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Antimicrobial Agents and Chemotherapy, May 2003, p. 1727-1731, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1727-1731.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Persistence of Salmonellae in Blood and Bone Marrow: Randomized Controlled Trial Comparing Ciprofloxacin and Chloramphenicol Treatments against Enteric Fever

M. Hussein Gasem,¹ Monique Keuter,^2* Wil M. V. Dolmans,² Johanna van der Ven-Jongekrijg,² Robert Djokomoeljanto,¹ and Jos W. M. van der Meer²

Department of Medicine, Dr. Kariadi Hospital, and Faculty of Medicine, Diponegoro University, Semarang, Indonesia,¹ Department of General Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands²

Received 26 September 2002/ Returned for modification 25 November 2002/ Accepted 18 February 2003

Top Abstract Introduction Materials and Methods Results Discussion References

 
We performed a randomized controlled trial involving 55 adult patients with enteric fever to compare ciprofloxacin and chloramphenicol. Blood and bone marrow cultures and cytokine profiles during therapy were done to compare the clinical and bacteriological efficacies of these drugs. All patients were randomly assigned to receive chloramphenicol (500 mg four times a day orally) for 14 days or ciprofloxacin (500 mg twice a day orally) for 7 days. In each treatment group, patients were subsequently randomized to have blood and bone marrow cultured after either 3 or 5 days of treatment. Twenty-seven patients received chloramphenicol, and 28 received ciprofloxacin. The two groups were similar in terms of baseline characteristics. No significant differences in clinical cure and time to defervescence were found. All strains isolated were susceptible to both antibiotics. Although ciprofloxacin was more effective in the elimination of Salmonella enterica serovars Typhi and Paratyphi A from bone marrow than chloramphenicol, there was still an impressive persistence of Salmonella in the bone marrow culture (67%). In the ciprofloxacin-treated patients the suppressed cytokine production capacity showed a trend to normalize earlier than in patients treated with chloramphenicol.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Typhoid fever, one of the most prominent infections in Indonesia, still produces considerable morbidity, complications, and mortality despite antibiotic treatment (25). For decades, chloramphenicol has been the drug of choice for enteric fever in Indonesia. All Salmonella enterica strains in our studies in Semarang were susceptible to chloramphenicol (11). Despite this fact, a large proportion of bone marrow cultures taken over the first week of chloramphenicol treatment appeared to remain positive for Salmonella (9). This remarkable persistence of Salmonella in the bone marrow, probably inside macrophages, may be responsible for relapses, which are seen in 10% of patients (22). It also implies that there is room for improvement regarding antimicrobial treatment.

Studies comparing the outcomes of bone marrow culture after various typhoid fever treatment options have not been done so far. The fluoroquinolones are currently recommended for treatment of typhoid fever and also of the carrier state (17), not only because they are less toxic than chloramphenicol but also because many experts consider them more effective. A fluoroquinolone such as ciprofloxacin not only achieves a high concentration in the bowel mucosa (2, 3) but also reaches high intracellular concentrations in human phagocytic cells and bone marrow tissue (6, 16, 19) and is able to kill intracellular pathogens, at least in vitro (7). We expected that ciprofloxacin would eliminate Salmonella from macrophages in the bone marrow faster than chloramphenicol due to its rapid bactericidal effect and its effect on stationary-phase bacteria, in addition to its intracellular action. If so, this might prevent relapses.

We have previously found that the capacity for the production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-) and interleukin-1ß (IL-1ß) by peripheral blood cells was suppressed during the acute phase of typhoid fever and restored during convalescence. The degree of suppression was a marker for severity of disease (13). Thus we expect that cytokine production would be restored more rapidly if a more effective antimicrobial treatment were given (e.g., with ciprofloxacin as opposed to chloramphenicol). In view of the considerations mentioned above we performed a randomized clinical trial comparing chloramphenicol and ciprofloxacin in patients with enteric fever in which, besides clinical end points such as defervescence and complications, elimination of Salmonella from bone marrow and restoration of capacity to produce cytokines were investigated.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Study design. A prospective, randomized, open-label, parallel controlled trial was designed. The protocol was approved by the Medical Ethics Committee of the Dr. Kariadi Hospital, Semarang, Indonesia, and written informed consent was obtained from all patients or their relatives.

