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Vancomycin-dependent enterococcus
T H E LANCET
CORRESPONDENCE Vancomycin-dependent enterococcus SIR-Farrag and colleagues (Dec 7, p 1581)’ report and The Lancet’s press release raise interesting issues. First, the actual identity of the organism(s) that were vancomycin dependent is not clear. Although the isolate from patient 2 is described as an Enterococcztsfaecalis, the identity of that from patient 1 is not given, although it is implied that it is an E faecium; yet the two patients are described as being infected with the same organism. Pulse-field gel electrophoresis (PFGE) apparently showed that they were the same strain-presumably meaning that they were indistinguishable by PFGE. Are Farrag and colleagues suggesting that cross infection has occurred? Second these workers claim that vancomycin dependence is “undetectable unless it is specifically looked for, necessitating a review of current practices”, but do not suggest what changes might be necessary. In the first report of vancomycin dependence the organism was able to grow weakly in the absence of antibiotic and was therefore isolated by conventional means.’ In Farrag’s case, is the dependence so striking that the organism will not grow at all in the absence of antibiotic and therefore only be detectable by growth on a vancomycin-containing medium or near a vancomycin disc? Third, in the accompanying press release Farrag and colleagues are quoted as saying that “The ultimate step in the evolution of resistance is when an organism only grows in the presence of antibiotic”. Aside from the fact that there is of course no ultimate step in evolution, since evolution is by its very nature a dynamic process; surely “evolutionary dead-end” would be a more appropriate description? In the absence of antibiotic, the bacteria will not survive, and are unlikely to be of major clinical importance. Lastly, although antibiotic dependence in enterococci is very rare, it is not new and was first reported in two presentations to the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy in October, 1993. Neither these presentations, nor their subsequent publication caused any alarm at the time.’a3 How do Farrag et a1 justify the rhetorical flourish with which the letter concludes: “Have we at last witnessed the emergence of a true
Vo1349 * February 8,1997
superbug?”. The use of this phrase inevitably attracted worldwide coverage with reports of “antibiotic munching bugs”, raising an interesting finding into the status of a minor health panic. Mark Wiiks Department of Medical Microbiology, S t Barthoiomew’sHospital, London E C l A 7BE, UK 1 Farrag N, Eltringham I, Liddy H . Vancomycin-dependent Enterococcus faecalis. Lancet 1996; 348: 1581-82. 2 Fraimow HS, Jungkind DL, Lander DW, Delso DR, Dean JL. Urinary tract infection with an Enterococcus faecalis isolate that requires vancotnycin for growth A n n Int Med 1994; 121: 22-26. 3 Green M, Shlaes JH, Barbadora I<, Shlaes DM. Bacteremia due to vancomycindependent Enterococcus faecalis. Clin infect Dis 1995; 20: 712-14.
Authors‘ reply SIR-Wilks correctly points out that the reported identities of the two organisms from our patients differed, whereas typing data from the Streptococcal Reference Laboratory, Colindale, confirmed them as being the same strain. We apologise for this discrepancy and confirm that all the isolates were identical strains of E faecium. This finding indeed suggests the possibility of cross-infection, although the two patients were situated on separate wards under the care of different medical and nursing staff at different times, so evidence is lacking. We disagree with his other comments. The demonstration of true dependence requires the presence of an antibiotic. Its discovery in these two patients was fortuitous because we were using vancomycin discs to screen for resistant organisms. In addition, the photograph clearly showed an E-test strip, which is used specifically for the quantification of resistance and showed a complete absence of growth outside the vancomycin-diffusion zone. We stand by our assertion that a review of current practices is needed, and suggest that a vancomycin disc should be included during primary culture of specimens in patients who are not responding to vancomycin, have previously had negative cultures, and who are known carriers of vancomycinresistant enterococci; we are not the first to suggest this.’ Although Wilks’ suggestion that
antibiotic dependence is an evolutionary dead-end in the absence of antibiotic may be true, patients being given the antibiotic provide a very different niche. The dismissal of dependence as being of no clinical importance is not supported by published ~ o r k . ’ ’ ~ Finally, the so called rhetorical flourish “Have we at last witnessed the emergence of a true superbug”, was included in our report in deference to the achievement of the organism rather than any impending threat to humanity. The decision to issue a press release was an Editorial one, and in the main the media reacted in a responsible manner. Since the press release we have received only two phone calls from members of the public, both of whom expressed interest rather than concern over the issue. Wilks’ suggestion that our letter caused “minor health panic” is unfounded. *N
Farrag, iJ €itringham
Public Health Laboratory, Department of Medical Microbiology, St George’sHospital Medical School, London SW17 ORE, UK Dever LL, Smith SM, Handwerger S, Eng M I < . Vancomycin-dependent Enterococcus faecalis isolated from stool following oral vancomycin therapy. J Clin Micro 1995; 33: 2770-73. Frainmow HS, Jungkind DL, Lander DW, Delso DR, Dean JL.Urinary tract infection with an Enterococcusfaecalis isolate that requires vancomycin for growth. Ann int Med 1994; 121: 22-26. Green M, Shlaes JH, Barbadora K, Shlaes DM. Bacteremia due to vancomycindependent Enterococcus faecalis. Clin Infect Dis 1995; 20: 712-14.
