1172 • CID 2001:32 (15 April) • Khan et al.
M A J O R A R T I C L E
Brucellosis in Pregnant Women
M. Yousuf Khan,1a
Manuel...
Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1173
Table 1. Characteristics of 92 pregnant women
with acute bru...
1174 • CID 2001:32 (15 April) • Khan et al.
Table 2. Occurrence of spontaneous abortion
and intrauterine death, according ...
Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1175
Table 3. Incidence of spontaneous abortion and intrauterine ...
1176 • CID 2001:32 (15 April) • Khan et al.
tions more frequently than do other bacterial pathogens.
Clearly, there is a n...
Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1177
17. Spink WW. The nature of brucellosis. Minneapolis: The Un...
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Brucelosis

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Brucelosis

  1. 1. 1172 • CID 2001:32 (15 April) • Khan et al. M A J O R A R T I C L E Brucellosis in Pregnant Women M. Yousuf Khan,1a Manuel W. Mah,1,2b and Ziad A. Memish1,2 1 Department of Medicine and the 2 Department of Infection Prevention & Control, King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia Brucella species occasionally cause spontaneous human abortion, but theories regarding whether they do so more frequently than do other infectious pathogens remain controversial. We reviewed 92 pregnant women who presented with acute brucellosis at a Saudi Arabian hospital. From 1983 through 1995, the cumulative incidence of pregnancy and brucellosis was 1.3 cases per 1000 delivered obstetrical discharges. The incidence of spontaneous abortion in the first and second trimesters was 43%, and the incidence of intrauterine fetal death in the third trimester was 2%. Antepartum antimicrobial therapy with cotrimoxazole or cotrimoxazole/ rifampin was protective against spontaneous abortion (relative risk, 0.14; 95% confidence interval, 0.06–0.37; ). The beneficial effect of treatment occurred in women with febrile illness; vaginal bleeding atP ! .0001 presentation usually led to spontaneous abortion. This study demonstrated that the incidence of spontaneous abortion among pregnant women with brucellosis is high and that these women should receive prompt therapy with antimicrobial agents when they present for medical care. Brucellosis, a zoonotic disease of global importance [1], is endemic in Saudi Arabia (national seroprevalence, 15%) [2]. Endemicity in this region results from the persistence of domestic animal reservoirs for Brucella species and the human consumption of unpasteurized dairy products [3, 4]. Various Brucella species are well-known causes of con- tagious abortion in cattle, sheep, goats, swine, and dogs [5]. There is also evidence that brucellosis can produce spontaneous abortion in humans, which has been dem- onstrated by rare cases in which Brucella species were isolated from fetal or placental tissues, but it has not been demonstrated that brucellosis causes abortions more frequently than do other bacterial infections [6]. Received 10 July 2000; revised 8 September 2000; electronically published 2 April 2001. a Current affiliation: Department of Medicine, Maricopa Medical Center, Phoenix, Arizona. b Current affiliation: Department of Medicine, University of Calgary, Canada. Reprints or correspondence: Dr. Ziad Memish, Infection Prevention & Control, Dept. 2134, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426, Kingdom of Saudi Arabia (memish@ngha.med.sa). Clinical Infectious Diseases 2001;32:1172–7 ᮊ 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3208-0007$03.00 It is believed that brucellosis causes fewer spontaneous abortions in humans than it does in animals because of the absence of erythritol in the human placenta and fetus [7]. Erythritol is a constituent of normal ungulate fetal and placental tissue and, in cases of bovine abortion, promotes overwhelming infection of the placenta and fetus. An additional reason for the lesser role of Brucella infection in human abortion is the presence of anti- Brucella activity in human amniotic fluid [8]. In the present study, we reviewed the experience with brucellosis in pregnant women at a tertiary-care hospital in Saudi Arabia during a 13-year period. We sought to characterize clinical presentations, the incidence of abor- tion, and the effect of treatment with antimicrobialagents on the occurrence of spontaneous abortion. PATIENTS AND METHODS The King Fahad National Guard Hospital (Riyadh, Saudi Arabia) has served the secondary- and tertiary- level medical needs of Saudi National Guard soldiers and their extended families since 1983. Guardsmen come from bedouin tribes that have retained a nomadic pas- toral lifestyle that includes the consumption of unpas- teurized milk from goats, camels, and sheep; many of atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom
