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Antimicrobial Agents and Chemotherapy, September 2000, p. 2395-2398, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Therapeutic Responses to Quinine and Clindamycin in
Multidrug-Resistant Falciparum Malaria
Sasithon
Pukrittayakamee,1
Arun
Chantra,1
Sirivan
Vanijanonta,1
Ralf
Clemens,1,2
Sornchai
Looareesuwan,1 and
Nicholas J.
White1,3,*
Department of Tropical Medicine, Faculty of
Tropical Medicine, Mahidol University, Bangkok,
Thailand1; Centre for Tropical Medicine,
Nuffield Department of Clinical Medicine, Oxford University, Oxford,
United Kingdom3; and SmithKline Beecham,
Collegeville, Pennsylvania2
Received 9 March 2000/Returned for modification 12 May
2000/Accepted 12 June 2000
 |
ABSTRACT |
Therapeutic responses to clindamycin in combination with quinine
were assessed in adult Thai patients with uncomplicated
multidrug-resistant Plasmodium falciparum malaria. In total
204 patients were randomized to receive a 7-day oral treatment regimen
of quinine (Q7) either alone (n = 68), in
combination with clindamycin (Q7C7;
n = 68), or in combination with tetracycline
(Q7T7; n = 68). All patients had uncomplicated recoveries with no serious adverse effects. Fever
clearance times for both of the two combination regimens (median of
47 h and range of 8 to 120 h for Q7C7
and median of 36 h and range of 8 to 117 h for
Q7T7) were significantly shorter than that for
the Q7-only regimen (median, 56; range, 4 to 152 h)
(P = 0.002). Parasite clearance times (overall
mean ± standard deviation, 78 ± 23 h) were not
significantly different between the three treatment groups
(P = 0.98). The cure rates assessed at 28 days of
follow-up were 100% for Q7C7 and 98% for
Q7T7, whereas the cure rate was 87% for the
Q7-only regimen (P 
0.04). Clindamycin in combination with quinine is a safe and effective treatment for
multidrug-resistant P. falciparum malaria. This combination may be of particular value in children and pregnant women, in whom
tetracyclines are contraindicated.
| |
INTRODUCTION |
Multidrug-resistant Plasmodium
falciparum malaria is of increasing public health concern in the
tropics. For adult patients, combination treatments with
quinine-tetracycline, artesunate-mefloquine, or artemether-lumefantrine
are effective worldwide. These regimens yield high cure rates of 95 to
100% (3, 7, 14, 15, 17). When quinine is used for the
treatment of children and pregnant women, it is often given alone, as
the tetracyclines are contraindicated in these two important high-risk
groups. Combinations with other antibiotics with antimalarial activity
such as erythromycin or rifampin (9) have shown
disappointing efficacies.
Clindamycin, usually combined with quinine, had been used extensively
in South America and has also proved effective in adults and children
with acute malaria in Africa (4-6, 13). The efficacy of
clindamycin plus quinine has not been evaluated in the Southeast Asian
region (12), where the most drug-resistant P. falciparum strains are found. We have recently assessed the
antimalarial activity of clindamycin in adult patients with
Plasmodium vivax malaria and found that it has antimalarial
activity similar to that of tetracycline or doxycycline
(9). The present study assessed the efficacy of clindamycin
in combination with quinine in comparison with those of
quinine-tetracycline and quinine alone for the treatment of adult
patients with falciparum malaria in Thailand, which harbors the
world's most drug-resistant P. falciparum.
| |
MATERIALS AND METHODS |
Patients.
The study was conducted with adult male patients
with acute P. falciparum malaria admitted to the Bangkok
Hospital for Tropical Diseases, Bangkok, Thailand, between 1995 and
1997. Fully informed consent was obtained from each subject. Exclusion
criteria were severe malaria (18) or mixed malaria parasite
infections. Patients who gave a history of drug hypersensitivity,
patients who had taken any antimalarial drugs within the previous
48 h, or patients whose urine was positive in screening tests for
sulfonamides (lignin test) or 4-aminoquinolines (Wilson-Edeson test)
were also excluded. The study was approved by the ethics committee of
the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Management.
After clinical assessment and confirmation of
the diagnosis from thick and thin blood smears, baseline blood samples
were taken for routine hematology and biochemistry analyses. Patients were then allocated by simple randomization to a 7-day oral treatment regimen: quinine sulfate (10 mg of salt/kg of body weight three times a
day; Thai Government Pharmaceutical Organization) either alone
(Q7) or in combination with tetracycline (4 mg/kg four
times a day; Thai Government Pharmaceutical Organization)
(Q7T7) or with clindamycin (5 mg of base/kg
four times a day; Dalacin C; Pharmacia & Upjohn Pharmaceuticals)
(Q7C7).