SIR-Farrag and colleagues’ report’ reminds me that this laboratory isolated an antibiotic-dependent organism in 1976. The photograph shows a sensitivity plate of Pseudornonas aeruginosa isolated from the urine of an elderly woman. There is a ring of growth around the polymyxin B disc, outside a zone of inhibition of a size, which at the time we believed indicated normal sensitivity to this antibiotic. The organism did not initially grow elsewhere on the plate but after a few days scattered colonies appeared in other areas. When subcultured the polymyxin-B-dependent organism repeatedly showed the same features but the variants growing in the polymyxin-free area behaved normally. Experiments done at the time showed that this finding could also be 429
THE LANCET
Sensitivity plate of P aeruginosa
reproduced with other polymyxins, chlorhexidine, and, to a lesser extent, vancomycin. Because all these agents act on the cell membrane we thought that some slight damage to an otherwise abnormal or impermeable cell membrane might be necessary to allow passage of nutrients into the cell. We were unable to find any evidence of previous polymyxin treatment, but because the patient had had an indwelling urinary catheter for some time it is possible that chlorhexidine bladder washouts had been used, leading to selection of the organism we isolated. I do not think that in our case we had witnessed the emergence of a superbug. On the contrary, it was unable to exist without the presence of a low concentration of a rarely used antibiotic. We have not isolated antibiotic-dependent P aeruginosa since that time. Laurence Hayeh Department of Pathology, Torbay Hospital, Torquay TQ2 7AA. UK
1 Farrag N, Eltringham I, Liddy H. Vancomycin-dependent Enterucuccars faecalis. Laizcet 1996; 348: 1581-82.
SIR-such isolates as Farrag and colleagues report’ might be more widespread or develop more frequently than recent publications s ~ g g e s t . We ~~’ have isolated a vancomycin-resistant and teicoplanin-resistant nutritionallydependent Enterococcus spp from the urine of a 54-year-old woman who presented with acute lymphocytic leukaemia and pneumonia in September, 1996. She was given cotrimoxazole 960 mg thrice weekly as prophylaxis against Pneumocystis carinii infection. While neutropenic during induction chemotherapy, this patient had three episodes of fever and infection: a Hickman catheter-tunnel infection and two Staphylococcus epidemidis central-line infections. She was treated with gentamicin, pipericillinitazobactam, and teicoplanin. Three courses of teicoplanin were given for a total of 32 days. During her second course of
430
teicoplanin, vancomycin-resistant and teicoplanin-resistant enterococci were isolated from urine and she was treated with nitrofurantoin. 3 weeks later, while receiving her third course of teicoplanin, urine yielded vancomycindependent and teicoplanin-dependent enterococci. Nitrofurantoin therapy was instituted and teicoplanin discontinued. The patient’s condition was complicated by the presence of urinary tract infection with Escherichia coli 4 days before and 5 days after the recovery of the glycopeptide-dependent enterococci. Subsequently E coli was also isolated from her blood. The glycopeptide-dependent enterococcal isolate failed to grow on blood agar, cysteine lactose electrolytedeficient agar, diagnostic sensitivity test agar, or McConkey agar unless these media were supplemented with vancomycin, teicoplanin, or the patient’s urine. New York City medium (which contains the antimicrobial agents vancomycin, colistin, trimethoprim, and amphotericin) supported the growth of this isolate. A previous study of glycopeptidedependent enterococci reported an isolate that was dependent on vancomycin only.* The present isolate was resistant to both vancomycin and teicoplanin, suggesting a VanA phen~type.~ This isolate has not been characterised fully, but we concur with Farrag and colleagues’ concern that current routine microbiological practice may fail to detect h c h nutritionally-dependent isolates, especially from blood specimens. These specimens can pose a particular problem because, unlike urine specimens that may provide the factor(s) necessary to support growth of glycopeptide-dependent isolates, most blood-culture protocols require specimen dilution in the blood-culture medium, a procedure that could result in the presence of insufficient glycopeptide to allow growth of such dependent isolates. *Angela S Rossney, Samuei I McConkey, Conor T Keane Department of Clinical Microbiology,
