°C by day 2 of treatment.

Adverse events were reported by patients as symptoms not present before therapy (table 2), and these were mild or moderate in severity, except for a seizure that occurred before death in 1 patient. Treatment was not interrupted in any surviving patient because of adverse events.

Serum creatinine concentrations were measured after the last dose of antibiotic was given on day 8 of treatment. Mean serum creatinine concentrations were normal in both groups (table 2). In the patients treated with doxycycline, all values were <1.5 mg/dL, but 4 patients treated with gentamicin had values >1.5 mg/dL. In patients treated with gentamicin, a comparison of creatinine concentrations before and after therapy by a paired t test showed significant increases (P < .05).

Serum Concentrations of Antibiotics

The peak concentrations (mean ± SD) of gentamicin 1 h after the first dose and of doxycycline 2 h after the first dose were 5.5 ± 5.2 mg/dL (n = 26) and 1.6 ± 1.5 mg/dL (n = 27), respectively. The trough values (mean ± SD) measured 12 h after the last doses were given were 0.4 ± 0.5 mg/dL (n = 23) and 2.5 ± 2.3 mg/dL (n = 24), respectively. The concentrations of gentamicin indicated adequate therapeutic levels in most patients at the peak and no accumulation of antibiotic at trough times that might cause nephrotoxicity or ototoxicity. Concentrations of doxycycline were also in the therapeutic range. Mean trough values after the last dose was given were higher than the peak values after the first dose was given.

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Discussion

The success of both gentamicin and doxycycline in this randomized trial to cure or improve the conditions of 94% and 97% of patients with plague, respectively, compares favorably with the 94% success rate of streptomycin used alone or in combination with chloramphenicol or trimethoprim-sulfamethoxazole in previous uncontrolled studies in Vietnam [10–13]. The 3 deaths that occurred after the start of therapy happened on the first or second day of treatment and were attributed to advanced disease and complications of pneumonia, septicemia, hemorrhage, and renal failure that could not be reversed by antimicrobial treatment. These were examples of known complications of plague, including spontaneous abortion, postpartum hemorrhage, and septicemia [3, 35], although the death of the patient with suspected primary pneumonia on the second day of illness was faster than the usual 3 days [15, 26]. The high rates of successful outcomes in this study can be explained in part by early initiation of therapy after only 1 day of symptoms in most of the patients. Delays in initiating treatment of >3 days increased mortality and are largely responsible for a worldwide mortality rate of 7%; a mortality rate in the United States of 12%, which was reported to the World Health Organization in the 1990s [16]; and a mortality rate of 22% in a series study of selected patients in United States [35, 36].

These results indicate that gentamicin may be an effective alternative treatment to streptomycin as a drug of choice for the treatment of plague. Alternative therapies are needed because streptomycin is no longer available in most countries, because drug manufacturing has been severely curtailed. An exception is Madagascar, which manufactures its own drug and uses it to treat domestic cases of plague. In vitro plasmid-mediated resistance to streptomycin has been reported in Y. pestis isolated from 2 patients with bubonic plague in Madagascar in 1995; both of these patients survived their infections while receiving streptomycin, probably because they were treated concomitantly with trimethoprim-sulfamethoxazole, to which their isolates were susceptible. These streptomycin-resistant strains would have been susceptible to gentamicin because of the specificities of the responsible enzymes [37, 38].

Both antibiotics were well tolerated in these patients, with the infrequent occurrence of adverse events that were short lived. Most of the adverse events, which were symptoms and signs reported after treatment was initiated, were probably not caused by the drugs, because they included known nonspecific symptoms of plague infection, such as headache, cough, and gastrointestinal symptoms [35]. On the other hand, 4 patients treated with gentamicin had increases in their serum creatinine concentrations to >1.5 mg/dL at the end of therapy. It was not determined whether these increases in creatinine concentrations were reversible, because the study design did not include blood sampling at a subsequent visit. The mean serum creatinine concentration measured after treatment in gentamicin-treated patients was 1.04 mg/dL; this was in the normal range and represented a modest increase from the pretreatment mean of 0.78 mg/dL. Although the increases were determined to be statistically significant by a paired t test (P < .05), the clinical significance of the nephrotoxicity is doubtful. The serum creatinine concentration is sometimes elevated in patients with plague because of sepsis, especially in patients who have subsequent fatal outcomes [35]. The increases in serum creatinine concentrations in surviving patients treated with gentamicin were likely caused by gentamicin use, because patients treated with doxycycline did not show increases in their creatinine concentration. On testing, no gentamicin recipients had evidence of ototoxicity. It is likely that once daily administration could be effective in reducing the risk of renal toxicity and the cost and the logistics of twice-daily injections. Such a modification would need to be field tested. Both intravenous and intramuscular routes achieve similar serum concentrations.

