Biomedical subjects
Publications and source records attributed to A R Ronald.
This article discusses the pathogenesis, etiology, and diagnosis of bacterial urinary tract infections. Initial therapy is outlined, as is the treatment of recurrent infections.
Clinical isolates of Haemophilus ducreyi were shown to be resistant to tetracycline. Resistance was associated in some strains with a 30-megadalton plasmid capable of transferring resistance in conjugative matings with other strains of H. ducreyi and other species of Haemophilus. Restriction endonuclease digestion patterns suggest a relationship between H. ducreyi plasmids and other tetracycline resistance plasmids in Haemophilus. The presence of plasmid-mediated resistance to the tetracyclines limits the use of these agents for the treatment of chancroid.
Forty-three women with acute, symptomatic urinary tract infections were randomized to receive either norfloxacin (400 mg) twice daily or trimethoprim-sulfamethoxazole (160-800 mg) twice daily for 10 days. Of the 43 patients, 7 (16%) had low-count bacteriuria and pyuria and were included in the evaluation. Escherichia coli was isolated in 72% of the infections, whereas coagulase-negative staphylococci were isolated in 14%. All isolates were susceptible to the assigned study drug. The MICs for 90% of the strains susceptible to norfloxacin and trimethoprim-sulfamethoxazole were less than or equal to 2 and less than or equal to 0.8-16 micrograms/ml, respectively. The cure rates for norfloxacin and trimethoprim-sulfamethoxazole were 95 and 90%, respectively. There were 17 patients with presumptive upper tract infections; only 1 of these relapsed after therapy. The effects on the periurethral flora were similar in both groups, but the infecting organism was eradicated from the fecal flora in 93% of the patients treated with norfloxacin and in 57% of the patients treated with trimethoprim-sulfamethoxazole. More early reinfections occurred in the trimethoprim-sulfamethoxazole group, with resistant organisms appearing in urine and in the periurethral and fecal flora in all cases. Three patients in each group experienced adverse clinical effects, but these were more severe in the trimethoprim-sulfamethoxazole group. No adverse hematological or biochemical changes were noted. From these results, we concluded that norfloxacin is at least as effective as trimethoprim-sulfamethoxazole in the therapy of acute, symptomatic urinary tract infections in women.
We investigated the susceptibility of virulent and avirulent strains of Haemophilus ducreyi to the bactericidal activity of normal human serum and to phagocytosis and killing by human polymorphonuclear leukocytes (PMNL). Strains were defined as virulent if intradermal inoculation into a rabbit produced a typical necrotic lesion. Nonvirulent strains produced no cutaneous lesions in rabbits. Virulent strains were resistant to the complement-mediated lethal action of normal human and rabbit sera, whereas avirulent strains were susceptible (greater than 95% kill, 60 min). Virulent strains were relatively resistant to phagocytosis and killing by human PMNL, in contrast to the avirulent strains. In past studies polymyxin resistance has been correlated with virulence in H. ducreyi. In our studies, polymyxin resistance could not be correlated with virulence, since polymyxin-sensitive mutants obtained from polymyxin-resistant parent strains remained virulent for rabbits and resistant to bactericidal action of normal serum and phagocytosis and killing by human PMNL. Similarly, polymyxin-resistant mutants obtained from polymyxin-sensitive parent strains remained avirulent for rabbits and susceptible to bactericidal action of normal serum and PMNL. The acquisition of polymyxin resistance was accompanied by the loss of a 47,000-molecular-weight protein. The association of serum resistance and resistance to phagocytosis and killing by human PMNL with virulent strains, as defined by the rabbit intradermal test, suggests that these factors may mediate the pathogenicity of H. ducreyi.
The origin of replication of Haemophilus ducreyi and Neisseria gonorrhoeae ampicillin resistance plasmids was located by cloning BamHI restriction fragments into vector plasmid pAT153 and a derivative plasmid, pAT2. Selection was made for plasmid maintenance in a polA mutant. Direction of replication was determined by in vitro replication of plasmid DNA in the presence of radiolabeled deoxynucleotide.
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Of 300 men in Nairobi, Kenya, with culture-proven chancroid, 57% had acquired infection from prostitutes. The majority of infections were acquired in the city of Nairobi. All 10 female source contacts examined had genital ulcers. 13 of 29 female secondary contacts were culture-positive for Haemophilus ducreyi and 10 of these infected women had clinical chancroid. Of 122 prostitutes from the middle and lower social strata, 12 had genital ulcers, 5 of which were culture-positive for H ducreyi, and a further 5 had symptomless genital carriage of H ducreyi. Prostitutes are a major reservoir of H ducreyi in Nairobi. No evidence of transmission of H ducreyi by women without clinical chancroid was detected.
