- Email: [email protected]
Resistance to methicillin
THE LANCET combination with leucovorin (LV) and cisplatin (CDDP). Presented at 33rd annual meeting of American Society of Clinical Oncology, May 17–20, 1997. Denver, CO, USA; abstr 947.
Authors’ reply SIR—Victor Sandor acknowledges the striking and concurrent improvements in both tolerability and response rate of chemotherapy, which were brought about by chronotherapy, compared with constant-rate infusion. As far as we are aware, no randomised trial has reported any difference of such magnitude in patients with metastatic cancer, by simply altering the modality of drug delivery, especially if the chemotherapy regimen involved two or more drugs, as was the case in our trial. Sandor questions the validity of constant-rate infusion as an adequate control arm for testing chronotherapy, since the sequence of the drugs and their expected pharmacokinetics were not similar in both treatment groups. Indeed, the sequence in which two anticancer drugs are given and the time interval which separates them clearly influence cytotoxicity in in-vitro models; yet this theory failed each time it was tested in patients. We believe that one of the reasons for such failure has been the lack of consideration of a circadian regulation of cell cycle and metabolic determinants of cytotoxicity. Several experiments in tumour-bearing mice or rats have concurrently assessed the respective roles of sequence, interval, and circadian time of combination chemotherapy, and have shown a major influence of circadian dosing time for outcome (reviewed in ref 1). In any event, a sequence between oxaliplatin and 5-fluorouracil/folinic acid is only recognisable on the first infusional day in our chronotherapy schedule, in which variable rate 12-hour infusions of oxaliplatin and 5-fluorouracil/folinic acid are regularly alternated for 5 days. We feel we would have been fortunate to find by chance that 12 hours represents an ideal infusion duration for 5-fluorouracil, a drug which has been accommodated in nearly 100 schedules for the past 50 years. None of these schedules, including those in which 5fluorouracil was combined to a platinum complex made any reference to the circadian time dependency of drug toxicity or metabolism, and none achieved any clearcut improvement in therapeutic index in randomised trials. Both constant-rate infusion and chronotherapy produced similar areas under the time-concentration curves of 5-fluorouracil, although the circadian variations in plasma concentrations In addition were different.2 chronomodulated schedules with
1326
differing times of maximum delivery rate produced large differences in drug pharmacokinetics and in toxicities, as we recently reported.3,4 Taken together, the results show that anticancer drug metabolism and toxicities are exquisitely dependent on circadian rhythms. Our trial has established the clinical relevance of chronotherapy. We invite our colleagues to systematically investigate the circadian dimension in the design and validation of optimally sequenced drug regimens. *Francis Lévi, Gérard Metzger, Rachid Zidani, Jean-Louis Misset, for the International Organisation for Cancer Chronotherapy Centre de Chronothérapie, Service des Maladies Sanguines, Immunitaires et Tumorales, H˚opital Paul Brousse, 94807 Villejuif, France 1
2
3
4
Lévi F. Cancer chemotherapy. In: Redfern PH, Lemmer B, eds. Chronopharmacology of anticancer agents. In: Handbook experimental pharmacology: physiology and pharmacology of biological rhythms. Berlin; Springer-Verlag, 1997: 299–331. Metzger G, Massari C, Etienne MC, et al. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in cancer patients. Clin Pharm Ther 1994; 56: 190–201. Langou˘et AM, Metzger G, Comisso M, et al. Plasma drug concentration control through time-programmed administration. Presented at 87th meeting of American Association of Cancer Research, Washington DC, USA, March 20–24, 1996: abstract 1253. Gruia G, Giacchetti S, Deprés P, et al. Role of time of peak delivery of chronomodulated 5-fluorouracil (5-FU), l-leucovirin (LV) and oxaliplatin (L-OHP) in patients with metastatic colorectal cancer. Presented at 32nd meeting of American Society of Clinical Oncology, Philadelphia, PA, USA, May 18–21, 1996: abstract 372.
