Rifampicin-resistant meningococci causing invasive disease and failure of chemoprophylaxis

1152

THE LANCET

creatinine clearance, immunoreactive endothelin concentrations in plasma, blood pressure, and heart rate (measured automatically) in 30 patients with stones in the kidney, and in 19 patients with ureteric

improved efficacy or decreased toxicity. It is important to emphasise that most patients were evaluated unblinded (fourteen of sixteen studies were open and two were double-blind) and treated

stones.

with concomitant antibiotics. Crucial to the choice between the two regimens is whether one is prepared to run a risk of 28% of not detecting an increase in nephrotoxicity of 10% if the single-dose regimen is chosen. Although comparison of Prins and colleagues’ results with our meta-analysis shows that the results on efficacy and ototoxicity are much the same, we disagree about the possible beneficial effect on nephrotoxicity of the single-dose treatment.

One day after ESWL, 24 h urinary albumin excretion was increased by 125 (6) mg (p < 0-01 vs before ESWL) in patients with renal sones, and by 72 (3) mg in patients with ureteric stones (p < 0-05 vs before ESWL, p < 0-01 vs patients with renal stones). Although pre-existing impairment of kidney function improved in most patients between two and five weeks after ESWL, creatinine clearance measured on the day after ESWL showed an increase in patients with reduced renal function (creatinine clearance < 80 mL/min) by 12% in those with renal stones, but only by 3% in patients with ureteric stones (p <: 005). Immediately after ESWL, patients with renal stones had higher plasma concentrations of immunoreactive endothelin than those with ureteric stones (4-1 [0.2] vs 3-7 [0’4] pg/mL, p<0-05). This endothelium-derived vasoconstrictor hormone mediates, among other effects, a reduction in glomerular filtration rate. Thereafter, as well as before ESWL, endothelin concentrations were not different. Compared with before ESWL, mean arterial blood pressure in patients with renal stones increased by 8 [3] mm Hg between two and five weeks after ESWL (p < 001), and fell by 4 [2] mm Hg in those with ureteric

(p < 0-05). Although ESWL

stones

is non-invasive, these results suggest that moderate mechanical damage of kidney tissue may lead, at least in some patients, to a temporary impairment of renal function and an increase in mean arterial blood pressure, which is more pronounced if stones are close to, or in, the kidney. THOMAS HAAK Centre of Internal Medicine and Department of Urology,

University Hospital,

ECKART JUNGMANN DIETGER JONAS

6000 Frankfurt 70, Germany

KLAUS HENNING USADEL

S, Fair W, et al. Report of the United States cooperative study of extracorporeal shockwave lithotripsy. J Urol 1986; 135: 1127-33. 2. Karlsen SJ, Smevik B, Hovig T. Acute morphological changes in kidney function following extracorporeal shock wave lithotripsy for renal stones. Br J Urol 1991; 76: 1. Drach GW, Dretler

241-45. 3. Ackaert KSJW, Schroder FH. Effects of extracorporeal shock wave lithotripsy (ESWL) on renal tissue. Urol Res 1989; 17: 3-7. 4. Kaude JV, Williams CM, Millner MR, Scott KN, Finlayson B. Renal morphology and function immediately after extracorporeal shock-wave lithotripsy. Am J Radiol 1985; 145: 305-13.

Aminoglycosides: single or multiple daily dosing? SIR,-Dr Prins and colleagues conclude (Feb 6, p 335) that a once daily dosing regimen of gentamicin is at least as effective as and less nephrotoxic than more frequent dosing. To establish the best aminoglycoside regimen, we extracted data for efficacy, nephrotoxicity, and ototoxicity from sixteeen randomised trials of more than 1000 patients and showed that the cure rate of the single-dose regimen was 82-2% compared with 81-6% for the multiple-dose regimen; the ototoxicity rate was 3-0% compared with 4-1%, and the rate of nephrotoxicity was 8-6% in each group.

Although these differences are small and not significant, the results do not exclude the possibility of missing a real difference in the meta-analysis (type II error). For example, the risk of not detecting that multiple daily dosing results in at least a 10% higher cure rate than a single dose is less than 0 001. Likewise, the risk of not detecting that a single dose results in an increased ototoxicity rate of at least 10% compared with multiple daily doses is less than 0-11, but the risk of not detecting that a single dose results in an increased nephrotoxicity rate of at least 10% compared with multiple daily doses is less than 0.28. Obviously, like Prins and co-workers, we recorded no difference in efficacy and ototoxicity between the two regimens, but by contrast with their findings our meta-analysis did not show any difference in nephrotoxicity. These results for nephrotoxicity are based on a total of 1356 evaluated patients-by contrast with the 85 patients in the study of Prins. The single-dose treatment may be ’1referred because of its convenience, but certainly not because of

Department of Medicine F, Hospital, Copenhagen, Denmark, Department of Medicine F and Y, Gentofte Hospital, and Department of Medicine P, Herlev