Patient selection and randomization. For enrollment in the study, patients had to be 14 years or older and had to have clinically suspected enteric fever based on a fever of >38.4°C (rectal) for at least 5 days before admission or, if clinical relapse was suspected, one or more of the following signs or symptoms: relative bradycardia, mental changes, hepato- and/or splenomegaly, and constipation and/or diarrhea. Patients were excluded from the study if they had severe complications on admission (coma, sepsis syndrome or shock, or intestinal bleeding or perforation), had treatment with chloramphenicol or ciprofloxacin or other quinolones before admission, had a history of allergy to chloramphenicol or quinolone derivatives, had malaria or any other apparent infectious disease, had a leukocyte count of <2,000/ml, or were pregnant or breast feeding.

After informed consent, patients were randomly assigned to either the chloramphenicol or ciprofloxacin treatment group by means of sealed envelopes containing the names of the study drugs. The distribution of the envelopes was derived from a randomly permuted table. Chloramphenicol (500 mg) was given orally four times a day for 14 days, and ciprofloxacin (500 mg) was given orally two times a day for 7 days. Ciprofloxacin tablets were administered before breakfast and dinner. If patients needed concomitant antacids or sucralfate, the administration of these drugs was postponed until at least 2 h after the ciprofloxacin dose. All patients were observed by the investigators or the nurses while taking medication.

After the culture results were obtained, patients with positive culture for S. enterica serovar Typhi or S. enterica serovar Paratyphi A underwent a second blood culture as well as a second bone marrow culture. They were randomized to have these procedures either on day 3 or on day 5 of treatment. The method of subsequent randomization involved sealed envelopes containing the number of days, 3 or 5, from a randomly permuted table.

Clinical and bacteriological evaluations. Histories were taken and physical and laboratory examinations were performed on admission before the start of antibiotic treatment. Vital signs (rectal temperature, pulse, blood pressure, and respiratory rate) were recorded every 8 h. Symptoms and signs of the patients were assessed daily until the end of treatment. In principle, patients were hospitalized until treatment was finished (at least 8 days for ciprofloxacin and 15 days for chloramphenicol). If the patient insisted on earlier discharge, instruction about possible complications and continuation of medication was given and follow-up at the outpatient department was arranged.

Patients were defined as clinically cured if they were afebrile within 7 days of antibiotic therapy. The time of defervescence was defined as the first day that a patient's temperature fell to <37.5°C and remained below that level for at least 48 h. Early relapse was defined as reappearance of fever after defervescence during hospitalization.

For Salmonella culture, two specimens of blood and bone marrow aspirate were obtained before treatment and, according to the randomization protocol, at day 3 or day 5. Eight to 10 ml of blood and 5 ml of bone marrow aspirate were cultured by using the BACTEC 9120 (Becton Dickinson, Rutherford, N.J.). MICs were determined by the microtiter dilution method with Sceptor System Panel Enteric MIC/ID (Becton Dickinson) for ciprofloxacin and other antibiotics. The disk diffusion test as described by Kirby-Bauer was performed for chloramphenicol. Susceptibility testing was carried out by following the NCCLS guidelines (18).

Hematological and biochemical tests were performed before and after ciprofloxacin and chloramphenicol treatment on days 8 and 15, respectively. Other investigations such as electrocardiography and chest radiography were done if indicated. The microbiologist and pathologist who did culture and other tests remained blind to the treatments given until the trial was completed.

Cytokine measurements. Three venous blood samples for cytokine measurements were collected aseptically in sterile 4-ml tubes containing EDTA (Vacutainer; Becton Dickinson) on admission and after 3, 5, and 8 days of antibiotic treatment. To each tube 250 µl of aprotinin (Trasylol; Bayer, Leverkusen, Germany; final concentration, 625 kallikrein-inactivating units/ml) was added through the stopper by a tuberculin needle and syringe. One tube was centrifuged directly (1,250 x g for 10 min). The platelets from supernatant plasma were removed by a second centrifugation (15,000 x g for 1 min), and the plasma was collected and stored at -20°C until assayed for cytokines. To one of the two remaining tubes 50 µl of lipopolysaccharide (LPS; Escherichia coli serotype 055:B5; Sigma, St. Louis, Mo.; final concentration, 10 mg/ml) was added to stimulate cytokine production. Unstimulated samples contained no LPS. Both tubes were incubated at 37°C for 24 h.