  2. 2. Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1173 Table 1. Characteristics of 92 pregnant women with acute brucellosis in Saudi Arabia. Characteristic No. (%) of patients Age range, y (n p 92) 16–20 14 (15) 21–25 32 (35) 26–30 19 (21) 31–35 15 (16) 36–42 10 (11) 43–47 2 (2) No. of pregnancies prior to the study period (n p 88) 0 4 (4) 1 6 (7) 2 7 (8) у3 71 (81) No. of spontaneous abortions prior to the study period (n p 86)a 0 62 (72) 1 16 (18) 2 4 (5) у3 4 (5) Trimester of pregnancy (n p 92) 1 23 (25) 2 44 (48) 3 25 (27) a Includes patients who had intrauterine deaths. these animals are known to be infected with Brucella species. Because of their nomadic lifestyles, not all pregnant women re- ceive prenatal care, some are lost to follow-up, and some are treated for brucellosis at our hospital but subsequently deliver elsewhere. The medical record database at the hospital was reviewed, and all patients who had a discharge diagnosis of brucellosis and pregnancy from 1983 through 1995 were identified. The diagnosis of acute brucellosis was based on compatible clinical features and a serum agglutinin titer of у1:320 or a positive blood culture result. Patient records were reviewed, and the following information was extracted: patient age, obstetrical history, gestational age at the time of infection, symptoms, results of serological testing and blood cultures for Brucella, antimicrobial therapy, delivery outcome, results of placental cultures and histological findings, neonatal status, and neonatal results of serological testing and cultures for Brucella. The first trimester of pregnancy was defined as a gestational age of р12 weeks; the second trimester of pregnancy, 112 to р24 weeks; and the third trimester of pregnancy, 124 weeks. Patients with brucellosis were considered to have been treated if they received therapy with cotrimoxazole, rifampin, or a tetracycline for at least 4 weeks. Fetal deaths that occurred at р24 weeks’ gestation were designated “spontaneous abortions,” while deaths that occurred at 124 weeks’ gestation were designated “intrauterine fetal deaths.” A variety of microbiological methods were used at our hos- pital during the 13-year period to isolate Brucella species, de- termine antimicrobial susceptibility, and detect agglutinating antibodies; these methods have been described in detail else- where [9–11]. In brief, samples of blood and body fluids were cultured by use of the automated BACTEC System (Becton Dickinson). Before 1987, identification of Brucella organisms to the species level was not done because of technical limitations in the microbiology laboratory. In subsequent years, Brucella isolates were identified to the species level by use of standard biochemical methods. Antimicrobial susceptibility tests were performed according to a standard disk diffusion method. Ag- glutination tests for antibody to Brucella were performed by means of a microtiter serial dilution technique. Epidemiological associations were expressed as relative risk with 95% CIs, and statistical significance was assessed by use of the x2 test or 2-tailed Fisher’s exact test where appropriate. All statistical measures were generated by use of Epi-Info, ver- sion 6 (Centers for Disease Control and Prevention). RESULTS From 1983 through 1995, there were 545 cases of brucellosis at the hospital, of which 92 (17%) occurred in pregnant women (cumulative incidence, 1.3 cases of brucellosis in pregnant women per 1000 delivered obstetrical discharges [0.3 cases of brucellosis in pregnant women per 1000 hospital admissions]). The characteristics of the 92 pregnant women with acute bru- cellosis are shown in table 1. The mean age of the women was 26.9 years. Seventy-one (81%) of 88 women had 3 or more pregnancies prior to the study period, 62 (72%) of 86 had never spontaneously aborted before, and 44 (48%) of 92 pre- sented during the second trimester of pregnancy. Overall, 40 (43%) of 92 pregnant women with acute bru- cellosis had spontaneous abortions during the first or second trimester, and 2 (2%) had intrauterine fetal deaths in the third trimester (table 2). The incidence of abortion was significantly higher during the first and second trimesters than it was during the third trimester. To put these rates in context, we calculated the incidence of spontaneous abortion or intrauterine fetal death for all women for the period from July 1999 through June 2000. During this 1-year interval, the total rate of spon- taneous and missed abortions (i.e., early fetal death before com- pletion of 24 weeks of gestation with retention of dead fetus or retained products of conception, not following spontaneous atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom
  3. 3. 1174 • CID 2001:32 (15 April) • Khan et al. Table 2. Occurrence of spontaneous abortion and intrauterine death, according to trimester of pregnancy, in 92 women with acute brucellosis in Saudi Arabia. Trimester of pregnancy No. of patients No. (%) of spontaneous abortions First 23 12 (52) Second 44 28 (64) Third 25 2 (8) a Total 92 42 (46) a NOTE. Difference in the incidence of abortion was significant for first vs. third trimester ( ) and secondP ! .001 vs. third trimester ( ), but not for first vs. secondP ! .0001 trimester ( ).P p .4 a These were or included intrauterine fetal deaths. abortion, induced abortion, or delivery) during the first and second trimesters combined was 2.8% (589 spontaneous abor- tions and 121 missed abortions among the 25,540 women who received antenatal care), and the rate of intrauterine fetal death during the third trimester was 0.3% (66 intrauterine fetal deaths among the remaining 24,830 pregnant women who did not abort during the first or second trimesters). Of the 92 pregnant women with brucellosis, 91 had positive serum agglutinin titers that ranged from 1:320 to у1:20,480; the geometric mean titer was 1:2560. Serological testing was not performed for 1 patient; brucellosis in this patient was diagnosed by a blood culture result that was positive for Brucella species. There was no apparent relationship between the mag- nitude of the titer and the occurrence of bacteremia. Serum agglutinin titers у1:2560, compared with those !1:2560, were not significantly associated with the occurrence of spontaneous abortion ( ).P p .5 Fifty-two of the 92 women had blood cultures performed. Twenty-two (42%) of these cultures had positive results: 16 yielded Brucella melitensis, 1 yielded Brucella abortus, and 5 yielded Brucella species that were not identified to the species level. Antimicrobial susceptibility testing for these 22 isolates revealed that 18 were susceptible to cotrimoxazole and 4 were resistant. Eight (36%) of 22 women with brucella bacteremia aborted, and 16 (53%) of the 30 women for whom blood cultures were negative aborted; this difference in the incidence of abortion was not statistically significant ( ).P p .2 The incidence of abortion according to pregnancy trimester, clinical presentation, and treatment is shown in table 3. Overall, of the 92 pregnant women with brucellosis, 41 (45%) received treatment. With all pregnancy trimesters represented, 100% of 38 women who presented with preterm febrile illness received antimicrobial therapy, and there was 1 intrauterine fetal death (3%). Of the women in the first and second trimesters who presented with vaginal bleeding and either with or without fever, 3 (8%) of 40 were treated with antimicrobial agents, and all aborted. None of 14 women with febrile illness at term or postpartum were treated, and there was 1 fetal death. Overall, 60 (65%) of the 92 women with brucellosis were febrile. The details of antepartum antimicrobial treatment are pre- sented in table 4. Cotrimoxazole was administered as 1 double- strength tablet (800 mg or sulfamethoxazole and 160 mg of trimethoprim), given orally b.i.d., and rifampin was adminis- tered as 600–900 mg, given orally q.d. Antepartum treatment with antimicrobial agents was significantly more protective against the occurrence of abortion than was inadequate treat- ment or no treatment (RR, 0.14; 95% CI, 0.06–0.37; P ! ). However, the incidence of abortion among 22 patients.0001 who received treatment with cotrimoxazole was not signifi- cantly different from that of 17 patients who received treatment with a combination of cotrimoxazole and rifampin ( ).P p .6 Follow-up data were available for 36 infants of the 41 women who were treated: 33 (92%) were normal and well at follow- up, and 3 (8%) delivered prematurely (2 of the premature infants died). Serum agglutinin titers were measured for 7 of the infants born to women with brucellosis, and 4 of them had titers у1: 320. Cultures of blood specimens