St James’s Hospital, Dublin 8, Ireland 1 Farrag N, Eltringham I, Liddy H. Vancomycin-dependent Enterucuccus faecalis. Lancet 1996; 348: 1581-82. 2 Fraimow HS, Jungkind DL, Lander DW, Urinary tract infection Delso DR, Dean JL. with an Enterucoccusfaecalis isolate that requires vancomycin for growth. A n n Int Meed 1994; 121: 22-26. 3 Rosato A, Pierre J, Billot-IUein D, Buu-Hoi A, Gutmann L. Inducible and constitutive expression of resistance to glycopeptides and vancomycin dependence in glycopeptide-resistant Enterucuccus avium. Antimicrub Agents Chemuther 1995; 39: 830-33.
Gastric safety and entericcoated aspirin SIR-I
1 Kelly JP,Kaufman DW, Jurgelon JN, Sheehn J, Koff RS, Shipiro S. Risk of aspirin-associated major upper
Vol349
*
February 8, 1997
CORRESPONDENCE Vancomycin-dependent enterococcus SIR-Farrag and colleagues (Dec 7, p 1581)’ report and The Lancet’s press release raise interesting issues. First, the actual identity of the organism(s) that were vancomycin dependent is not clear. Although the isolate from patient 2 is described as an Enterococcztsfaecalis, the identity of that from patient 1 is not given, although it is implied that it is an E faecium; yet the two patients are described as being infected with the same organism. Pulse-field gel electrophoresis (PFGE) apparently showed that they were the same strain-presumably meaning that they were indistinguishable by PFGE. Are Farrag and colleagues suggesting that cross infection has occurred? Second these workers claim that vancomycin dependence is “undetectable unless it is specifically looked for, necessitating a review of current practices”, but do not suggest what changes might be necessary. In the first report of vancomycin dependence the organism was able to grow weakly in the absence of antibiotic and was therefore isolated by conventional means.’ In Farrag’s case, is the dependence so striking that the organism will not grow at all in the absence of antibiotic and therefore only be detectable by growth on a vancomycin-containing medium or near a vancomycin disc? Third, in the accompanying press release Farrag and colleagues are quoted as saying that “The ultimate step in the evolution of resistance is when an organism only grows in the presence of antibiotic”. Aside from the fact that there is of course no ultimate step in evolution, since evolution is by its very nature a dynamic process; surely “evolutionary dead-end” would be a more appropriate description? In the absence of antibiotic, the bacteria will not survive, and are unlikely to be of major clinical importance. Lastly, although antibiotic dependence in enterococci is very rare, it is not new and was first reported in two presentations to the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy in October, 1993. Neither these presentations, nor their subsequent publication caused any alarm at the time.’a3 How do Farrag et a1 justify the rhetorical flourish with which the letter concludes: “Have we at last witnessed the emergence of a true
Vo1349 * February 8,1997
superbug?”. The use of this phrase inevitably attracted worldwide coverage with reports of “antibiotic munching bugs”, raising an interesting finding into the status of a minor health panic. Mark Wiiks Department of Medical Microbiology, S t Barthoiomew’sHospital, London E C l A 7BE, UK 1 Farrag N, Eltringham I, Liddy H . Vancomycin-dependent Enterococcus faecalis. Lancet 1996; 348: 1581-82. 2 Fraimow HS, Jungkind DL, Lander DW, Delso DR, Dean JL. Urinary tract infection with an Enterococcus faecalis isolate that requires vancotnycin for growth A n n Int Med 1994; 121: 22-26. 3 Green M, Shlaes JH, Barbadora I<, Shlaes DM. Bacteremia due to vancomycindependent Enterococcus faecalis. Clin infect Dis 1995; 20: 712-14.