The cerebrospinal fluid is a dynamic, metabolically active substance that has many important functions. It is invaluable as a diagnostic aid in the evaluation of inflammatory conditions, infectious or noninfectious, involving the brain, spinal cord, and meninges. The cerebrospinal fluid may be obtained with relative ease with the use of lumbar puncture, but failing this, alternative techniques are available. With the judicious use of the computerized axial tomographic scan, the removal of cerebrospinal fluid has little attendant risk. Age-related and compartmental variations in chemical and cellular composition are important considerations in the interpretation of results. Alterations in cerebrospinal fluid constituents from different pathologic processes may be similar in certain circumstances and cause interpretation difficulties.
We conducted a randomized double-blind trial comparing a single dose of trimethoprim-sulfametrole (640 to 3200 mg) with five-day regimens of either trimethoprim-sulfametrole (160 to 800 mg twice daily) or trimethoprim alone (200 mg twice daily) for the treatment of men with chancroid. Of 95 patients, 78 had cultures positive for Hemophilus ducreyi. Twenty-seven, 23, and 28 patients, respectively, were assigned to the single-dose trimethoprim-sulfametrole, the five-day trimethoprim-sulfametrole, and the five-day trimethoprim treatments. The rate of ulcer and bubo resolution, the mean (+/- S.D.) healing times (10.3 +/- 5.7, 11.0 +/- 7.4, and 11.9 +/- 8.2 days, respectively), the microbiologic response, the number of treatment failures, and the number of recurrent ulcers were similar in all three treatment groups. We conclude that single-dose trimethoprim-sulfametrole is a highly effective, inexpensive therapy for chancroid in men and may prove to be an important strategy for the control of H. ducreyi infection.
The causes of death were reviewed in 53 patients from two prospective randomized trials on the efficacy of trimethoprim/sulfamethoxazole as prophylaxis of gram-negative bacillary infection in granulocytopenic patients. Twenty-nine deaths occurred in patients treated with TMP/SMX prophylaxis while 24 occurred in patients who served as controls in the first trial. The two groups were similar, with the exception that more patients in the TMP/SMX group had acute leukemia (82 versus 50%; P less than 0.02). Microbiologically documented gram-negative rod infection preceeded death in 8/24 control patients as compared to 2/29 TMP/SMX recipients (P less than 0.02). This decrease in gram-negative related deaths was most pronounced in the patients with acute leukemia. Fatal gram-negative rod infection occurred in 7/12 control leukemic patients as compared to 2/24 TMP/SMX treated patients. Despite the reduction in numbers of gram-negative rod-related deaths, infectious deaths accounted for 16/24 and 15/29 patients in control and TMP/SMX treated patients, respectively. Similar numbers of fungal, viral, and gram-positive bacterial infections occurred in each group. Fever with pulmonary infiltrates but without proven etilogic agents were included in the category of "clinically documented infections;" 6/7 patients with fever and undiagnosed pulmonary infiltrates were in the TMP/SMX group. Prophylactic administration or oral trimethoprim/sulfamethoxazole reduces the frequency of fatal gram-negative rod infections in neutropenic patients.
The whole-cell proteins of 105 clinical isolates of Haemophilus ducreyi from several geographic sources (North America, Africa, Asia, and Europe) were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The protein profiles were reproducible and unaffected by repeated subculturing or age of culture. At least seven different subtypes were determined by proteins in the molecular weight range of 24,000-50,000. These proteins are located in the outer membrane of the cell, as determined by SDS-PAGE of the sarcosinate-insoluble membrane preparations of these strains. Thirteen isolates from a Winnipeg, Manitoba, Canada, outbreak of chancroid had identical patterns, suggesting a common origin. Although H ducreyi shares a number of proteins in common with other Haemophilus species, the protein profiles appear to be species specific. Heterogeneity in the protein composition of H ducreyi has provided a basis for subtyping, which could be of value in future epidemiologic studies.
The emergence of Haemophilus ducreyi resistant to multiple antibiotics has limited the effectiveness of sulfonamides and tetracycline for the therapy of chancroid. A randomized, double-blind study compared 10-day courses of erythromycin base (500 mg) and rosaramicin (250 mg) each given four times daily for the treatment of men with chancroid in Nairobi, Kenya. Of 99 evaluable patients, 84 were positive for H ducreyi. H ducreyi-positive genital ulcers in men treated with either drug resolved with mean +/- SD healing times of 10.8 +/- 5.1 days for erythromycin and 10.7 +/- 5.5 for rosaramicin. There were no clinical or bacteriologic failures with either agent. Fifteen men with H ducreyi-negative genital ulcers for whom no other etiology could be determined also responded rapidly to treatment with either agent. Both erythromycin and rosaramicin are highly effective in the treatment of chancroid.