Resistance to methicillin SIR—D C E Speller and colleagues (Aug 2, p 323)1 present robust evidence that the proportion of bacteraemic isolates of methicillin-resistant Staphylococcus aureus (MRSA) has increased substantially since 1993 in England and Wales. But they make no mention of resistance to mupirocin, an antibiotic which is recommended for eradicating nasal carriage of MRSA.2 Unfortunately, isolates in our Trust are mostly epidemic MRSA-16—ie, resistant to mupirocin and ciprofloxacin—which explains our high failure in eradicating nasal carriage of MRSA with mupirocin and the alternative nasal cream, naseptin (chlorhexidine hydrochloride, neomycin sulphate). We were reassured to note that Speller and co-workers did not detect vancomycin resistance among
the MRSA isolates studied, and, therefore, vancomycin remains the cornerstone for the treatment of serious MRSA-associated infections. Contamination from skin areas colonised with MRSA is a possibility that should be excluded by careful clinical assessment before prescribing vancomycin in a bacteraemic case without evidence of sepsis syndrome. This restriction reduces the possibility of vancomycin resistance developing, avoids vancomycin side-effects, and reduces drug and laboratory costs associated with vancomycin assays. Most hospitals in the Thames region have implemented control measures,2 such as screening for MRSA, isolating and treating positive patients with mupirocin and other agents, and rescreening to confirm MRSA clearance. As Speller and colleagues suggest, it seems unlikely that intensive surveillance for MRSA will substantially reduce risk-adjusted MRSA attributable morbidity or mortality rates. The most effective and easily resourced approach is improvements in general hygiene and the environment of hospitals and adherence to universal precautionary measures and bodysubstance isolation procedures, including handwashing, among medical and nursing staff.3,4 We have stopped routine screening for MRSA, the use of nasal creams, and traditional category-specific isolation procedures, and have replaced them with body-substance isolation precautions and the use of triclosan body wash in selected patients. As a monitoring tool, it is advisable to compare risk-adjusted mortality rates attributed to MRSA with those associated with methicillin-sensitive S aureus (MSSA). However, most NHS Trusts, including our own, are not yet able to provide these riskadjusted rates as part of performance statistics. In the interim, I suggest that data on process audits should be supplied instead. Simon Namnyak Department of Medical Microbiology, Havering Hospital NHS Trust, Harold Wood, Romford RM3 OBE, Essex, UK 1
2
3
4
Speller DCE, Johnson AP, James D, Marples RR, Charlett A, George RC. Resistance to methicillin and other antibiotics in isolates of Staphylococcus aureus from blood and cerebrospinal fluid, England and Wales, 1989–95. Lancet 1997; 350: 323–25. Duckworth GJ. Diagnosis and management of methicillin-resistant Staphylococcus aureus infection. BMJ 1993; 307: 1049–52. Larson EL, Bryan JL, Adler LM, Blane C. A multifaceted approach to changing handwashing behavior. Am J Infect Ccontrol 1997; 25: 3–10. Malone N, Larson E. Factors associated with a significant reduction in hospital-wide infection rates. Am J Infect Control 1996; 24: 180–85.
Vol 350 • November 1, 1997
Authors’ reply SIR—Victor Sandor acknowledges the striking and concurrent improvements in both tolerability and response rate of chemotherapy, which were brought about by chronotherapy, compared with constant-rate infusion. As far as we are aware, no randomised trial has reported any difference of such magnitude in patients with metastatic cancer, by simply altering the modality of drug delivery, especially if the chemotherapy regimen involved two or more drugs, as was the case in our trial. Sandor questions the validity of constant-rate infusion as an adequate control arm for testing chronotherapy, since the sequence of the drugs and their expected pharmacokinetics were not similar in both treatment groups. Indeed, the sequence in which two anticancer drugs are given and the time interval which separates them clearly influence cytotoxicity in in-vitro models; yet this theory failed each time it was tested in patients. We believe that one of the reasons for such failure has been the lack of consideration of a circadian regulation of cell cycle and metabolic determinants of cytotoxicity. Several experiments in tumour-bearing mice or rats have concurrently assessed the respective roles of sequence, interval, and circadian time of combination chemotherapy, and have shown a major influence of circadian dosing time for outcome (reviewed in ref 1). In any event, a sequence between oxaliplatin and 5-fluorouracil/folinic acid is only recognisable on the first infusional day in our chronotherapy schedule, in which variable rate 12-hour infusions of oxaliplatin and 5-fluorouracil/folinic acid are regularly alternated for 5 days. We feel we would have been fortunate to find by chance that 12 hours represents an ideal infusion duration for 5-fluorouracil, a drug which has been accommodated in nearly 100 schedules for the past 50 years. None of these schedules, including those in which 5fluorouracil was combined to a platinum complex made any reference to the circadian time dependency of drug toxicity or metabolism, and none achieved any clearcut improvement in therapeutic index in randomised trials. Both constant-rate infusion and chronotherapy produced similar areas under the time-concentration curves of 5-fluorouracil, although the circadian variations in plasma concentrations In addition were different.2 chronomodulated schedules with
