441
Treatment of Human Brucellosis with Netilmicin and Doxycycline
Javier Solera, Alfredo Espinosa, Paloma Geijo,
Elisa Martinez-Alfaro, Lourdes Saez,
Maria Antonia Sepulveda, and Maria Dolores Ruiz-Rib6,
for the GECMEI*
From the Department of Medicine, Unit of Infectious Diseases, Albacete
Hospital, Albacete; Department of Medicine, Cuenca Hospital, Cuenca;
and Department of Medicine, Toledo Hospital, Toledo, Spain
For many years, the standard treatment for acute brucellosis
has been combination therapy with tetracycline/streptomycin
[1]. Although other antibiotics have been used, no substantial
improvement in relapse rates has been reported in association
with any new treatment regimen in the past 45 years [2]. In
1986 the WorId Health Organization recommended the use of
a 6-week course of doxycycline plus rifampin in the treatment
of human brucellosis [3]. However, a recent meta-analysis of
eight controlled trials that included 1,059 patients indicated
that therapy with a rifampin!doxycycline combination was associated with more relapses than was that with a streptomycin!
tetracycline combination (17% and 5%, respectively) [4].
The search for alternative treatments for human brucellosis
has been prompted mainly by the frequency of relapses, the
potential toxic effects associated with the use of streptomycin
and tetracycline, and the inconvenience of parenteral administration of streptomycin. Clinical experience with other aminoglycoside antibiotics in the treatment of brucellosis has been
limited [2, 5-7]. Lubani et al. [5] treated 1,100 children with
brucellosis. No relapse was seen in 89 children receiving com-
Received 11 July 1995; revised 20 September 1995.
Presented in part at the 7th European Congress of Clinical Microbiology
and Infectious Diseases (abstract no. 1492, p. 288), held 26-30 March 1995
in Vienna.
Informed consent was obtained from patients or their parents, and the guidelines of the Ethical Review Committees of the hospitals of Albacete, Cuenca,
and Toledo, Spain, were followed in the conduct of this study.
* The members of the GECMEI (Grupo de Estudio de Castilla-la Mancha
de Enfermedades Infecciosas) who participated in this study are listed in the
Appendix.
Reprints or correspondence: Dr. Javier Solera, Unidad de Enfermedades
Infecciosas, Hospital General, ClHermanos Falco SIN, 02006 Albacete, Spain.
Clinical Infectious Diseases 1996;22:441-5
© 1996 by The University of Chicago. All rights reserved.
1058--4838/96/2203-0007$02.00
binations of gentamicin with doxycycline or oxytetracycline.
Intramuscular gentamicin (5 mg/[kg' d] ) was given for 5 days
bj.d. with doxycycline or oxytetracycline (the latter two were
given for 3, 5, or 8 weeks) [5]. Lubani et al. considered that
both streptomycin and gentamicin were effective as antibrucella drugs; however, gentamicin was better because it was
given for 5 days only, and the side effects of long treatment
with streptomycin could be avoided [5].
It has been suggested that netilmicin is the least toxic aminoglycoside available [8]. Madkour has reported that the MIC of
netilmicin against clinical isolates of Brucella species is 0.6
jLg/mL [6]. These properties make it attractive for treating
human brucellosis. Moreover, two limited clinical studies have
shown the efficacy of netilmicin combined with tetracycline or
doxycycline [6, 7] . We conducted a prospective, noncomparative, multicenter study to assess the safety and efficacy of doxycycline and netilmicin in the treatment of human brucellosis.
To our knowledge, this report describes the largest series of
patients for whom a doxycycline and netilmicin combination
has been used as therapy for acute brucellosis; it is also the
first prospective assessment of a combination regimen of doxycycline with an aminoglycoside other than streptomycin used
for treatment of adults with brucellosis.
Methods
Patients
Ambulatory and hospitalized patients ~ 7 years of age who
had brucellosis, as defined below, were eligible for the study.