A multicentre prospective randomized control trial was done to compare the efficacy and toxicity of ceftazidime with that of cefazolin/tobramycin in the treatment of hospitalized patients with non-pneumococcal pneumonia. The results for 50 patients are reported in this paper; 24 in the ceftazidime group and 26 in the cefazolin/tobramycin group. Measurements of clinical response show no differences between the two groups: the same is true for bacteriological response. Minimal toxicity was seen with both treatment groups. The results support the use of ceftazidime as single-drug treatment of hospitalized patients with pneumonia.
We compared the activity of norfloxacin (MK-0366), a new orally absorbable derivative of naladixic acid, with those of other antipseudomonal agents against Pseudomonas aeruginosa. Norfloxacin was the most active against both gentamicin-susceptible and gentamicin-resistant strains, having 90% minimal inhibitory concentrations of 2 and 8 micrograms/ml, respectively. This excellent in vitro activity may make norfloxacin effective for oral therapy of P. aeruginosa urinary tract infections.
Restriction endonuclease maps of the ampicillin resistance plasmids of Haemophilus ducreyi and Neisseria gonorrhoeae show marked structural similarities. Transfer frequencies obtained by mobilization correlated with physical structure and were enhanced by increased homology with the conjugative plasmid. The origin of transfer of each plasmid was located within a specific restriction fragment.
A study was undertaken to evaluate the effectiveness of the MS-2 (Abbott Laboratories, Dallas, Tex.) in screening urine specimens in a large clinical laboratory. A total of 15,319 urine specimens (9,954 midstream specimens and 5,365 catheter specimens) were evaluated with the MS-2 and by a surface streak procedure. The study was conducted in two phases, differing in that phase II urine specimens were evaluated in the MS-2 by using a program software update (03.01). For midstream urine specimens, MS-2 detection rates in phases I and II were, respectively, 94.5 and 94.3% at a plate count of greater than 10(5) CFU/ml, 74.4 and 65.3% at plate counts of 5 X 10(4) to 1 X 10(5) CFU/ml, 55.0 and 52.4% at plate counts of 1 X 10(4) to 5 X 10(4) CFU/ml, 31.2 and 20.5% at plate counts of 10(3) to 10(4) CFU/ml, and 15.7 and 6.4% at plate counts of less than 10(3) CFU/ml. For catheter urine specimens, the MS-2 detection rates in phases I and II were, respectively, 95.4 and 96.8% at plate counts greater than 10(5) CFU/ml, 74.4 and 85.7% at plate counts of 5 X 10(4) to 1 X 10(5) CFU/ml, 50.0 and 44.4% at plate counts 10(4) to 5 X 10(4) CFU/ml, 25.6 and 14.9% at plate counts of 10(3) to 10(4) CFU/ml, and 14.7 and 5.2% at plate counts less than 10(3) CFU/ml.
Since sulphonamides are no longer predictably effective in the treatment of chancroid the combination of trimethoprim-sulphamethoxazole (TMP-SMX) was evaluated to identify other effective regimens. One hundred and nine patients with genital ulcers (75 men and 34 women) seen at the Special Treatment Clinic in Nairobi, Kenya, were randomly assigned to treatment with a seven day course of either sulphamethoxazole 1000 mg twice daily or trimethoprim (160 mg)-sulphamethoxazole (800 mg) (TMP-SMX) twice daily. Haemophilus ducreyi was isolated from the ulcer in 57 patients (33 men and 24 women). 16 patients were subsequently diagnosed serologically as having syphilis. No aetiological diagnosis was made in 40 patients. Treatment with sulphamethoxazole failed in five of 21 (24%) culture positive patients who were available for evaluation after seven days, whereas all 19 of such patients who were treated with TMP-SMX responded to treatment. Of the 21 isolates available for susceptibility testing, all were susceptible to trimethoprim alone (MIC less than 0.5 mg/l) and three were resistant to sulphonamides, all three containing a 4.9 megadalton (Mdal) plasmid. Two of the three patients from whom these isolates had been obtained were treated with sulphamethoxazole and both were clinical and bacteriological failures. Five of six patients with sulphonamide-susceptible H ducreyi responded to treatment with sulphamethoxazole. Failure of sulphonamides to eradicate H ducreyi in some patients with chancroid is associated with the presence of a sulphonamide resistant plasmid. In regions where this plasmid is present in H ducreyi TMP-SMX is the preferred treatment for chancroid.
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