Ciprofloxacin to prevent catheter-associated urinary tract infection

1421

Neurological symptoms and coma associated with doxorubicin administration during chronic cyclosporin therapy SiR,-Cyclosporin (CsA) to prevent graft rejection is associated with major side-effects, including renal toxicity and hypertension.1,2 There is now convincing evidence that vascular endothelium is one of the major targets of these toxic effects.3,4 We report the clinical course of a patient who was on chronic CsA therapy after heart transplantation and who had major neurological signs followed by coma on two separate occasions soon after doxorubicin was given, as part of chemotherapy for lymphoproliferative disease. A 49-year-old man underwent orthotopic heart transplantation because of end-stage dilated cardiomyopathy. Twenty-two months after transplantation, while he was still on CsA (2 mg/kg daily), he had enlargement of supraclavicular and inguinal lymph-nodes, together with fever and weight loss. Lymph-node biopsy fmdings were consistent with Burkitt lymphoma stage IVB. CsA was discontinued and chemotherapy was started: doxorubicin 60 mg; vincristine 2 mg; cyclophosphamide 600 mg; prednisone 80 mg. Eight hours later, disturbances of consciousness leading to stage I coma developed. He had no nuchal rigidity or other focal neurological signs. Platelets were 70 000 x 109/1 and metabolic causes of coma were excluded. He suddenly and apparently spontaneously recovered twelve hours later. After one week he was well and a striking reduction in the size of palpable lymph-nodes A second course of chemotherapy, including was noted. doxorubicin 60 mg and vincristine 2 mg, was therefore given. After 10-15 min, heralded by a sudden loss of consciousness, progressive and generalised tonic clonic seizures developed. Computed tomography of the brain was normal. In the next few days sepsis due to Listeria monocytogenes was documented and after 8 days the patient died, without ever recovering from coma. At necropsy no evidence of ischaemic or haemorrhagic damage of the central nervous system was found. We then examined whether doxorubicin and CsA have synergistic deleterious effects on the central nervous system in laboratory animals. Male Sprague-Dawley rats (Charles River, Calco, Italy) were given a daily oral dose of CsA (20 mg/kg, n 7) (Sandoz, Basel, Switzerland) or the vehicle (polyoxyethylenated castor oil, n 3) by gavage for 4 months. At the end of this time, all animals received a single intravenous injection of doxorubicin (5 mg/kg). As shown in , the table CsA-treated but not vehicle-treated rats had neurological complications characterised by progressive paresis of both sets of limbs within 17-23 h after doxorubicin injection. All animals died in a few hours after the development of this neurological syndrome. Measurements of doxorubicin concentration in brain tissue (by high-pressure liquid chromatography) of CsA-treated rats showed values 2-4-fold above the detection limit of the assay ( < 20 ng/g of tissue). Moreover, in the same animals doxorubicin concentration in the cerebellum was 3-25 times above the detection limit of the assay. By contrast, this drug was not detectable in animals who received doxorubicin alone (controls) both in the brain as well as in the cerebellum. =

=

INDIVIDUAL SURVIVAL IN RATS GIVEN CsA OR VEHICLE CHRONICALLY AND INJECTED WITH DOXORUBICIN

CsA=cyclosporin, Veh

=vehicle. h after doxorubicn tControl animals killed at 24 h

*Fmdmgs given

as

The mechanism of central nervous system toxicity of doxorubicin during CsA therapy is unclear. A possible explanation rests on the toxicity of CsA on vascular endothelium3 which has been documented in laboratory animals and man. Thus, during the course of chronic CsA therapy blood-brain barrier changes may favour doxorubicin diffusion into the brain (which usually does not effectively penetrate an intact barrier) and eventually causes neurotoxic effects. In keeping with this possibility were the detectable brain concentrations of doxorubicin in rats on chronic CsA given this drug but not in controls. Our results, whatever the underlying mechanism, suggest caution in giving doxorubicin to cancer patients on CsA. Divisions of Nephrology, Haematology, and Cardiac Surgery, Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Milan, and Mario Negri Institute for Pharmacological Research, 24100 Bergamo, Italy