from 6 newborns (р1 week of age) were performed, but only 1 had a result that was positive for Brucella species; culture of blood from the mother of this infant with bacteremia was not done. The mothers of 4 of the 6 newborns for whom cultures were performed had brucella bacteremia, and all presented during the second trimester. Placentas and fetuses were not systematically studied in this case series. Cultures of 11 placental specimens and 1 fetal spec- imen did not yield Brucella species. Histological examination of 28 placental samples revealed nonspecific inflammatory changes in 22 of them. DISCUSSION We found that the incidence of spontaneous abortion and intrauterine death among a retrospective cohort of 92 pregnant women with acute brucellosis due primarily to B. melitensis was 46%. As shown in the Results section, the rates of spon- taneous abortion and intrauterine death among women with active brucellosis substantially exceeded the rates of sponta- neous abortion and intrauterine death among the general pop- ulation of pregnant women at our institution during the cor- responding trimesters. The frequency of fetal loss among patients with brucellosis was comparable in the first and second trimesters, but intrauterine fetal death during the third tri- mester was uncommon. Most of these women were older than 20 years of age, were not primigravid, and most had not had a spontaneous abortion prior to the study period. Our rate of incidence exceeds the 10% rate reported by Criscuolo and di atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom
  4. 4. Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1175 Table 3. Incidence of spontaneous abortion and intrauterine death, according to pregnancy trimester and clinical presentation, among 92 pregnant women with acute brucellosis in Saudi Arabia. Trimester of pregnancy, presentation No. of patients Total Treated Had spontaneous abortion First Vaginal bleeding with or without febrile illness 12 a 1 12 Predominantly febrile illness 11 b 11 0 Second Vaginal bleeding with or without febrile illness 28c 2 28 Predominantly febrile illness 16d 16 0 Third Febrile illness at term or postpartum 14e 0 1f Preterm febrile illness 11 g 11 1 f Total 92 41 42 a Brucella bacteremia in 1 patient. b Brucella bacteremia in 2 patients, 9 normal deliveries, and 2 premature newborns. c Brucella bacteremia in 7 patients. d Brucella bacteremia in 6 patients, 15 normal deliveries, and 1 premature newborn. e Brucella bacteremia in 6 patients and 1 fetal death. All patients were treated postpartum. f Intrauterine death. g No patients had bacteremia, and all were treated before delivery. Table 4. Antepartum antimicrobial treatment and pregnancy outcomes for pregnant women with acute brucellosis in Saudi Arabia. Treatment No. of patients Treated Had normal deliveries Had spontaneous abortion or fetal death CMZ 23 19 3 CMZ ϩ Rif 17 16 a 1 Rif 1 1 0 Total 41 36 4 NOTE. Standard antimicrobial therapy was given to 51 patients after abortion or delivery. CMZ, cotrimoxazole; Rif, rifampin. a Three deliveries were premature. Carlo [12] in 200 cases of B. melitensis infection in pregnant women; however, it is similar to the rate of abortion of 31% among 35 women who were in the first trimester of pregnancy and who had brucellosis, which was reported by Lulu et al. [13], and a 40% rate among 30 pregnant women with bru- cellosis, which was reported by Madkour [14]. Conversely, Sar- ram et al. [15] observed that, among 51 women who had spon- taneous abortions during their second trimester, 11.6% had B. melitensis infection, while Makhseed et al. [16] diagnosed acute or chronic brucellosis in 7% of 29 women who had spontaneous abortions and 10% of 51 women who had intrauterine fetal deaths. In his classic monograph, Spink [17] stated that “. . . the passage of time has produced no definitive evidence that the Brucellae produce abortions any more frequently than do other species of bacteria.” This statement is difficult to verify because data on the incidence of abortion caused by other micro- organisms are lacking or are not directly comparable. For ex- ample, Campylobacter species, like Brucella species, are well- described causes of abortion in animals; however, in a series of 10 pregnant women with Campylobacter jejuni infection who were at a single hospital, only 1 (10%) had premature labor at 28 weeks’ gestation that resulted in a neonatal death [18]. Other reports of Campylobacter infection in pregnant women include a report of a series of cases