The diagnostic criteria were (1) the isolation of a Brucella
species from blood or other fluids or tissues or (2) the finding
of a > 1: 160 standard tube agglutination titer of antibodies to
Brucella, in association with compatible clinical findings (fe-
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
We conducted a prospective, noncomparative, multicenter study to assess the safety and efficacy
of doxycycline and netilmicin in the treatment of human brucellosis. The study included 64 patients
who had acute brucellosis without endocarditis or neurobrucellosis. The treatment schedule consisted
of the administration of 100 mg of doxycycline (or 5 mg/[kg· d] if body weight :::;40 kg) twice a day
orally for 45 days, plus 300 mg of netilmicin (6 mg/[kg· d] if body weight :::;50 kg) intramuscularly
once daily for 7 days. Therapeutic failure was noted in 5 patients (7.7%; 95% confidence interval
[CI], 2.5%-17.1%), of whom 2 had spondylitis, 1 had sacroiliitis, and 1 had a splenic abscess that
required splenectomy. Relapse was noted in eight patients (12.5%; 95% CI, 5.6%-23.2%). When
relapse was considered in combination with initial lack of efficacy, 13 patients (21.9%; 95% CI,
12.3%-33.9%) failed to respond to therapy. Fifteen patients (23%; 95% CI, 13.5%-35.2%) had
adverse effects, and one patient (1.5%) had a treatment-limiting adverse effect. Combination therapy
with netilmicinldoxycycline may be effective in treating acute brucellosis. However, prospective
controlled trials must confirm these results.
442
Solera et al.
ver, sweats, arthralgias, hepatomegaly, splenomegaly, and/or
signs of focal disease). Enrollment was limited to patients without endocarditis or neurobrucellosis. Patient-exclusion criteria
were pregnancy or nursing; known or suspected hypersensitivity to or other contraindication for tetracyclines or aminoglycosides; severe concomitant disease; and effective antimicrobial
therapy within 7 days before enrollment in the study. Patients
could be enrolled in the study only once.
Study Design
Definition of End Points
The main end points of interest were therapeutic failure due
to lack of efficacy and relapse of brucellosis. Therapeutic failure due to lack of efficacy was defined by symptoms or signs
of the disease that persisted at the end of treatment. A relapse
of brucellosis was defined by the reappearance of symptoms
or signs of the disease or by new positive blood cultures after
therapy. Safety was assessed on the basis of all reported adverse
events, laboratory tests, and other investigations. Clinical adverse events were recorded and evaluated for severity, outcome,
and relation to the study drugs.
Clinical and Laboratory Assessment
Patients were monitored for therapeutic efficacy and signs
of drug toxicity by the obtaining of clinical data; determination
of complete blood cell counts (with differential and platelet
counts) and erythrocyte sedimentation rates; urinalysis; measurements of the creatinine, aspartate aminotransferase, alkaline phosphatase, bilirubin, and electrolyte levels; Brucella serology; and blood culture. The patients were assessed initially,
on day 7, and at the end of therapy. At these visits, the subjects
were asked whether they had missed any dosings. After the
end of therapy, patients were reassessed (as outpatients) at
months 1, 2, 3, 6, 9, and 12, as well as whenever clinical
symptoms reappeared. Diagnosis of spondylitis, sacroiliitis, or
hip arthritis was made by appropriate findings on physical
1996;22 (March)
examination and with use of radiological, bone scintigraphic,
or magnetic resonance imaging studies. Cochlear and vestibular
toxicities were assessed clinically. Serum concentrations of
netilmicin were monitored by serum assay between days 4 and
7 of treatment. Samples for determining peak concentrations
were taken 1 hour after intramuscular injection, and those for
determining trough concentrations were obtained immediately
before the drug was administered. Serum netilmicin assays
were performed with the Abbott Therapeutic Drug Monitoring
System (TDX; Abbott Cientifica, Madrid).
Microbiological Studies
Standard tube agglutination testing, the Rose-Bengal test,
and the Coombs test for antibodies to Brucella species were
done according to standard methods [9] with commercial reagents (Knickerbocker, Barcelona). Blood cultures were performed as previously reported [9] and incubated for 30 days;
BACTEC NR-730 (Becton Dickinson-Spain, Madrid) was
used. All isolates were identified as recommended by Hausler
et al. [10]. Twenty-two of the isolated strains were sent to a
Reference Center (Laboratorio Regional de Brucelosis, Valladolid, Spain) for confirmation and biotyping. All Brucella isolates were identified as Brucella melitensis.
Statistical Analysis
Confidence intervals for response and relapse were calculated by use of the normal approximation to the binomial with
Epi Info Version 6 [11].
Results
From October 1993 through November 1994, 65 consecutive
patients with brucellosis were enrolled in our study. We excluded 1 patient (1.5%), for whom follow-up data were lacking,
7 days after the beginning of treatment. The characteristics of
the remaining 64 patients are summarized in table 1. The median follow-up term was 9 months (range, 1-18 months). Fiftyseven patients (89%) were followed up for at least 6 months.
Seven patients were lost to follow-up; therefore, data for these
patients were censored at the last visit. Two patients discontinued the treatment after 30 and 37 days, respectively, and
another required alternative therapy after 4 weeks because of
drug intolerance, but they were monitored nonetheless. A patient was considered to be noncompliant because she took
< 80% of the doxycycline doses prescribed.