TIZIANO BARBUI ALESSANDRO RAMBALDI LUCIO PARENZAN MASSIMO ZUCCHELLI NORBERTO PERICO GIUSEPPE REMUZZI

1. Perico N, Remuzzi G. Cyclosporine-induced renal dysfunction in experimental animals and humans. Transplant Rev 1991; 5: 63-80. 2. Myers BD. Cyclosporine nephrotoxicity. Kidney Int 1986; 30: 964-74. 3. Zoja C, Furci L, Ghilardi F, Zilio P, Benigni A, Remuzzi G. Cyclosporin-induced endothelial cell injury. Lab Invest 1986; 55: 455-62. 4. Voss BL, Hamilton KK, Samara ENS, McKee MP. Cyclosporine suppression of endothelial prostacyclin generation. Transplant 1988, 45: 793-96. 5. Henderson ES, Lister TA. Leukemia. Philadelphia: WB Saunders, 1990.

Ciprofloxacin to prevent urinary tract infection

catheter-associated

SIR,-Dr van der Wall and colleagues (April 18, p 946) report the for the prevention of catheter-associated infection urinary (UTI). On the basis of their findings in 202 patients, they recommend ciprofloxacin for the prophylaxis of patients needing bladder drainage for 3 days to 2-3 weeks. Several points in their study require clarification. The median duration of catheterisation in this group was 7 days, which is much longer than that noted in most series (2-4 days),1,2 as well as the 3 days cited by the same workers.3 In Hustinx and colleagues’ reportmedian durations of catheterisation of 2, 5, and 7 days were found in patients in gynaecology, orthopaedic, and surgery wards, at the same two hospitals where the prophylaxis study was done. Clearly, patients undergoing long durations of temporary catheterisation were included in the prophylaxis study. This fact may also explain the observation that bacteriuria generally develops in 10-30% (35% noted by Hustinx et al) of catheterised patients,1,2 and yet 40 of 57 placebo recipients (70%) had 105 or more colony forming units/ml of urine in van der Wall and colleagues’ study. Of 608 short-term catheterised patients reported by Garibaldi et aJ,4 25 (4%) had symptomatic UTI, and 2 (0-3%) became bacteraemic. Corresponding figures in placebotreated patients in van der Wall co-workers’ study were 18% and 5%. Similarly, the proportion of controls with pyuria at catheter removal (47%) is also high, although the definition of pyuria used by van der Wall et al is not referenced. Thus, in van der Wall and colleagues’ patients the duration of catheterisation is longer, and the incidences of bacteriuria, UTI, and bacteraemia are higher than are usually found in patients needing temporary bladder drainage. The development of resistance to ciprofloxacin in gram-negative bacteria was not seen in this study; it should be noted that guidelines in the UK5 and USA6 recommend a cut-off ciprofloxacin concentration of 1 mg/1 to define resistance, and not 2 mg/l, as van der Wall et al use. Nevertheless, longer periods of intensive administration of ciprofloxacin may well select for resistance to this valuable antibiotic. Ominously, Aguiar et aF have reported the emergence of resistance to fluoroquinolones in Escherichia coli isolated from patients with community-acquired UTI in Spain. Resistance to norfloxacin, which is closely related to ciprofloxacin, increased from 0% to 4-4% over 3 years when the use of these antibiotics rose about 2 5-fbld. Since 15-25% of patients in acute-care hospitals are catheterised during their stay, the use of prophylactic ciprofloxacin, even in "well defined" subpopulations