Levels of TNF-, IL-1ß, and IL-1 receptor antagonist were determined by radioimmunoassay as described earlier (detection levels, 20, 300, and 2,500 pg/ml, respectively) (13, 27).

IL-6 was measured by enzyme-linked immunosorbent assay in accordance with the prescriptions of the manufacturer (detection level, 20 pg/ml) (13, 27).

For IL-1 soluble receptor 2 (IL-1-RII), levels in serum appeared to be reproducibly higher than plasma levels; thus IL-1-RII data obtained in serum were corrected according to the following formula: plasma value = 0.775 x serum value + 3.17 (formula calculated from 29 paired serum and plasma samples) (r = 0.995) (27).

Statistical analysis. Descriptive statistics (mean, standard deviation [SD], range, and proportion) were used to characterize the baseline measurements for patients with enteric fever in the chloramphenicol and ciprofloxacin groups. To confirm appropriate randomization, Student's t test or Fisher's exact test was used to compare respective means and proportions in both treatment groups. Differences in responses to therapy in the two treatment groups were analyzed by using Student's t test for continuous variables and Fisher's exact test for dichotomous variables. We calculated approximate 95% confidence intervals (CI) for the differences in bacteriological responses. To compare the baseline (day 0) cytokine concentrations for the treatment groups, an unpaired Student t test was used. Differences in cytokine concentrations between day 0 and day 8 within each treatment group were analyzed by using a paired Student t test. Differences in cytokine concentrations during therapy between the treatment groups were analyzed by using repeated-measure analysis of covariance with the mean baseline (day 0) cytokine concentrations as the covariate in a linear model for treatment comparison, after log transformation of the data (8). A P value of <0.05 was considered to be the level of statistical significance.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Patient characteristics. A total of 100 patients (53 males and 47 females; mean age ± SD, 24.6 ± 7.7 years) were enrolled in the study and randomized to receive chloramphenicol or ciprofloxacin. After the culture results were obtained, 50 and 5 patients with positive S. enterica serovar Typhi and S. enterica serovar Paratyphi A cultures, respectively, from blood and/or bone marrow were randomized for a second blood and/or bone marrow culture after 3 or 5 days of treatment. Of these, 27 patients were in the chloramphenicol group and 28 were in the ciprofloxacin group. All patients with positive cultures were assessed until treatment was finished. Forty-five patients with negative cultures (23 in the chloramphenicol group and 22 in the ciprofloxacin group) were monitored clinically, not bacteriologically, but were not included in the data analysis. Of these, three patients had been eventually proven to have other diseases, i.e., two patients had active pulmonary tuberculosis and one patient had meningoencephalitis. One patient died due to meningoencephalitis, and one died due to irreversible shock. The remaining culture-negative patients had clinical enteric fever without or with complications (pneumonia, sepsis syndrome, or myocarditis) and responded well to treatment.

Table 1 shows the baseline characteristics of patients. Members of the two treatment groups were similar with respect to age, gender, mean duration of fever before admission, mean temperature on admission, and the use of antibiotics before admission. The weights of the patients varied between 40 and 50 kg; this means that they received either 50 mg of chloramphenicol or 20 mg of ciprofloxacin/kg of body weight.

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TABLE 1. Baseline characteristics of patients with enteric fever

Seven patients in the chloramphenicol group and 13 patients in the ciprofloxacin group had received antibiotic treatment before admission (² = 2.497, df = 1, P = 0.11). Ampicillin, amoxicillin, cotrimoxazole, and tetracycline, all given orally and with a duration of treatment ranging between 1 and 15 days, were prescribed by their physicians. In each treatment group, two of five patients with initial cultures positive for Salmonella in bone marrow but negative in blood had a history of antibiotic treatment before admission.