Response to Therapy
At the end of the first week of treatment, the proportion of
patients whose blood yielded a Brucella species was 18% (six
of 33). The mean time to defervescence was 3.9 ± 2.4 days
(range, 1-10 days). Lack of therapeutic efficacy was noted in
five of the 64 patients (7.7%; 95% CI, 2.5%-17.1 %). The
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This was a prospective, noncomparative, multicenter study
to evaluate the efficacy and safety of doxycycline plus netilmicin in the treatment of acute brucellosis. The patients were
recruited from three general hospitals in Spain. The study was
approved by the institutional review board at each center, and
informed consent was obtained from all patients. The treatment
schedule consisted of the administration of doxycycline (Retens, Wassermann, Barcelona) at a dosage of 100 mg (5 mg!
[kg'd] if body weight :::;;40 kg) twice a day orally for 45 days,
plus netilmicin (Netrocin, Schering Plough, Madrid) at a dosage
of 300 mg (6 mg/[kg' d] if body weight :::;; 50 kg) intramuscularly once daily for 7 days. For patients with spondylitis, oral
treatment with doxycycline was prolonged for 60-90 days.
Patients could not receive any other antibiotics. Patients were
categorized according to the end points defined below.
em
em
1996; 22 (March)
Treatment of Human Brucellosis
Table 1. Characteristics of 64 patients with brucellosis at enrollment
in the study.
Patients' characteristics
Spondylitis
Peripheral arthritis
Bursitis
Orchitis
Splenic abscess
Follow-up
Median no. of months (range)
No. (%) of patients followed for:
<6mo
<12 mo
34.7 ± 17.8
32 (7-73)
46 (72)
44 (69)
29 (45)
7 (11)
30 (4-365)
67.2 ± 16.8
67 (28-126)
45 (70)
640 (20-20, 480)
22 (34)
12
4
2
2
2
I
9 (1-18)
7 (11)
20 (31)
* Values are means ± SDs, medians (ranges), or numbers and percentages,
as indicated in column one.
t Some patients had more than one risk factor.
t Brucella was isolated from the bursal fluid of a patient with prepatellar
bursitis.
§ Reciprocal of the standard tube agglutination (STA) titer.
II One patient had spondylitis and sacroiliitis simultaneously.
clinical characteristics of these patients are summarized in table
2. All but one had focal disease at enrollment. Among these,
2 had spondylitis with paravertebral abscess (1 of them had
concomitant sacroiliitis), I had sacroiliitis, and 1 had a splenic
abscess. The two patients who had spondylitis and the patient
who had sacroi1iitis continued to have prominent back pain at
the end of treatment. The patient with sacroiliitis had discontinued treatment prematurely after 37 days. Another patient
had positive blood cultures and arthralgias after having completed 45 days oftherapy. All five patients whose therapy failed
(because of lack of efficacy) received maintenance treatment
with doxycycline or cotrimoxazole over longer periods (3 - 8
months). A patient with a splenic abscess required surgery after
90 days of therapy. Overall, the long-term clinical response
was favorable. None of these five patients have relapsed since
the end of treatment.
Relapse
Among the 64 patients included in this study, 8 have had a
relapse (12.5%; 95% CI, 5.6%-23.2%). Of these 8 patients, 5
had a clinical relapse with characteristic clinical findings, and
4 of them had associated brucella bacteremia. Two other patients had only mild clinical symptoms despite new positive
blood cultures. In one patient bacterial relapse occurred without
clinical signs or symptoms. A patient with orchitis had focal
disease that relapsed in the same location. Another patient
had spondylitis in relapse. The clinical characteristics of these
patients are summarized in table 2. All relapses were treated
with the previously used antibiotic schedule. Clinical response
was excellent in all but one patient. One patient (12.5%) had
positive blood cultures after 30 days of therapy, and treatment
was maintained for a total of90 days. When relapse was considered together with initial lack of efficacy, 13 patients (21.9%;
95% CI, 12.3%-33.9%) failed to respond to therapy.
Adverse Events
Fifteen patients (23%; 95% CI, 13.5%-35.2%) had adverse
effects: 7, phototoxicity; 4, epigastric discomfort; 3, nausea; 2,
vomiting; I, vertigo; 1, dizziness; 1, gray-brown discoloration
of the teeth; and 1, abscess at the injection site. Most of these
reactions were classified as mild, and only one patient (1.5%)
had an episode of a treatment-limiting adverse effect. Discoloration of teeth led to discontinuation of doxycycline therapy
after 28 days for this 7-year-old patient. The most frequently
observed adverse effects were photosensitivity and gastrointestinal complaints, both considered to be related to doxycycline.