1326
differing times of maximum delivery rate produced large differences in drug pharmacokinetics and in toxicities, as we recently reported.3,4 Taken together, the results show that anticancer drug metabolism and toxicities are exquisitely dependent on circadian rhythms. Our trial has established the clinical relevance of chronotherapy. We invite our colleagues to systematically investigate the circadian dimension in the design and validation of optimally sequenced drug regimens. *Francis Lévi, Gérard Metzger, Rachid Zidani, Jean-Louis Misset, for the International Organisation for Cancer Chronotherapy Centre de Chronothérapie, Service des Maladies Sanguines, Immunitaires et Tumorales, H˚opital Paul Brousse, 94807 Villejuif, France 1
2
3
4
Lévi F. Cancer chemotherapy. In: Redfern PH, Lemmer B, eds. Chronopharmacology of anticancer agents. In: Handbook experimental pharmacology: physiology and pharmacology of biological rhythms. Berlin; Springer-Verlag, 1997: 299–331. Metzger G, Massari C, Etienne MC, et al. Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in cancer patients. Clin Pharm Ther 1994; 56: 190–201. Langou˘et AM, Metzger G, Comisso M, et al. Plasma drug concentration control through time-programmed administration. Presented at 87th meeting of American Association of Cancer Research, Washington DC, USA, March 20–24, 1996: abstract 1253. Gruia G, Giacchetti S, Deprés P, et al. Role of time of peak delivery of chronomodulated 5-fluorouracil (5-FU), l-leucovirin (LV) and oxaliplatin (L-OHP) in patients with metastatic colorectal cancer. Presented at 32nd meeting of American Society of Clinical Oncology, Philadelphia, PA, USA, May 18–21, 1996: abstract 372.
Resistance to methicillin SIR—D C E Speller and colleagues (Aug 2, p 323)1 present robust evidence that the proportion of bacteraemic isolates of methicillin-resistant Staphylococcus aureus (MRSA) has increased substantially since 1993 in England and Wales. But they make no mention of resistance to mupirocin, an antibiotic which is recommended for eradicating nasal carriage of MRSA.2 Unfortunately, isolates in our Trust are mostly epidemic MRSA-16—ie, resistant to mupirocin and ciprofloxacin—which explains our high failure in eradicating nasal carriage of MRSA with mupirocin and the alternative nasal cream, naseptin (chlorhexidine hydrochloride, neomycin sulphate). We were reassured to note that Speller and co-workers did not detect vancomycin resistance among
the MRSA isolates studied, and, therefore, vancomycin remains the cornerstone for the treatment of serious MRSA-associated infections. Contamination from skin areas colonised with MRSA is a possibility that should be excluded by careful clinical assessment before prescribing vancomycin in a bacteraemic case without evidence of sepsis syndrome. This restriction reduces the possibility of vancomycin resistance developing, avoids vancomycin side-effects, and reduces drug and laboratory costs associated with vancomycin assays. Most hospitals in the Thames region have implemented control measures,2 such as screening for MRSA, isolating and treating positive patients with mupirocin and other agents, and rescreening to confirm MRSA clearance. As Speller and colleagues suggest, it seems unlikely that intensive surveillance for MRSA will substantially reduce risk-adjusted MRSA attributable morbidity or mortality rates. The most effective and easily resourced approach is improvements in general hygiene and the environment of hospitals and adherence to universal precautionary measures and bodysubstance isolation procedures, including handwashing, among medical and nursing staff.3,4 We have stopped routine screening for MRSA, the use of nasal creams, and traditional category-specific isolation procedures, and have replaced them with body-substance isolation precautions and the use of triclosan body wash in selected patients. As a monitoring tool, it is advisable to compare risk-adjusted mortality rates attributed to MRSA with those associated with methicillin-sensitive S aureus (MSSA). However, most NHS Trusts, including our own, are not yet able to provide these riskadjusted rates as part of performance statistics. In the interim, I suggest that data on process audits should be supplied instead. Simon Namnyak Department of Medical Microbiology, Havering Hospital NHS Trust, Harold Wood, Romford RM3 OBE, Essex, UK 1
2
3
4
Speller DCE, Johnson AP, James D, Marples RR, Charlett A, George RC. Resistance to methicillin and other antibiotics in isolates of Staphylococcus aureus from blood and cerebrospinal fluid, England and Wales, 1989–95. Lancet 1997; 350: 323–25. Duckworth GJ. Diagnosis and management of methicillin-resistant Staphylococcus aureus infection. BMJ 1993; 307: 1049–52. Larson EL, Bryan JL, Adler LM, Blane C. A multifaceted approach to changing handwashing behavior. Am J Infect Ccontrol 1997; 25: 3–10. Malone N, Larson E. Factors associated with a significant reduction in hospital-wide infection rates. Am J Infect Control 1996; 24: 180–85.
Vol 350 • November 1, 1997