Bispebjerg Hospital, Copenhagen

A. M. GALLØE L. B. MADSEN N. GRAUDAL J. P. KAMPMANN

Rifampicin-resistant meningococci causing invasive disease and failure of

chemoprophylaxis SIR,-Rifampicin is recommended for the prevention of secondary cases among contacts of patients with invasive meningococcal disease. Despite the fact that rifampicin has been associated with the emergence of resistance in strains persisting in the throats of carriers,1-3 there are few reports of meningococcal disease due to rifampicin-resistant organisms after prophylaxis.4-6 We describe two small clusters of invasive meningococcal infection due to rifampicin-resistant meningococci, in which failure of chemoprophylaxis resulted in several secondary cases. In the first outbreak, a 6-year-old boy from a town in southern Israel (population about 15 000) was admitted on Jan 31,1993, with meningococcal meningitis. Within 72 h of onset, and before sensitivity results were known, rifampicin had been administered to all his family and other close contacts, including other children at the day-care centre and children attending a first-grade class there. Cultures of the patient’s cerebrospinal fluid (CSF) and blood yielded a serogroup C meningococcus, susceptible to penicillin (minimum inhibitory concentration [MIC] 0-001 mg/L) but resistant to rifampicin (MIC 256 mg/L). On Feb 14, a 7-year-old boy from the neighbouring class developed a clinical picture of meningococcaemia. He had received rifampicin after the initial case. CSF was normal, but blood cultures yielded a rifampicin-resistant (MIC 256 mg/L) group C meningococcus. As a result, chemoprophylaxis was repeated with intramuscular ceftriaxone for children (a single dose of 125 mg) and ciprofloxacin 500 mg in a single dose for adults. Both children recovered with appropriate antibiotic and supportive therapy. In the second outbreak, a 19-year-old man was admitted in February in central Israel with meningococcal meningitis. Close contacts were given rifampicin 600 mg orally twice a day for 2 days. CSF and blood cultures yielded a serogroup C meningococcus susceptible to penicillin (MIC 0 06 mg/L) and rifampicin (MIC 0-06 mg/L). 10 days later, a room-mate, who had taken rifampicin under supervision, was also admitted with meningitis. Again a group C meningococcus was grown from CSF and blood, this time fully resistant to rifampicin (MIC 256 mg/L), although sensitive to penicillin. Another round of chemoprophylaxis started with ceftriaxone 250 mg intramuscularly in a single dose. About 2 weeks later, the father of a third room-mate developed meningitis. The patient had had no contact with the first cases, but had spent some time with his son who had received attention for an undiagnosed febrile illness after receiving rifampicin in association with the first case. Again, a rifampicin-resistant (MIC 256 mg/L) group C strain was isolated. All the patients recovered. This report emphasises that rifampicin-resistant meningococci can cause systemic disease, and that rifampicin chemoprophylaxis may fail to prevent secondary cases. High-level resistance to rifampicin has not previously been observed in Israel and poses an important public health question. Israel is a small land with a small population (about 5 000 000), where the total number of cases of meningococcal disease reported per year rarely exceeds 90. These figures lend

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THE LANCET

a) indicated a deletion at the 3’ end of atk. This finding was confirmed by hybridising a 1 1 kb EcoRI fragment of the 3’ part of the 14-6 cDNA clone to the patient’s DNA digested with several other restriction enzymes. The absence of the abnormal 1 kb Taql

weight to the potential importance of our four rifampicin-resistant isolates compared with the 2 out of 1398 resistant strains reported for 1991 in England and Wales? Physicians and public health officials should be aware of the emergence of rifampicin-resistant meningococci. We further recommend that clinical laboratories encountering meningococci test and report rifampicin sensitivity promptly. While alternatives to rifampicin exist, they are not always convenient to administer (ceftriaxone) or easily adapted for children (minocycline and ciprofloxacin).

fragment in the patient’s mother indicated that this deletion arose de novo. However, both his daughters inherited the mutation, as evidenced by the segregtion of abnormal 5 kb PvuI! fragments in the family (data not shown). Northern blotting revealed a lower molecular weight transcript of about 1-9 kb (figure, b) compared with a 2-6 kb message found in all XLA cases studied so far (ref 2

Soroka Medical Centre, Beer Sheva

and our data). The patient

PABLO YAGUPSKY

showing this atk deletion was born in 1944. He had respiratory infections from infancy, lacked immunoglobulins of all isotypes, had less than 1 % B cells among peripheral blood mononuclear cells, and had 3 healthy brothers and no family history of immunodeficiency. No associated growth hormone deficiency5 or history of growth delay were observed in this patient. The picture was thus compatible with CVID and an recurrent

National Centre for Meningococci, Clinical Microbiology, Sheba Medical Centre, Tel Hashomer 52621, Israel

SHAI ASHKENAZI COLIN BLOCK

1. Guttler RB, Counts

GW, Avent CK, Beaty HN. Effect of rifampicin and minocycline meningococcal carrier rates. J Infect Dis 1971; 124: 199-205. 2. Eickhoff TC. In-vitro and in-vivo studies of resistance to rifampin in meningococci. J Infect Dis 1971; 123: 414-20. 3. Weidmer CE, Dunkel TB, Pettyjohn FS, Smith CD, Leibovitz A. Effectiveness of rifampicin in eradicating the meningococcal carrier state in a relatively closed population: emergence of resistant strains. J Infect Dis 1971; 124: 172-78. 4. Cooper ER, Ellison RT, Smith GS, Blaser MJ, Reller LB, Paisley JW. Rifampicinresistant meningococcal disease in a patient given prophylactic rifampicin. J Pediatr on