The mean serum creatinine concentrations at baseline and after
7 days of netilmicin treatment were 0.95 ± 0.16 mg/dL and
0.93 ± 0.15 mg/dL, respectively (P > .2). The magnitude of
the change is too small to have clinical relevance, but it does
demonstrate that there was no trend toward impairment of renal
function. Plasma concentrations of netilmicin were measured
in 12 patients. The mean peak and trough serum netilmicin
levels were 11.6 ± 3.8 mg/L (range, 5.4-18.2 mg/L) and 0.26
± 0.12 mg/L (range, 0.10-0.46 mg/L), respectively.
Discussion
The key variables in the assessment of treatment regimens
of brucellosis are the rate of therapeutic failure and the rate of
relapse [2]. The therapeutic failure rate of 7.7% in this study
was similar to the rates in our two previous trials [9, 12]. Other
studies of patients with brucellosis who received treatment with
streptomycin for 14-21 days and doxycycline for 4-6 weeks
yielded therapeutic failure rates of zero to 3% [13-17]. We
considered that the high proportion of initial lack of efficacy
in this trial as related to that in other studies may have been
due to the high number of patients with focal disease (34%).
Our 18% rate of therapeutic failure among patients with focal
disease was also similar to rates found in other studies [18].
On the other hand, the 12.5% relapse rate in this study was
slightly higher than in previous studies in which streptomycin
and doxycycline were given for 14-21 days and 30-45 days,
respectively [9, 12-18]. The higher rates in this study could
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Age (y)
Mean ± SD
Median (range)
No. of males (%)
No. (%) with risk factor for brucellosis t
Occupational exposure
Ingestion of unpasteurized dairy products
No. (%) with brucellosis previously
Duration of symptoms before therapy: median
no. of days (range)
Weight (kg)
Mean ± SD
Median (range)
No. (%) with positive blood cultures t
Median agglutination titer§ (range)
No. (%) with focal disease
Sacroiliitis II
Data*
443
Table 2.
cm
Solera et al.
444
1996;22 (March)
Characteristics of 13 patients with acute brucellosis whose therapy failed or who relapsed.
Characteristics before therapy
Duration (d)
Patient
no.
Age
(y)/sex
Occupational
risk
71/F
2
45/F
3
49/F
4
391M
5
261M
+
of
symptoms
Blood
culture
result
120
+
160
30
+
160
Focal disease
(diagnostic
procedure)
STA
titer*
360
640
+
14
1,280
+
15
320
Spondylitis, L4-5
(MRI)
Spondylitis, L3-4;
sacroiliitis (MRI)
Splenic abscess
(CT, MRI)
Sacroiliitis (MRI)
Orchitis
Outcome
Time
(mo) to
relapse
Persistent back paint
Therapy failed
Persistent back paint
Therapy failed
Fever, abdominal pain;
splenectomy
Dox withdrawn at 37 days;
persistent buttock paint
Knee arthralgia, positive
blood cultures after 45
days of treatment
Dox withdrawn because of
side effects after 30 d;
TMP-SMZ given for 15 d
Fever, sweats, arthralgias
By mistake, Dox withdrawn
after 30 d
Fever, sweats, arthralgias
Fever, sweats, orchitis
Therapy failed
Therapy failed
7IM
7
8
321M
9
321M
10
47IM
11
12
13
261M
NOTE.
+
161M
+
13/F
70IM
B
+
4
+
5,120
None
Relapse (B)
45
30
+
+
640
5,120
None
None
Relapse (B/C)
Relapse (B)
4
5
+
+
160
320
Relapse (C/B)
Relapse (C)
4
10
16
+
+
+
320
1,280
None
Orchitis
(ultrasonography)
None
Sacroiliitis (MRI)
None
40
Relapse (B)
Relapse (C/B)
Relapse (C/B)
7
I
11
6
0.3
6
11
5
Treatment compliance 80%
Fever, sweats, arthromyalgia
Fever, lumbar pain,
spondylitis at L5-S1
(MRI)t
= bacterial; C = clinical (see text with regard to clinical relapse); Dox = doxycycline; TMP-SMZ = trimethoprim-sulfamethoxazole; - = negative;
+ = positive.