use

of

ciprofloxacin

tract

1422

of these individuals, would represent huge antibiotic selective pressure. We have also noted a striking increase in the frequency of ciprofloxacin resistance in coagulase-negative staphylococci that is associated with the use of this antibiotic for prophylaxis in neutropenic patients.8 In a 2’5-year period, the proportion of such staphylococci isolated from patients on general wards in our hospital who remained susceptible to ciprofloxacin ranged from 80% to 95%. By comparison, the figure for isolates causing septicaemia in patients on the haematology ward decreased from 60% to 38%. The use of ciprofloxacin on general and haematology wards increased 2’5-fold and 6-fold, respectively, during this time. van der Wall et al comment that 75% of gram-positive bacteria recovered at follow-up were susceptible to ciprofloxacin. Nevertheless, 25% of such bacteria remained ciprofloxacin resistant in patients who received antibiotic prophylaxis, compared with 1 isolate (5%) in the controls. Also, the number of gram-positive isolates at follow-up was 21 (from 54 controls) compared with 102 in the 111 ciprofloxacin-treated individuals. van der Wall et al and others8,9 have confirmed that ciprofloxacin-resistant coagulase-negative staphylococci can cause septicaemia in patients treated prophylactically with this antibiotic. We believe that the evidence for the efficacy of ciprofloxacin in the prevention of catheter-asociated UTI, as presented by van der Wall et al, is not generally applicable to patients requiring short-term bladder drainage. We also fear the consequences in terms of increased bacterial resistance if this antibiotic is used for such purposes. Department of Bacteriology, MARK H. WILCOX Royal Hallamshire Hospital, Sheffield 510 2JF, UK ROBERT C. SPENCER 1. Garibaldi RA, Burke JP, Dickman ML, Smith CB. Factors predisposing to bacteriuria during indwelling urethral catheterisation. N Engl J Med 1974, 291: 215-19. 2. Johnson, JR, Roberts PL, Olsen RJ, Moyer KA, Stamm WE. Prevention of catheter associated urinary tract infections with a silver oxide-coated urinary catheter: clinical and microbiological correlates. J Infect Dis 1990; 162: 1145-50. 3. Hustinx WNM, Mintjes-de Groot AJ, Verkooyen RP, Verbrugh HA. Impact of concurrent antimicrobial therapy on catheter-associated urinary tract infection. J Hosp Infect 1991; 18: 45-46. 4. Garibaldi RA, Mooney BR, Epstein BJ, et al. An evaluation of daily bacteriological monitoring to identify preventable episodes of catheter-associated urinary tract infection. Infect Control 1982; 3: 466-70 5. British Society for Antimicrobial Chemotherapy A guide to sensitivity testing. J Antimicrob Chemother 1991; 27 (suppl D). 6. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-second edition; approved standards M7-A2. Villanova: NCCLS, 1990. 7. Aguiar JM, Chacon J, Canton R, Baquero F. The emergence of highly fluoroquinolone-resistant Escherichia coli in community-acquired urinary tract infections. J Antimicob Chemother 1992; 29: 349-50. 8. Wilcox MH, Finch RG, Spencer RC Ciprofloxacin and CAPD peritonitis. J Antimicrob Chemother 1991; 27: 685-87. 9. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence of ciprofloxacin-resistant coagulase-negative staphylococcal skin flora in immunocompromised patients receiving ciprofloxacin. J Infect Dis 1990; 161:41-44.

** This letter has been shown follows.-ED. L.

to

Dr

Verbrugh, whose reply

SIR,-Dr Wilcox and Dr Spencer correctly conclude that our patients differ substantially from those in the studies they cited. They do not seem to appreciate that in this study prophylaxis was, from the outset, directed at selected groups of patients needing temporary bladder catheters for at least 3 days. Selection was crucial and was not only service-specific (ie, gynaecology, orthopaedics, and general surgery) but also procedure-specific (eg, in gynaecology only colporrhaphy but not hysterectomy). Thus, the effect of prophylaxis was investigated in patients, all with bladder drainage planned for 3-14 days, who were at high risk of bacteriuria, pyuria, and associated clinical infectious morbidity. We clearly showed that ciprofloxacin prophylaxis protected these patients from such unwanted consequences of catheterisation. We have thus not advocated prophylaxis for all patients needing short-term bladder drainage, as Wilcox and Spencer suggested. However, we do feel that prophylaxis may be appropriate for patients or groups of patients who can be identified in advance as needing bladder drainage for at least 3 days but not more than 2 or 3 weeks. As