Clinical response to therapy. No significant differences in time to defervescence, clinical cure, and hospital stay between the treatment groups were observed. The mean times to defervescence ± SD for the chloramphenicol and ciprofloxacin groups were 5.7 ± 2.2 days (range, 3 to 12 days) and 5.1 ± 1.4 days (range, 2 to 8 days), respectively (P = 0.21). Our data do not support the suggestion by others (24) that the longer the duration of symptoms before admission the longer the time to defervescence (data not shown). Twenty-five of 27 (92%) patients treated with chloramphenicol and 27 of 28 (96%) treated with ciprofloxacin were clinically cured (P = 0.61). Twenty-two (81.5%) chloramphenicol-treated patients were discharged from the hospital before treatment was finished, but all patients in both treatment groups stayed in the hospital for at least 8 days. The mean hospital stays ± SD were 12.1 ± 2.6 days (range, 9 to 17 days) for the chloramphenicol group and 11.7 ± 2.0 days (range, 8 to 14 days) for the ciprofloxacin group (P = 0.53). Data for two patients in the chloramphenicol group considered to have clinically failed treatment were as follows: one patient remained febrile after 7 days of chloramphenicol, and treatment was changed to cotrimoxazole; the other patient had multiple complications (sepsis syndrome, myocarditis, pneumonia, and urinary tract infection caused by E. coli) on day 3 of hospitalization and received additionally 1 g of cefotaxime three times a day intravenously for 7 days. Both patients became afebrile 12 days after the initiation of chloramphenicol. One patient in the ciprofloxacin group became afebrile on day 8. No relapse was found in either group, but long-term follow-up (beyond day 14) was not systematically pursued.

Pneumonia was found in two patients in the chloramphenicol group and in three patients in the ciprofloxacin group during hospitalization. These five patients became afebrile within 7 days of treatment without any additional antibiotic treatment, except for one patient with multiple complications described earlier. One patient in the chloramphenicol group had intestinal bleeding on day 3 of hospitalization; therefore, chloramphenicol was switched from the oral to the intravenous route and the patient recovered and defervesced on day 7. Only one patient had a clearly adverse event, i.e., skin rash after 2 days of chloramphenicol. The skin rash disappeared after the patient received antihistamine tablets (chlorpheniramine maleate) for 1 day. No antacids or sucralfate was used by the patients during the study.

In the chloramphenicol group, hemoglobin decreased from a mean ± SD of 11.4 ± 1.7 to 9.9 ± 3.8 g/dl (P = 0.07), whereas levels of leukocytes and platelets and the percentage of eosinophils increased but were still in the normal range of values. In the ciprofloxacin group, levels of leukocytes and platelets and the percentage of eosinophils also increased but stayed within the range of normal values. Alanine-aspartate aminotransferase (ASAT) levels decreased from 57.5 ± 72 to 26 ± 21.3 U/liter (P = 0.04) and from 67.3 ± 48.1 to 33.7 ± 20.4 U/liter (P = 0.001) in the chloramphenicol and ciprofloxacin groups, respectively; alanine aminotransferase (ALAT) levels did not change or differ between the groups (normal level of ASAT, <35 IU; normal level of ALAT, <40 IU). No differences in other laboratory tests were noted before and after treatment.

Bacteriological response to therapy. Table 2 compares the degrees of persistence of Salmonella after 3 and 5 days of treatment in blood and bone marrow. There was no statistical difference in the elimination of Salmonella in blood between chloramphenicol and ciprofloxacin. With respect to bone marrow, ciprofloxacin was more effective after 5 days of treatment in eliminating Salmonella (P < 0.05), but still the positivity rate was 67% for the ciprofloxacin group versus 100% for the chloramphenicol group (the difference between the groups was 33%; 95% CI of the difference: 9 to 57%).

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TABLE 2. Numbers of patients with positive cultures of blood and bone marrow

All Salmonella strains were sensitive to ciprofloxacin (MICs < 1 mg/liter) and chloramphenicol (mean inhibitory zone = 21 mm; range, 18 to 25 mm). Four isolates of S. enterica serovar Typhi were resistant to cotrimoxazole (MIC > 2 mg/liter), and one isolate was resistant to either ampicillin or amoxicillin (MICs > 32 mg/liter). Two of five isolates of S. enterica serovar Paratyphi A were resistant to antibiotics: one was resistant to ampicillin (MIC > 32 mg/liter), and the other was resistant to cotrimoxazole (MIC > 2 mg/liter) (Table 1).