* Reciprocal of the standard tube agglutination (STA) titer.
t Pain was severe; limited movement and spasms in the surrounding muscles. Functional capacity was inadequate to perform the duties of usual occupation
(patients 2 and 4) or of self-care (patients 1 and 13).
be accounted for by several factors. First, our study differed
from most other studies of treatment for brucellosis in that
blood cultures were performed systematically at each follow-up
visit. Second, reinfection with new strains of Brucella species is
plausible in an area where brucellosis is endemic, such as
Spain. Third, positivity of blood cultures before therapy has
been identified as an independent predictor of relapse [19]. In
our study there was a high proportion of positive blood cultures
at baseline (70%) as compared with the proportion in other
studies [5, 14-16]. This fact could have influenced the relapse
rate. Fourth, compliance with treatment may have been suboptimal, even though drug compliance was emphasized in interviews conducted during the treatment period. In this respect,
a patient whose therapy failed and two patients who relapsed
were deemed noncompliant (table 2). Finally, the treatment
regimen- with administration of doxycycline for 45 days plus
netilmicin on the first 7 days-could be slightly less effective
than regimens used in previous studies (involving administration of doxycycline for 45 days plus streptomycin on the first
14 days).
As in other studies of combination therapy with doxycycline/
streptomycin [9, 12-18], in our trial severe toxic effects were
uncommon and most adverse effects were considered to be
related to doxycycline. The greatest concern associated with
netilmicin treatment is nephrotoxicity [8]. In this study there
was no renal toxicity because of the strict exclusion criteria,
the relatively young age of the patients, and the short duration
of treatment. According to previous reports [20, 21], only the
height of the trough levels seem to be a risk factor for aminoglycoside toxicity. In our study those levels were <2 mglL, as
has been recommended by Parker et al. [22].
Administration of a tetracycline/streptomycin combination
is currently considered the treatment of choice for acute brucellosis [9, 12-17]. However, streptomycin must be administered
by the parenteral route for 14-21 days. Ototoxicity, vestibular
and auditory dysfunction, nephrotoxicity, and hypersensitivity
reactions can follow the administration of streptomycin [20].
An important advantage oftherapy with this netilmicin/doxycycline regimen is that intramuscular injections are given for 7
days. Although netilmicin [6] and gentamicin [5] have been
Downloaded from http://cid.oxfordjournals.org/ by guest on September 9, 2014
Therapy failed
(ultrasonography)
6
Comment
cm
1996;22 (March)
Treatment of Human Brucellosis
Acknowledgments
The authors are indebted to Belen de la Hoz for editorial assistance; to Emilio Serna, R.N., Maria Luisa Castillejos, R.N., and
Dolores Cuenca, R.N., of the Unit of Infectious Diseases, Albacete
General Hospital; to the many staff members of the clinical microbiology laboratories and of the division of internal medicine services affiliated with the GECMEI who collected the study data;
and to the patients who volunteered to assist in this effort.
Appendix
The following persons and institutions participated in this trial,
enrolled research subjects, or both. Albacete Hospital: Francisco
Medrano; Antonio Alamillo; Miguel Angel Barba; Angel Fernandez; Fernando Martinez-Salazar; Jose Antonio Saez-Barcelona;
Miguel Torralba; Diego Cebrian; Anunciacion Perez-Tello; and
Maria Isabel Serrano. Cuenca Hospital: Jaime Calderon; Maria
Enriqueta Peiro; Juan Ruiz-Gonzalez; and Alberto Roldan. Toledo
Hospital: Jose Largo and Fernando Cuadra.
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administered parenterally in a twice-daily regimen, we gave
netilmicin as a single daily intramuscular injection. This mode
of therapy was chosen because against other infectious diseases
it has been at least as effective and safe as multiple daily doses
and because it may lead to more efficient use of this drug [8,
21, 22]. With administration of 6 mg/(kg' d) in intramuscular
once-daily doses, netilmicin reached peak concentrations that
were ;:::9 times the MIC of B. melitensis [6].
It is possible that a longer netilmicin regimen could decrease
relapse and failure rates. However, neither experimental nor
clinical data are available about the optimal treatment duration.
Although prolonged courses of netilmicin injection have been
well tolerated [6], it is particularly important that patients
treated for longer than usual periods be carefully monitored
for changes in renal, auditory, and vestibular functions, a necessity that could increase the cost of care [20]. In any event, it
is desirable to limit the duration of treatment with aminoglycosides to a short term whenever feasible.
The role of a netilmicin/doxycycline combination in the
treatment of acute brucellosis requires prospective controlled
trials. Although our findings support the notion that treatment
with netilmicin plus doxycycline is safe and effective, this
combination does not seem to be more effective than that of
streptomycin and doxycycline [4]. The advantage of giving
intramuscular injections of netilmicin in only the first 7 days
of therapy, as compared with 14-21 days of therapy with
streptomycin, must be weighed against the greater cost of netilmlcm.
445