summarised by Stamm,’ catheter-associated urinary tract infection is not a benign condition but, rather, should be viewed as the most common source of gram-negative septicaemia in hospital patients that increases their risk of dying. We agree that prolonged periods of intensive administration of ciprofloxacin, or any other antimicrobial agent, may well select for resistance. Aguiar et al2 emphasise the need for selective, judicious use of fluoroquinolones, especially in community-medicine, for which protocols and regulations may be lacking in parts of Spain. We have not seen the emergence of ciprofloxacin resistance among received gram-negative bacteria in over 100 patients who prophylactic ciprofloxacin, as have others.3 Continued fluoroquinolone prophylaxis for this purpose for two years following this study has likewise not induced the epidemic or endemic emergence of resistant Escherichia coli or other Enterobacteriaceae in our hospitals (unpublished data). Ciprofloxacin resistance among such strains remains a sporadic event that, through the chromosomal origin of the mutation, is not

readily spread. The selection of inherently ciprofloxacin-resistant gram-positive bacteria in the faeces and urinary tracts of patients receiving prophylaxis was only transient, albeit that repopulation of the urinary tract with ciprofloxacin-sensitive strains after cessation of prophylaxis was not completed at six weeks’ follow-up. From our data, however, one cannot conclude, as Wilcox and Spencer suggest, that 25 % of the gram-positive isolates will remain resistant beyond six weeks. Nor did we state that ciprofloxacin-resistant coagulase-negative staphylococci caused septicaemia in one patient, but rather that clinical septicaemia in this patient was associated with such bacteria; coagulase-negative staphylococci bacteraemia was not documented. We believe that fluoroquinolone prophylaxis may be indicated in selected patients at high risk of catheter-associated urinary tract infection, that ciprofloxacin is highly effective in this setting, and that the likelihood of the emergence of resistant gram-negative bacteria is so low that the risk is acceptable. If used in this way ciprofloxacin prophylaxis does not constitute a "huge" antibiotic selective pressure, but prevents the need for therapeutic antibiotics during or after bladder catheterisation.

Finally, the reference for the definition of pyuria was to Stamm,4 and the NCCLS regards 2 mg ciprofloxacin/I as the cut-off for (moderately) susceptible strains, resistance being defined by MICs of 4 mg/1 or more.5 Laboratory for Medical Microbiology, Diakonessen Hospital, 3582 KE, Utrecht, Netherlands

HENRI A. VERBRUGH

1. Stamm WE. Catheter-associated urinary tract infections: epidemiology, pathogenesis, and prevention. Am J Med 1991; 91 (suppl 3B): 65S-71S. 2. Aguiar JM, Chacon J, Canton R, Baquero F. The emergence of highly fluoroquinolone-resistant Escherichia coli in community-acquired urinary tract infections. J Antimicrob Chemother 1992; 29: 349-50.

3. Rozenberg-Arska M, Dekker AW, Verhoef J. Ciprofloxacin for selective decontamination of the alimentary tract in patients with acute leukaemia during remission induction treatment: the effect on faecal flora. J Infect Dis 1985; 152: 104-07. 4. Stamm WE. Measurement of pyuria and its relation to bactenuria. Am J Med 1973; 75 (suppl 1B); 53-58. 5. NCCLS. Methods for dilution antimicrobial susceptibility tests for bacteria that grow

aerobically-method edition. Approved Standard M7-A2, 1990. Villanova, PA. NCCLS, 1990.

SIR,-We believe that Dr van der Wall and colleagues’ results interpreted with caution. Clearly, ciprofloxacin prophylaxis (either 250 mg or 1000 mg daily) was more effective than placebo in reducing the incidence of catheter-associated urinary-tract infection in selected groups of surgical patients. The study, however, did not examine how variations in the timing and duration of prophylaxis affect the occurrence of such infections. In all patients, medication was given from the second postoperative day until catheter removal-ie, for more than 2 but less than 14 days. Since the evidence now indicates that prophylactic agents should not be prescribed for more than 48 h,l we wonder what the results would be if ciprofloxacin had been given in single dose at the should be

time of insertion of the catheter?