Oral acetaminophen (0.5 to 1 g every 4 h) was given for a
temperature of >38°C. Vital signs were recorded every 4 h until resolution of fever and thereafter every 6 to 12 h. Fever
clearance times (FCTs) were expressed as FCTA, which was
the time taken for the body temperature first to fall below 37.5°C,
and FCTB, which was the time taken for the body temperature
to fall below 37.5°C and remain below this value for >48 h. Patients
who were subsequently unable to stay in the hospital until clearance of both fever and parasites were excluded from the study. Reappearance of
infection was assessed in patients who remained in Bangkok either in
the hospital or at home (i.e., outside the malaria transmission area)
for at least 28 days. Patients with recrudescences were retreated with
a 7-day course of quinine (10 mg of salt/kg three times a day) in
combination with tetracycline (4 mg/kg four times a day), and those who
had late vivax appearances were treated subsequently with the standard
dose of chloroquine and primaquine.
Laboratory investigations.
Parasite counts were measured
every 12 h in thin films or thick films until clearance and
thereafter daily for 28 days. Parasite density was expressed as the
number of parasites per microliter of blood, derived from the numbers
of parasites per 1,000 red blood cells in a thin film stained with
Giemsa or Field stain or was calculated from the white cell count and
the numbers of parasites per 200 white blood cells in a thick film. The
following variables were chosen prospectively to describe parasite
clearance (PC): time taken from the start of antimalarial treatment
until the asexual malaria parasite count fell to 50%
(PC50) and 90% (PC90) of the value at the time
of admission and the time taken for the parasite count to fall below
detectable levels in a peripheral blood smear (PCT). The
variables used to define the parasite reduction rates (PRRs) were the
ratio of the parasite count before treatment to the counts at 24 h
(PRR24) or 48 h (PRR48) and the ratio of the parasite count at 48 h to the count at 96 h
(PRR48/96). Routine biochemical and hematological tests
were repeated on days 7, 14, 21, and 28 after admission.
Statistical analysis.
The data for each treatment group were
compared by one-way analysis of variance with post hoc multiple
comparisons with the Bonferroni correction. Nonparametric data were
compared by the Kruskal-Wallis test. The cumulative FCTs, PC rates, and
cure rates were calculated by Kaplan-Meier survival analysis and were
compared by the log-rank test. Associations between FCT, PC rate, and
PRR were measured with Spearman's rank correlation coefficient. All statistical analyses were performed with the statistical computing package SPSS, version 8, for Windows (SSPS Inc.).
| |
RESULTS |
Patients.
The study included 204 male patients with P. falciparum malaria (age range, 15 to 64 years; mean ± standard deviation [SD] age 25.8 ± 9.5 years). These patients
were randomized to three treatment groups (n = 68 each;
Table 1). The majority of patients (n = 157; 77%) came from the western border of
Thailand, where the most multidrug-resistant P. falciparum
parasites are prevalent. Less than half the patients (n = 92; 45%) had a history of malaria. There were no significant
differences in age or geographic distributions, parasite counts on
admission, or incidence of previous malaria attacks between the three
treatment groups, (P 
0.09) (Table 1). Elevated serum
bilirubin levels (total bilirubin concentration, 3 mg/dl) were noted
in 26 patients (Q7 group, n = 13;
Q7C7 group, n = 10;
Q7T7 group, n = 3). None of
these patients had any other complications, and all came from areas
where malaria is endemic. The overall total bilirubin levels for the
Q7C7 and Q7 groups on admission
were not different (P = 0.68), but the levels for both
groups were slightly higher than those for the
Q7T7 group (P 0.004). Other
baseline laboratory findings (Table 1) were not statistically
significant among the groups studied. None of the patients had or
developed severe anemia (hematocrit, >15% for all patients) or
elevated serum creatinine levels (serum creatinine levels, <3 mg/dl
for all patients) or other complications of malaria.
Clinical response.
Clinical recovery following treatment
occurred in all patients (Table 1). FCTAs ranged from 2 to
100 h (median, 8 h) and were not significantly different
between the three treatment groups (P = 0.10). The
overall median (range) FCTB was 48.0 h (4 to 152 h). As shown in Fig. 1, the
FCTBs for the two combination regimens (Q7C7 group, 47 h;
Q7T7 group, 36 h) were not significantly
different (P = 0.08), but the FCTBs for
both combination regimens were significantly shorter than the
FCTB for the Q7-only regimen (56 h) (P
0.005). Patients admitted with hyperbilirubinemia had
significantly longer FCTs (median, 72 h; range, 8 to 124 h)
than those for the remaining patients (median, 48 h; range 7 to
152 h) (P = 0.014). After stratification for
jaundice on admission, the FCTBs for the two combination
regimens remained not significantly different
(Q7C7 = 44 h,
Q7T7 = 36 h [P = 0.32]), and the FCTBs for both combination regimens
were significantly shorter than the FCTB for the
Q7-only regimen (53 h) (P 0.012).