There were no significant differences in bone marrow culture positivity rates between patients with and without antibiotic treatment before admission in both treatment groups. In addition, there were no significant differences in the defervescence rate between the patients who remained bacteremic or had positive bone marrow culture at days 3 and 5 and those who had sterile cultures by days 3 and 5.

Cytokine profiles during therapy. (i) Circulating cytokines and inhibitors. On admission, equally elevated concentrations of TNF- were found in both treatment groups (means ± standard errors: 185 ± 22.3 pg/ml for the chloramphenicol group and 182 ± 20.4 pg/ml for the ciprofloxacin group; P > 0.05). These concentrations decreased significantly (P < 0.05) during the disease course, but at the same rate (day 8: 143 ± 16.4 pg/ml for the chloramphenicol group and 153 ± 15.6 pg/ml for the ciprofloxacin group; P = 0.54). For IL-6, similar results were found (62 ± 13.9 pg/ml for the chloramphenicol group and 54 ± 7.9 pg/ml for the ciprofloxacin group on day 0 and 17 ± 5.3 and 23 ± 9.4 pg/ml, respectively, on day 8). Circulating concentrations of IL-1ß and IL-1-RII were low and remained low; they did not differ between the two groups (P = 0.39 and P = 0.22, respectively).

(ii) Ex vivo production of cytokines and inhibitors. In these sequential samples, the capacity for production of TNF- and IL-1ß, which was suppressed at day 0 (means ± standard errors: 2,619 ± 325 pg/ml for the chloramphenicol group and 2,371 ± 239 pg/ml for the ciprofloxacin group), returned to normal after day 5 (3,432 ± 397 and 3,668 ± 297 pg/ml, respectively). Throughout the disease course, the capacity for LPS-stimulated production of IL-1 receptor antagonist was preserved (10,418 ± 693 and 9,215 ± 645 pg/ml for the chloramphenicol group at days 0 and 8, respectively; 11,790 ± 621 and 9,785 ± 489 pg/ml for the ciprofloxacin group at days 0 and 8, respectively). In the analysis of covariance, there were no significant differences in the restoration of the LPS-stimulated production capacity of proinflammatory cytokines during the course of treatment. However, the LPS-stimulated IL-1ß production on day 8 was significantly higher in the ciprofloxacin group (4,901 ± 660 pg/ml) than in the chloramphenicol group (6,059 ± 718 pg/ml) (Fig. 1; P < 0.05).

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FIG. 1. Mean concentrations of IL-1ß due to LPS-stimulated production over time for chloramphenicol- and ciprofloxacin-treated patients. The concentrations of IL-1ß due to ex vivo production for the two treatment groups were not significantly different (P > 0.05). At day 8, the LPS-stimulated production of IL-1ß was significantly higher in ciprofloxacin-treated patients (P < 0.05).

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this randomized study, ciprofloxacin appeared to be more effective than chloramphenicol in the elimination of Salmonella from bone marrow in patients with enteric fever after 5 days of antibiotic treatment. However, we would have expected that ciprofloxacin, as an intracellularly active and bactericidal drug, would be considerably more effective. Still 10 of 15 (67%) bone marrow cultures remained positive on day 5. One should bear in mind that the nucleated bone marrow cells probably contain ciprofloxacin in bactericidal concentrations, which could account for the negative cultures in the ciprofloxacin group. We did not measure these concentrations, but this finding could mean that the differences between chloramphenicol and ciprofloxacin are even smaller. One explanation for the relatively poor performance of ciprofloxacin may be that, despite good intracellular penetration, the quinolone does not readily kill the Salmonella within the macrophage. That this may be the case is suggested in experiments by van den Broek et al. showing that the quinolone trovafloxacin did not kill Staphylococcus aureus as well intracellularly as in a cell-free medium (26).