1986; 108: 93-96. 5. Berkey P, Rolston K, Zukiwski A, Gooch G, Bodey GP. Rifampicin-resistant meningococcal infection in a patient given rifampicin chemoprophylaxis. Am J Infect Control 1988; 16: 250-52. 6. Cooke RPD, Riordan T, Jones DM, Painter MJ. Secondary cases of meningococcal infection among close family and household contacts in England and Wales, 1984-7. BMJ 1989; 298: 555-58. 7. Jones DM, Kaczmarski EB. Meningococcal infections in England and Wales: 1991. Commun Dis Rep 1992; 2 (review no 6): R61-63.

Molecular

diagnosis of X-linked agammaglobulinaemia

SiR,—We and others2 have isolated the gene that is defective in patients with X-linked agammaglobulinaemia (XLA) (Bruton disease).3 The gene, named atk, is located on the long arm of chromosome X in the region Xq22 and encodes for a novel

protein-tyrosine kinase involved in B-cell development in vivo.1,2 In Southern blot analysis with the full-length atk cDNA, deletions and point mutations in this gene have been found in about 20% of families with XLA.1 Common variable immunodeficiency (CVID) is sometimes clinically and immunologically indistinguishable from XLA if it starts early in childhood and occurs sporadically in males with a decreased number of B cells.4 Thereibre, we have used the cDNA clone 14-6, which represents the full-length atk cDNA,l in Southern blot analysis of 39 Swedish male patients diagnosed with CVID or possible CVID. One patient with a gene abnormality was detected. A 09-1 0 kb fragment shift, absence of 24 kb band, and decreased signal intensity of 2-1 kb band with TaqI digests (figure,

Southern blot revealing deletion of 3’ part of atk (a) accompanied by truncated specific transcript of northern blot (b).

Signal intensity from 2 kb 0-actin

individuals, 3= patient.

Bands in kb.

mRNA

(c).

Lanes 1-2= unaffected

isolated case of XLA. Our report demonstrates that direct detection of a mutation in the atk gene has been used to identify a sporadic case of XLA and distinguish XLA from CVID. Also an XLA patient has been shown to produce an atk messenger RNA of different length. It is therefore possible that other male patients with characteristics of CVID and lacking B cells are associated with mutations in the atk gene. Center for BioTechnology, Karolinska Institute at Novum, S-14157 Huddinge, Sweden; Division of Medical and Molecular Genetics, UMDS of Guy’s and St Thomas’s Hospitals, London SE1, and Division of Allergology, Asthma and Allergy Research Center,

Sahlgrenska Hospital, Gothenburg

I. VORECHKOVSKY

J.-N. ZHOU D. VETRIE D. BENTLEY

J. BJÖRKANDER L. HAMMARSTRÖM C. I. E. SMITH

Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993; 361: 226-33. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;

1. Vetrie D,

2.

72: 279-90. 3. Bruton OC. Agammaglobulinemia. Pediatrics 1952; 9: 722-27. 4. Asherson GL, Webster ADB. Diagnosis and treatment of immunodeficiency diseases. Oxford: Blackwell, 1980. 5. Fleisher TA, White RM, Broder S, et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med 1980; 302: 1429-34.

Neurosyphilis and

HIV

SIR,-Dr Esselink and colleagues (Feb 27, p 571) imply that the positivity of the VDRL test in CSF should be a major serological criterion for establishing the diagnosis of neurosyphilis in HIVinfected individuals. One cannot completely agree with this standpoint. In a substantial majority of non-HIV infected patients with neurosyphilis, the VDRL test is negative in CSF.1 This finding is even more true in initial testing of HIV-infected patients with clinical symptomless neurosyphilis.2 The high specificity of a positive VDRL test in CSF (providing one ensures the absence of contamination with blood) is indeed an invaluable diagnostic feature-but only when positive. However, its low sensitivity for this use3 urges one to reconsider the usefulness of VDRL in CSF for initial screening (exclusion) of neurosyphilis in favour of the more sensitive Treponema pallidum haemagglutination assay (TPHA) and fluorescent treponemal antibody-absorption tests. The use of such tests may be especially important in a longstanding non-treated or insufficiently treated infection. High TPHA titres (> 1/2560) in serum may be a useful indicator for selecting such patients for lumbar puncture.An attempt has to be made to answer the most relevant question-ie, is there an intrathecal synthesis of anti-treponemal antibodies? Evaluation of CSF IgG index might help to resolve this issue.5 A more accurate approach might be the combination of IgG index with CSF and serum-titre for TPHA-the TPHA-IgG indexThis latter method is being used in our laboratory both in HIV-positive and HIV-negative patients with a negative CSF/VDRL test.