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FIG. 1.
Cumulative fever clearance rates for the three treatment
groups of patients with P. falciparum malaria.
|
|
PC and parasite reduction.
Following the start of treatment,
the overall mean ± SD PCT was 77.7 ± 22.8 h. Between the treatment groups, there were no significant differences
in PCTs (P = 0.98), and this remained after
stratification for jaundice on admission (P = 0.82).
There were also no significant differences in PRRs or clearance of
parasitemia for the groups studied, as assessed from the
PC50, the PC90, and the calculated PRRs
(PRR24, PRR48, and PRR96) (P
0.65) (Table 2). The overall
PCT for all patients correlated directly with the
PC50 and PC90 (r = 0.34 and
0.68; respectively; P 0.001) and inversely with the
calculated PRRs (PRR24 and PRR48; r = 0.31 and 0.42, respectively; P < 0.001). There
were weak but statistically significant correlations between
PCT and FCTs (r = 0.24 for FCTA and r = 0.33 for FCTB; P
<0.01).
Clinical course.
Overall, 161 (79%) of the recruited patients
completed at least 28 days of follow-up or remained in the hospital
until the appearance of vivax or falciparum malaria (Table
3). Of these 161 patients, 8 (5.0%) had
a subsequent reappearance of falciparum malaria and another 33 (21%)
had a delayed appearance of vivax malaria. Recrudescences of falciparum
malaria were observed for patients who received the Q7-only
regimen (n = 7; 13%) and in one patient treated with
the Q7T7 regimen (2%) but not in patients treated with the Q7C7 regimen. The time to the
onset of recrudescence ranged from 15 to 23 days (mean ± SD = 19.3 ± 2.5 days). The cure rates (i.e., no recrudescence of
falciparum malaria) for the two combination regimens (98 and 100%)
were both significantly higher than the cure rate for the
Q7 regimen (87%) (P 0.04) (Fig.
2).
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|
TABLE 3.
Clinical outcomes for monitored patients with subsequent
appearances of malaria infection which occurred within 28 days after
the start of treatment
|
|
Cryptic infection with
P. vivax was found in 33 (21%)
patients. Despite the differences in the 28-day follow-up rates between
the three groups, the rates of mixed infection among the three
treatment groups were not significantly different (
P = 0.9). The
overall mean ± SD time taken for the appearance of
vivax malaria
was 23.7 ± 3.0 days and ranged from 16 to 28 days
after the start
of treatment. There was no significant difference in
the time
to the appearance of vivax malaria (within the 28-day
follow-up
period) between the two combination regimens (for
Q
7C
7, 25.1 ±
1.4 days; for
Q
7T
7, 24.8 ± 3.2 days [
P = 1.0]), although the times
to onset for both regimens were
significantly delayed compared
to the time to onset for the
Q
7 regimen (21.6 ± 3.0 days) (
P 0.028).
Of the 161 patients monitored, 16 patients returned for subsequent
monthly follow-up and none had a reappearance of falciparum malaria,
but five patients had later appearances of vivax malaria, between
days
38 and 61. These late episodes of vivax malaria were found
in all
groups: Q
7,
n = 2;
Q
7C
7,
n = 2;
Q
7T
7,
n = 1.
Therapeutic responses in patients with subsequent
recrudescences.
The eight patients with subsequent recrudescences
had significantly longer FCTs (83.5 ± 44 versus 50.4 ± 31.1 h [P = 0.023]) and PCTs
(95.4 ± 21.1 versus 77.2 ± 21.8 h [P = 0.005]) than those for patients with no recrudescence. Only one
of these patients had elevated serum bilirubin levels on admission;
there was no association between bilirubinemia and recrudescent
infections. Parasite counts on admission between patients with and
without recrudescences were not significantly different (geometric mean of 21,875 and range of 4,019 to 141,300 versus geometric mean of 14,475 and range of 30 to 276,948 [P = 0.32]). Between
patients with and without mixed P. vivax and P. falciparum infection, there were no significant differences in
parasite counts on admission, FCTs, or parasitological responses
(P 0.14).
Clinical and laboratory findings following treatment.
On
admission, gastrointestinal symptoms were noted in 93 (46%) patients.