that were selected on the basis of the occurrence of abortion [19] and single case reports of fetal loss in association with septic shock, bacteremia, and diarrheal illness [20–22]. A MEDLINE search of the literature published from 1966 through 2000 that used the terms “E. coli” and “abortion” did not yield any reports of studies of patients with Escherichia coli bacteremia or sepsis who experienced spontaneous abortion. A similar search for an association between Salmonella species and spontaneous abortion yielded 1 report of a study of 30 pregnancies that were complicated by typhoid fever and that resulted in 3 spontaneous abortions (10%) [23]. Although comparative data are limited, an incidence of abor- tion from 10% to 42% in patients with active brucellosis ex- ceeds that observed in patients infected with other organisms, such as Campylobacter species and Salmonella species, and sug- gests that Brucella species may indeed produce human abor- atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom
  5. 5. 1176 • CID 2001:32 (15 April) • Khan et al. tions more frequently than do other bacterial pathogens. Clearly, there is a need for better evidence to verify this sug- gestion, which would come from case-control studies; however, the selection of an appropriate control group is problematic, because our understanding of the pathogenesis of spontaneous abortion in women with brucellosis is poor. Bacteremia is mentioned as a risk factor for spontaneous abortion in the literature, but our study found no association between maternal bacteremic status and spontaneous abortion. Furthermore, although it was not systematically studied, 22 of 28 placental samples that we examined had only nonspecific inflammation. The lack of evidence of uteroplacental involve- ment in some cases of abortion has been noted by other in- vestigators [7, 14]. Collectively, these data reveal that women with active brucellosis may abort despite the absence of ery- thritol in the human placenta and fetus, the absence of bac- teremia, and the absence of specific histological abnormalities in the placenta. Endotoxin has been implicated in the patho- genesis of brucellosis [24], and it is possible that its promotility effect on uterine smooth muscle plays a role in abortion [25]. An important observation from the present study is that the natural history of brucellosis in pregnant women may be altered by early institution of antimicrobial therapy. When pregnant women with febrile brucellosis are treated with antimicrobial agents before vaginal bleeding occurs, most deliver normally. However, vaginal bleeding at presentation is an ominous sign: it rarely happens in women who receive treatment with antimi- crobial agents, and it is associated with a high rate of spontaneous abortion. Whether the low rate of treatment in cases of vaginal bleeding is a marker for failure to diagnose brucellosis and whether it plays a “permissive” role in subsequent abortion or intrauterine fetal death is difficult to determine from our data. The most important reservation against treating brucellosis in pregnant women is the possibility that the patient would experience adverse effects of the antimicrobial agents [26]. Al- though the number of patients in this study was not large, we were still able to extract from our findings that cotrimoxazole and rifampin appear to be safe agents for treating brucellosis in pregnant women, because there were no specific drug-related adverse effects in the 36 newborns for whom there were follow- up data. Other researchers have argued that the potential ad- verse effects of cotrimoxazole in pregnant women may be over- stated [27], and that the duration of treatment with rifampin is longer for pregnant women with tuberculosis than it is for pregnant women with brucellosis [28, 29]. In conclusion, this study demonstrated a remarkably high incidence of first and second trimester spontaneous abortions among pregnant women with active brucellosis. Occurrence of abortion was not associated with either the magnitude of the serum agglutinin titer or the presence of brucella bacteremia. However, antimicrobial therapy with either cotrimoxazole or cotrimoxazole plus rifampin had a strong protective effect against abortion. Future controlled studies are required before one can establish the pathogenetic role of brucellosis in causing human spontaneous abortion and whether Brucella species are more likely to cause abortion than are other infectious path- ogens. However, even in the absence of such studies, the ne- cessity of treating pregnant patients who have brucellosis im- mediately is clear, because brucellosis “can cause fetal death at any stage of pregnancy, whether maternal infection is mild or severe. Therefore, treatment must not be withheld” [30]. Acknowledgments We thank Dr. Frank Kiel for his valued collaboration in the brucellosis research conducted at King Fahad National Guard Hospital (Riyadh, Saudi Arabia). References 1. Matyas Z, Fujikura T. Brucellosis as a world problem. Dev Biol Stand 1984;56:3–20. 