1423

In a previous study/we demonstrated that ampicillin given at about the time of insertion of an indwelling catheter in patients with recent stroke significantly reduced the incidence of subsequent bacteriuria compared with that in patients receiving 7-day prophylactic therapy with the same drug or those not given antimicrobial prophylaxis. Moreover, prolonged antibiotic prophylaxis was associated with polymicrobial growth and the emergence of strains with multiple resistance. We have compared (unpublished data) the effect of single-dose ceforanide prophylaxis (2 g intramuscularly [im] given 2 h before insertion of indwelling catheter) with that of peri-insertion administration of ampicillin (3 g im in equal divided doses 1 h before, at the time of, and 6 h after insertion) on catheter-associated bacteriuria. The percentage of patients with pronounced bacteriuria did not differ between the two groups until the 5th day of catheterisation, but it was significantly lower in the ampicillin group (1 -6%) than in the ceforanide group (4-6%, p < 0-05) on the 6th day. The commonest strain isolated in the ampicillin group was Escherichia coli (28-5%). By contrast, enterococci prevailed in the

ceforanide group (58.0%). In van der Wall and colleagues’ study, ciprofloxacin prophylaxis did not lead to the emergence of resistant strains. It altered, however, the distribution of bacterial species cultured from urine in favour of gram-positive microorganisms largely resistant to ciprofloxacin. Evidence suggests that the incidence of nosocomial

urinary-tract infections due to enterococcus has progressively increased during the past several years. This increase has been attributed to selection for this pathogen related to the widespread of cephalosporin use antibiotics 3 Prolonged use of for in catheterised fluoroquinolones prophylaxis patients might be associated with a similar risk. Third Medical Department, Medical School, University of Athens, "Sotiria" General Hospital, 159 69 Athens, Greece

T. D. MOUNTOKALAKIS A. P. BETROSIAN

1. Wenzel RP. Preoperative antibiotic prophylaxis. N Engl J Med 1992; 326: 337-38. 2. Mountokalakis T, Skounakis M, Tselentis J. Short-term versus prolonged systemic antibiotic prophylaxis in patients treated with indwelling catheters. J Urol 1985; 134: 506-08. 3. Morrison AJ Jr, Wenzel RP. Nosocomial urinary tract infections due to enterococcus: ten years’ experience at a University hospital. Arch Intern Med 1986; 146: 1549-51.

Loss of

heterozygosity, chromosome 7q, and breast

cancer

SIR,-Dr Bieche and his colleagues (Jan 18, p 138) report a strong association between loss of heterozygosity (LOH) on chromosome 7q and poor prognosis in primary breast cancer. Using the rnetH polymorphic DNA probe that maps at 7q31, they found 49 of 121 (41%) informative cases. Bieche et al do not refer to five previous studies, including one from their own group,l in which no such high percentage of LOH at 7q was found. In four of these studies the same metH probe was used; in the study by Devilee et a 12 an additional probe for 7q (XV-2c) was used as well. The frequency of LOH for the combined data in the 86 informative cases from these five studies is much lower than that in the study of Bieche et al: InformProbe metH metH metH metH

JCZ67

MetH/XV-2c

Screened 245 14 20 52 38 44

LOH

ative 121 2

0

0 8 2 24 3 20 0 32

Ref

(41 %)J Bieche

49

f (6%)

J

Lundberg3 Ali’ Larsson4 Saws Devilee2

In three studies2,4,5 all autosomal chromosome arms were screened with polymorphic DNA markers, revealing, for example,