The high persistence rates of S. enterica serovar Typhi and S. enterica serovar Paratyphi A in bone marrow after 3 or 5 days of chloramphenicol treatment (85 and 100%, respectively) may be due to the fact that, pharmacodynamically, chloramphenicol is a slow bacteriostatic drug (4). The efficacies of the two antibiotics in the elimination of Salmonella from blood were not significantly different, but in both groups there was still considerable blood culture positivity at days 3 and 5. This is in contrast to a study comparing two regimens of ciprofloxacin, 500 and 750 mg twice a day, against typhoid fever, in which all blood cultures obtained on the third day were sterile, despite the fact that nearly one-half (48%) of the S. enterica serovar Typhi isolates were multidrug resistant (24). In an uncontrolled study of ciprofloxacin at 500 mg twice a day orally in 25 patients with typhoid fever, it was reported that blood cultures became negative after 5 days of treatment (5). This discrepancy with the literature is not due to poor compliance, since we directly observed treatment in all patients. In addition, there were no clinical conditions that may have influenced the drug absorption, such as diarrhea or concomitant use of antacids or sucralfate. The discrepancy is also not due to resistance to the antibiotics used. Despite multidrug resistance of S. enterica serovar Typhi in some Asian countries (12, 20), in our study all strains remained sensitive to chloramphenicol; resistance to ampicillin-amoxicillin or cotrimoxazole was present in 12.8% of the strains. Thus, the situation in the Semarang area in this respect has not changed between 1992 (11) and 1997, the year of the present study.

Our study showed no difference in clinical cure between patients treated with 14 days of chloramphenicol and those treated with 7 days of ciprofloxacin. This finding agrees with several studies in which ciprofloxacin was clinically as effective as chloramphenicol in the treatment of typhoid fever, with cure rates of more than 96% (15, 28), although none of these studies is sufficient to show superiority or equivalence. The mean time to defervescence in our ciprofloxacin group (5.1 days) was also similar to those in other comparative studies, in which a range of 4.0 to 5.2 days was found (10, 24, 28; J. L. Bran, J. F. Garcia, and O. Mendez, Program Abstr. 31st Intersci. Conf. Antimicrob. Agents Chemother., abstr. 751, 1991). Although it is difficult to assess the efficacy of the drugs in patients who had taken antibiotics before admission, this study showed that there was no significant difference in time to defervescence between the two treatment groups.

In this study we found cytokine activation patterns similar to those we found in a previous typhoid fever study (13). There was no significant difference between the rates of restoration of cytokine production in the two treatment groups; only a trend toward faster restoration of IL-1ß production in ciprofloxacin-treated patients was seen. We do not know whether this is explained by the slightly lower degree of Salmonella in the bone marrow in the ciprofloxacin group, implying slightly faster recovery. Another explanation may be that ciprofloxacin by itself is able to influence proinflammatory cytokine production. Recent studies have shown that ciprofloxacin can suppress proinflammatory cytokines in vitro (1, 21, 23) as well as in vivo (14). Since this effect is contrary to what we have observed, the effect may even have been greater.

It may be concluded that this study and the cumulative literature show that rates of clinical cure of patients with enteric fever after 7 days of ciprofloxacin and 14 days of chloramphenicol are similar. However, the studies are not sufficient to demonstrate that ciprofloxacin is equivalent or superior to chloramphenicol. On the basis of surrogate end points, i.e., the capacity to eliminate Salmonella from the bone marrow and the trend toward earlier normalization of proinflammatory cytokine production, ciprofloxacin may be somewhat more effective.

 
We are grateful to the patients and nursing and laboratory staffs of the infectious diseases ward of Dr. Kariadi Hospital who participated in this study. We thank Soeharyo Hadisaputro for his valuable advice; Djoko Wibisono, I. G. A. Putra-Hartana, and Budi Riyanto for assistance in clinical setting; and Bambang Isbandrio for cultures. We also thank Hans van Druten and Hardian for statistical analysis.

This study was partly supported by a grant from PT Sanbe Farma, Bandung, Indonesia, which also provided ciprofloxacin and chloramphenicol.

 
* Corresponding author. Mailing address: Department of General Internal Medicine, University Medical Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: 31 (24) 361 8819. Fax: 31 (24) 354 1734. E-mail: M.Keuter{at}aig.umcn.nl.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, May 2003, p. 1727-1731, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1727-1731.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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