2. Al Sekait MA. Seroepidemiological survey of brucellosis antibodies in Saudi Arabia. Annals of Saudi Medicine 1999;19:219–22. 3. Kiel FW, Khan MY. Brucellosis in Saudi Arabia. Soc Sci Med 1989; 29:999–1001. 4. Cooper CW. Risk factors in transmission of brucellosis from animals to humans in Saudi Arabia. Trans R Soc Trop Med Hyg 1992;86:206–9. 5. Young EJ. Brucella species. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995:2053–60. 6. Young EJ. Human brucellosis. Rev Infect Dis 1983;5:821–42. 7. Poole PM, Whitehouse DB, Gilchrist MM. A case of abortion con- sequent upon infection with Brucella abortus biotype 2. J Clin Pathol 1972;25:882–4. 8. Seoud M, Saade G, Awar G, Uwaydah M. Brucellosis in pregnancy. J Reprod Med 1991;36:441–5. 9. Memish Z, Mah MW, Al Mahmoud S, Al Shaalan M, Khan MY. Brucella bacteremia: clinical and laboratory observations in 160 patients. J Infect 2000;40:59–63. 10. Kiel FW, Khan MY. Analysis of 506 consecutive positive serologic tests for brucellosis in Saudi Arabia. J Clin Microbiol 1987;25:1384–7. 11. Bannatyne RM, Jackson MC, Memish Z. Rapid diagnosis of Brucella bacteremia by using the BACTEC 9240 system. J Clin Microbiol 1997;35:2673–4. 12. Criscuolo E, di Carlo FC. El aborto y ostras manifestaciones ginecob- stetricas en el curso de la brucelosis humana. Rev Fac Cien Med Univ Nac Cordoba 1954;12:321–30. 13. Lulu AR, Araj GF, Khateeb MI, Mustafa MY, Yusuf AR, Fenech FF. Human brucellosis in Kuwait: a prospective study of 400 cases. Q J Med 1988;66:39–54. 14. Madkour MM. Pregnancy and brucellosis. In: Madkour MM, ed. Bru- cellosis. London: Butterworth, 1989:197–204. 15. Sarram M, Feiz J, Foruzandeh M, Gazanfarpour P. Intrauterine fetal infection with Brucella melitensis as a possible cause of second-trimester abortion. Am J Obstet Gynecol 1974;119:657–60. 16. Makhseed M, Harouny A, Araj G, Moussa MA, Sharma P. Obstetric and gynecologic implication of brucellosis in Kuwait. J Perinatol 1998;18:196–9. atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom
  6. 6. Brucellosis in Pregnant Women • CID 2001:32 (15 April) • 1177 17. Spink WW. The nature of brucellosis. Minneapolis: The University of Minnesota Press, 1956:145–90. 18. Simor AE, Ferro S. Campylobacter jejuni infection occurring during pregnancy. Eur J Clin Microbiol Infect Dis 1990;9:142–4. 19. Simor AE, Karmali MA, Jadavji T, Roscoe M. Abortion and perinatal sepsis associated with campylobacter infection. Rev Infect Dis 1986;8: 397–402. 20. Sauerwein RW, Bisseling J, Horrevorts AM. Septic abortion associated with Campylobacter fetus subspecies fetus infection: case report and review of the literature. Infection 1993;21:331–3. 21. Farrell DJ, Harris MT. A case of intrauterine fetal death associated with maternal Campylobacter coli bacteraemia. Aust N Z J Obstet Gynaecol 1992;32:172–4. 22. Denton KJ, Clarke T. Role of Campylobacter jejuni as a placental path- ogen. J Clin Pathol 1992;45:171–2. 23. Buongiorno R, Schiraldi O. Treatment of typhoid fever in pregnancy. Chemioterapia 1984;3:136–9. 24. Ganado W, Bannister W. Bacteraemia in human brucellosis. BMJ 1960;1:601–3. 25. Urbascheck B. Motility-promoting effect of the Brucella abortus and Brucella melitensis endotoxin on the smooth uterine muscle. Nature 1964;202:883. 26. Hall WH. Modern chemotherapy for brucellosis in humans. Rev Infect Dis 1990;12:1060–99. 27. Williams E. Letter to the editor. The Practitioner 1983;227:339. 28. Centers for Disease Control and Prevention. Initial therapy for tuber- culosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1993;42(RR-7):1–8. 29. Davidson PT. Managing tuberculosis during pregnancy. Lancet 1995; 346:199–200. 30. Joint Food and Agriculture Organization/World Health Organization Expert Committee on Brucellosis. 6th report (WHO technical report series 740). Geneva: World Health Organization, 1986. atHINARIPeruAdministrativeAccountonDecember2,2012http://cid.oxfordjournals.org/Downloadedfrom

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