Authors‘ reply SIR-Wilks correctly points out that the reported identities of the two organisms from our patients differed, whereas typing data from the Streptococcal Reference Laboratory, Colindale, confirmed them as being the same strain. We apologise for this discrepancy and confirm that all the isolates were identical strains of E faecium. This finding indeed suggests the possibility of cross-infection, although the two patients were situated on separate wards under the care of different medical and nursing staff at different times, so evidence is lacking. We disagree with his other comments. The demonstration of true dependence requires the presence of an antibiotic. Its discovery in these two patients was fortuitous because we were using vancomycin discs to screen for resistant organisms. In addition, the photograph clearly showed an E-test strip, which is used specifically for the quantification of resistance and showed a complete absence of growth outside the vancomycin-diffusion zone. We stand by our assertion that a review of current practices is needed, and suggest that a vancomycin disc should be included during primary culture of specimens in patients who are not responding to vancomycin, have previously had negative cultures, and who are known carriers of vancomycinresistant enterococci; we are not the first to suggest this.’ Although Wilks’ suggestion that
antibiotic dependence is an evolutionary dead-end in the absence of antibiotic may be true, patients being given the antibiotic provide a very different niche. The dismissal of dependence as being of no clinical importance is not supported by published ~ o r k . ’ ’ ~ Finally, the so called rhetorical flourish “Have we at last witnessed the emergence of a true superbug”, was included in our report in deference to the achievement of the organism rather than any impending threat to humanity. The decision to issue a press release was an Editorial one, and in the main the media reacted in a responsible manner. Since the press release we have received only two phone calls from members of the public, both of whom expressed interest rather than concern over the issue. Wilks’ suggestion that our letter caused “minor health panic” is unfounded. *N
Farrag, iJ €itringham
Public Health Laboratory, Department of Medical Microbiology, St George’sHospital Medical School, London SW17 ORE, UK Dever LL, Smith SM, Handwerger S, Eng M I < . Vancomycin-dependent Enterococcus faecalis isolated from stool following oral vancomycin therapy. J Clin Micro 1995; 33: 2770-73. Frainmow HS, Jungkind DL, Lander DW, Delso DR, Dean JL.Urinary tract infection with an Enterococcusfaecalis isolate that requires vancomycin for growth. Ann int Med 1994; 121: 22-26. Green M, Shlaes JH, Barbadora K, Shlaes DM. Bacteremia due to vancomycindependent Enterococcus faecalis. Clin Infect Dis 1995; 20: 712-14.
SIR-Farrag and colleagues’ report’ reminds me that this laboratory isolated an antibiotic-dependent organism in 1976. The photograph shows a sensitivity plate of Pseudornonas aeruginosa isolated from the urine of an elderly woman. There is a ring of growth around the polymyxin B disc, outside a zone of inhibition of a size, which at the time we believed indicated normal sensitivity to this antibiotic. The organism did not initially grow elsewhere on the plate but after a few days scattered colonies appeared in other areas. When subcultured the polymyxin-B-dependent organism repeatedly showed the same features but the variants growing in the polymyxin-free area behaved normally. Experiments done at the time showed that this finding could also be 429
THE LANCET
Sensitivity plate of P aeruginosa
reproduced with other polymyxins, chlorhexidine, and, to a lesser extent, vancomycin. Because all these agents act on the cell membrane we thought that some slight damage to an otherwise abnormal or impermeable cell membrane might be necessary to allow passage of nutrients into the cell. We were unable to find any evidence of previous polymyxin treatment, but because the patient had had an indwelling urinary catheter for some time it is possible that chlorhexidine bladder washouts had been used, leading to selection of the organism we isolated. I do not think that in our case we had witnessed the emergence of a superbug. On the contrary, it was unable to exist without the presence of a low concentration of a rarely used antibiotic. We have not isolated antibiotic-dependent P aeruginosa since that time. Laurence Hayeh Department of Pathology, Torbay Hospital, Torquay TQ2 7AA. UK