LOH

at 17p in 48%, 56%, and 61% of informative cases, respectively. No significant chromosome 7 involvement in LOH has been reported in any other malignant disease so far.6 The only result suggestive of confirmation of the Bieche data, is that of Sato et al,’ obtained with another probe. Although the study of Lundberg et aP is referred to, that was done within a general context, not LOH on 7q. In view of the remarkable reported prognostic power of 7q

deletions Bieche et al should have discussed the apparent discrepancy between their findings and those from previous studies. Laboratorium

voor Pathologie, Rijksuniversiteit Te Leiden,

CEES J. CORNELISSE

2300 RC, Leiden

1. Ali

IU, Lidereau R, Theillet Ch, Callahan R. Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia. Science 1987; 238: 185-88. 2. Devilee P, van Vliet M, Van Sloun P, et al. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene 1991; 6: 1705-11. 3.

Lundberg C, Skoog L, Cavenee WK, Nordenskjold

M. Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13. Proc Natl Acad Sci USA 1987; 84: 2372-76. 4. Larsson C, Bystrom C, Skoog L, Rotstein S, Nordenskjold M. Genomic alterations in human breast carcinomas. Genes Chrom Cancer 1990; 2: 191-97. 5. Sato T, Tanigami A, Yamakawa K, et al. Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res 1990; 50: 7184-89. 6. Seizinger BR, Klinger HP, Junien C, et al. Report of the Committee on Chromosome and Gene Loss in Human Neoplasia. Cytogenet Cell Genet 1991; 58: 1080-86.

*** This letter has been shown to Dr Bieche and Dr Lidereau, whose

reply follows.-ED. L. SiR,—The published frequencies

of LOH on different chromosomes in solid tumours show wide variation, making it impossible to draw valid conclusions-indeed such discrepancies could call into doubt the contribution this approach can make to our knowledge of oncogenesis. However, the explanation may lie in differences in technique, or in heterogeneous cell populations in samples (tumours differ not only in their clinical manifestations but also histologically and cytologically). As a result, large populations and strict selection criteria are required if studies are to be compared; and tissue sampling and analytical techniques must also be standardised. Since 1986 more than 30 publications have provided an outline of LOH in breast cancer.1-3 As in other cancers, two types of LOH can be distinguished: (1) LOH on chromosome arms bearing the first known tumoursuppressor genes. These have been widely studied, and for breast cancer the focus has narrowed down to the short arm of chromosome 17.’ 17pl3-3 was the first to be studied because of the large number of deletions, and the frequency of LOH within this region has been reported at 37-61 % (48% in our study5). LOH at 17pl3-3 could alter a gene that regulates the expression of the p53 tumour-suppressor gene.4 A similar argument may hold for I lpl5 and 13ql4, which may inactivate anti-oncogenes: Series l1p15 13q14 77/33 Larsson Sato Devilee Our team

7/28 5/38 3/31 7/33 13/64 12/32 11/56 14/48 58/347 (16-7%) 123/432 (28’5%)

16/29 26/50 30/49 24/50 281/530 (530%)

Total* When several publications have appeared from the same team on LOH of the same chromosomal arm, data are from the study provtdmg the most mformation

on a

given region.

--

*Includmg cases In three reviews (2) The few recent studies of LOH on chromosome arms not bearing known tumour-suppressor genes have given widely different frequencies of the various LOH-not only for chromosome 7q (0-40%) but also 6q (9-48%) and 2p (0-27%) in breast cancer, for the same four series previously mentioned. In our first study of 7q (in only 8) informative cases, we did indeed find no clear alteration but publication of cytogenetic evidence of frequent alterations in chromosome 7 in breast cancer prompted our larger study, in which we found an LOH frequency of 40%. We went in to look at a further series of 100 primary breast tumours, using pmetH and several other probes, and confirmed an LOH frequency of 40% for 7q31 region (unpublished). It is no longer true to say that chromosome 7 is not involved in cancer. Sato et al6 have detected LOH on both the short arm (43%) and the long arm (21 %) in ovarian cancer (an epithelial cell cancer, like breast cancer), and chromosome 7 abnormalities have also been detected in mesotheliomas,’ and non-lymphocytic leukaemia.8