Clinical responses in surviving patients were prompt in both treatment groups, with temperatures normalizing after 1 day for most patients and buboes showing reduced size and tenderness over several days. These prompt responses suggest that treatment courses <7 days might also be effective in plague, although relapses might occur with shorter courses of treatment. Additionally, the administration of gentamicin once daily would likely be effective and would be more convenient and less costly for treating patients [39, 40].

A diagnosis of plague was confirmed in most of our patients by culture of bubo aspirates and serologic testing. A recently reported, rapid diagnostic test may offer additional speed and precision in the early recognition of plague [41]. The use of serologic testing with IgM capture, which is more sensitive than the passive hemagglutination test because it detects onset of acute disease earlier, allowed us to confirm the diagnosis in several patients with nondiagnostic passive hemagglutination titers. All 30 strains of Y. pestis belonged to biotype antigua, which is different from the biotype orientalis found as the predominant biotype in Madagascar and most other countries [33]. None of these strains showed antimicrobial resistance to any of the tested drugs, and this result is different from studies of 7 isolates from Lushoto, Tanzania, in 1991, that were resistant to trimethoprim [42]. MICs of gentamicin and doxycycline for all of the strains in our study were low, in the range of 0.06–0.5 mg/L, and were consistent with the good clinical responses to the drugs that occurred in this trial.

Serum concentrations of antibiotics that were measured in these patients showed mean values that were considered to be adequate for therapeutic effects. The mean concentrations of gentamicin 1 h after intramuscular injection at the expected peak of antibiotic absorption into blood was 5.5 mg/dL, which was many times higher than the MIC of 0.13 mg/dL for the isolates of Y. pestis. Twelve h after dosing, when the trough antibiotic concentration was expected, the mean concentration of gentamicin of 0.4 mg/dL was low enough to avoid nephrotoxic and ototoxic effects, but it was still above the MIC of Y. pestis. The serum concentrations of doxycycline were also higher than its MIC for Y. pestis at both the peak and trough times of measurement. However, the mean trough concentration was greater than the mean peak concentration, and this can be explained by the long half-life of doxycycline (>15 h) and that our peak samples were obtained 2 h after the first dose, with the trough samples obtained later in the course of therapy, after a steady state had been achieved. Although the dosages of 100 mg orally twice daily for adults and 2.2 mg/kg twice daily for children were clinically effective, it has been advised to give loading doses of twice these amounts for the first 72 h and then, for the maintenance dose, to reduce the dose size by one-half [43]. The use of a loading dose of doxycycline followed by a once-daily administration should be considered for patients with plague, because life-threatening infections require early attainment of high-tissue concentrations of antibiotic.

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Acknowledgments

We thank David Dennis and May Chu at the Centers for Disease Control and Prevention (Fort Collins, CO) for providing reference laboratory support, Juma Hamza at Gologolo Dispensary (Tanzania) for his assistance with patient care, and B.S. Kilonzo at Sokoine University (Morogoro, Tanzania) and Eligius Lyamuya at Muhimbili University (Dar Es Salaam, Tanzania) and Fred Marsik at the US Food and Drug Administration for technical advice.

Manuscript preparation. William B. Greenough, III, and Mrs. Terri Rigsby (Johns Hopkins University, Baltimore, MD) helped with manuscript preparation because of T.B.'s incarceration in the Federal Medical Center, Fort Worth, Texas [44].

Financial support. US Food and Drug Administration and Center for Drug Evaluation and Research.

Potential conflicts of interest. All authors: no conflicts.

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Footnotes

  • The views expressed in this paper are those of the authors and must not be interpreted as the policies or guidance of the US Food and Drug Administration.

  • Received July 27, 2005.
  • Accepted November 2, 2005.
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  1. Clin Infect Dis. (2006) 42 (5): 614-621. doi: 10.1086/500137
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