1 Farrag N, Eltringham I, Liddy H. Vancomycin-dependent Enterucuccars faecalis. Laizcet 1996; 348: 1581-82.
SIR-such isolates as Farrag and colleagues report’ might be more widespread or develop more frequently than recent publications s ~ g g e s t . We ~~’ have isolated a vancomycin-resistant and teicoplanin-resistant nutritionallydependent Enterococcus spp from the urine of a 54-year-old woman who presented with acute lymphocytic leukaemia and pneumonia in September, 1996. She was given cotrimoxazole 960 mg thrice weekly as prophylaxis against Pneumocystis carinii infection. While neutropenic during induction chemotherapy, this patient had three episodes of fever and infection: a Hickman catheter-tunnel infection and two Staphylococcus epidemidis central-line infections. She was treated with gentamicin, pipericillinitazobactam, and teicoplanin. Three courses of teicoplanin were given for a total of 32 days. During her second course of
430
teicoplanin, vancomycin-resistant and teicoplanin-resistant enterococci were isolated from urine and she was treated with nitrofurantoin. 3 weeks later, while receiving her third course of teicoplanin, urine yielded vancomycindependent and teicoplanin-dependent enterococci. Nitrofurantoin therapy was instituted and teicoplanin discontinued. The patient’s condition was complicated by the presence of urinary tract infection with Escherichia coli 4 days before and 5 days after the recovery of the glycopeptide-dependent enterococci. Subsequently E coli was also isolated from her blood. The glycopeptide-dependent enterococcal isolate failed to grow on blood agar, cysteine lactose electrolytedeficient agar, diagnostic sensitivity test agar, or McConkey agar unless these media were supplemented with vancomycin, teicoplanin, or the patient’s urine. New York City medium (which contains the antimicrobial agents vancomycin, colistin, trimethoprim, and amphotericin) supported the growth of this isolate. A previous study of glycopeptidedependent enterococci reported an isolate that was dependent on vancomycin only.* The present isolate was resistant to both vancomycin and teicoplanin, suggesting a VanA phen~type.~ This isolate has not been characterised fully, but we concur with Farrag and colleagues’ concern that current routine microbiological practice may fail to detect h c h nutritionally-dependent isolates, especially from blood specimens. These specimens can pose a particular problem because, unlike urine specimens that may provide the factor(s) necessary to support growth of glycopeptide-dependent isolates, most blood-culture protocols require specimen dilution in the blood-culture medium, a procedure that could result in the presence of insufficient glycopeptide to allow growth of such dependent isolates. *Angela S Rossney, Samuei I McConkey, Conor T Keane Department of Clinical Microbiology,
St James’s Hospital, Dublin 8, Ireland 1 Farrag N, Eltringham I, Liddy H. Vancomycin-dependent Enterucuccus faecalis. Lancet 1996; 348: 1581-82. 2 Fraimow HS, Jungkind DL, Lander DW, Urinary tract infection Delso DR, Dean JL. with an Enterucoccusfaecalis isolate that requires vancomycin for growth. A n n Int Meed 1994; 121: 22-26. 3 Rosato A, Pierre J, Billot-IUein D, Buu-Hoi A, Gutmann L. Inducible and constitutive expression of resistance to glycopeptides and vancomycin dependence in glycopeptide-resistant Enterucuccus avium. Antimicrub Agents Chemuther 1995; 39: 830-33.
Gastric safety and entericcoated aspirin SIR-I
1 Kelly JP,Kaufman DW, Jurgelon JN, Sheehn J, Koff RS, Shipiro S. Risk of aspirin-associated major upper
Vol349
*
February 8, 1997