Of these, 85 (91%) had nausea, 31 (33%) had vomiting, 27 (29%) had
abdominal pain, and 3 (3.2%) had diarrhea. There were no significant
differences in the incidences of gastrointestinal symptoms among the
three treatment groups (P = 0.45). Following treatment,
only six additional patients developed any of the gastrointestinal symptoms (n = 3 for Q7, n = 2 for Q7C7, n = 1 for
Q7T7). These patients complained of nausea
(n = 6) with or without vomiting (n = 4) or abdominal pain (n = 3) or diarrhea
(n = 2). After starting antimalarial treatment, all
patients recovered and the gastrointestinal symptoms disappeared within
1 to 7 days (median, 2 days).
The majority of patients (193; 93.7%) developed transient tinnitus.
The onset of tinnitus usually occurred after 3 days of
treatment. There
were no significant differences in the incidences
of cinchonism among
the three treatment groups (
P = 0.8). All
26 jaundiced
patients had normalization of bilirubin levels after
7 days (23 of 26;
88.5%) or 14 days (3 of 26; 11.5%) of treatment.
None of the studied
patients developed allergic rashes or other
serious adverse effects, as
monitored by clinical symptoms and
laboratory data (data not
shown).
| |
DISCUSSION |
The worsening of antimalarial drug resistance poses a considerable
threat to human populations in the tropics. In Thailand, where the
world's most drug-resistant malaria parasites are found, resistance to chloroquine, sulfadoxine-pyrimethamine, and more recently, mefloquine has limited the options for the treatment of
falciparum malaria (8, 10, 16). Since the 1970s there has
been a decline in the susceptibility to quinine, although there have
been few recent data. The current trial provides reassuring results.
The Q7 regimen was 87% effective, which is similar to that
reported 15 years ago from the Bangkok Hospital for Tropical Diseases
(2). Many had feared that mefloquine resistance would drive
resistance to quinine. Although in some parts of Thailand mefloquine
resistance has improved over the past 5 years with deployment of
combination treatment that included an artemisinin derivative
(8a), in other parts of the country mefloquine it is still
used alone, providing selective pressure to the emergence of
resistance. Whatever the explanation, quinine still retains good
clinical activity against the multidrug-resistant P. falciparum parasites prevalent in Thailand.
The addition of a tetracycline, most commonly, doxycycline, to quinine
consistently improves the cure rates for falciparum malaria (2, 7,
11, 14). Indeed, there has been no evident decline in the
efficacy of this combination since it was first introduced nearly 20 years ago in this area (3). Quinine in combination with a
tetracycline is a generally safe and effective regimen. Unfortunately,
minor toxicity from quinine (cinchonism) is usual, and the combination
of an extremely bitter taste and cinchonism compromises compliance, and
thus efficacy. A major limitation of this combination is that
tetracycline cannot be used in children less than 8 years old or during
pregnancy. These two patient groups are both at high risk from
falciparum malaria. In general, cure rates for children and pregnant
women are also inferior to those for nonpregnant adults living in areas
where malaria is endemic (1). Nevertheless, a 7-day course
of quinine alone remains the treatment of choice for acute falciparum
malaria in the first trimester of pregnancy in this area.
This study shows that clindamycin is an effective and well-tolerated
alternative to tetracycline in combination antimalarial treatment.
There were no treatment failures among the 60 patients treated with a
7-day course of quinine and clindamycin. Thus, estimated efficacy is
100%, and the lower 95% confidence interval for the true cure rate is
equal to or greater than 95%. The addition of either doxycycline or
clindamycin to quinine also delayed the appearance of P. vivax infections, suggesting additional activity against this
parasite. The clindamycin was very well tolerated, and there were no
adverse effects attributable to it. The principal adverse effect of
clindamycin is diarrhea and, in extreme cases, pseudomembranous colitis
caused by Clostridium difficile. This did not occur in the
present trial. Unfortunately, clindamycin is significantly more
expensive than tetracycline, and as cost is the major factor that
determines the use of antimalarial drugs, this represents a significant
drawback (US$15 for clindamycin versus <US$1 for doxycycline or
tetracycline per adult treatment course). Nevertheless, clindamycin may
be considered a safe and effective alternative to the tetracyclines in
combination treatment of drug-resistant falciparum malaria. It may be
of particular value for young children and pregnant women, as these two
groups cannot receive tetracycline. Further studies with these
high-risk groups should now be conducted.
| |
ACKNOWLEDGMENTS |
This study was part of the Wellcome-Mahidol University, Oxford
Tropical Medicine Research Programme. We are grateful to Pharmacia & Upjohn and to R. X. Company Limited, Bangkok, Thailand, for providing us with antimalarials.
This study was supported by The Wellcome Trust of Great Britain.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Faculty of
Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd.,
Bangkok 10400, Thailand. Phone: 66-2-246-0832. Fax: 66-2-246-7795. E-mail: fnnjw{at}diamond.mahidol.ac.th.
| |
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Antimicrobial Agents and Chemotherapy, September 2000, p. 2395-2398, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
