324
Correspondence References
trial of dproBoxadn ptas azlodnin versos netttmicin pins aztocflUn for the empirical treatment of fever in nentropenic patients Sir, Patients suffering prolonged neutropenia commonly experience multiple episodes of fever, most of which will respond to staged empirical antibiotic therapy (Barnes & Rogers, 1988). Initial empirical treatment of febrile episodes usually involves using a combination of bactericidal antibiotics, such as an extended spectrum penicillin with an aminoglycoside (Klastersky et al., 1986). This aims to provide cover for both the common Gram-positive and Gram-negative infections seen in neutropenic patients; although the former are increasing in prevalence the latter continue to present the
highest risk of early mortality. Ciprofloxacin is a 4-quinolone with broad spectrum bactericidal activity comparable to the aminoglycosides against many Gram-negative organisms, including Pseudomonas aentginosa (Eliopoulous, Gardella & Moellering, 1984). It is, however, much less toxic and serum levels do not need to be monitored. We undertook a prospective, randomized study comparing the efficacy and safety of parenteral ciprofloxacin 200 mg bd, plus azlocillin S g tds, with that of netitmicin 5-7-5 mg/kg/day plus azlocillin in the empirical treatment of fever in neutropenic patients. All patients received gut decontamination with colistin (1-5 mega units bd) and neomycin (500 mg qds). Inclusion criteria were: adult patient > 18 years and temperature > 38°C for 2 h or longer in the first or second pyrexial episode during a period of neutropenia (neutrophil count < 0-5 x lO'/L) following chemotherapy for remission induction or bone marrow transplantation for acute or chronic leukaemia. In the absence of either a response to first line therapy (ciprofloxacin plus azlocillin or netilmicin plus azlocillin) after 72 h, or the results of bacteriological cultures being used to modify therapy, antibiotic treatment was changed to vancomycin and ceftazidime; in patients persistently febrile after a further 48 h intravenous amphotericin B was added. Safety of drug treatment was monitored by careful clinical observations including evaluation of possible central nervous system effects and by tests of renal, hepatic and hacmatological function. Seventy-three episodes were evaluable out of an initial 78 recorded. Episodes not evaluable were the result of the patient not being neutropenic prior to or during the study period, or being placed on an inappropriate combination of antibiotics. Thirty-seven patients received ciprofloxacin plus azlocillin and 36 netilmicin plus azlocillin. Overall outcomes based on clinical and microbiological responses to antibiotics in the absence neutrophil recovery are shown in the Table. There was a greater frequency of response to initial therapy in the ciprofloxacin and azlocillin group but overall responses to staged antimicrobial therapy were comparable. The 16% response rate to azlocillin and netilmicin in microbiologically documented infections was low and was caused by the isolation of seven netilmkan-resistant Gram-positive organisms necessitating an early change in therapy. There were no differences in response rates between those patients experiencing their
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
Bakken, J. S., Sanders, C. C. & Thomson, K. S. (1987) Selective ceftazidime resiitasce in Escherichia coli: association with changes in outer membrane protein. Journal of Infectious Diseases 155, 1220-5. Bayer, A. S., Peters, J., Parr, T. R., Chan, L. & Hancock, R. E. W. (1987). Role of ^-lactamase in in vivo development of ceftazidime n^jftgriof in experimental Pseudomonas aentginosa endocarditis. Antimicrobial Agents and Chemotherapy 31, 253-8. Dance, D. A. B. (1991). Melioidoas: the tip of the iceberg? Clinical Microbiology Reviews 4, 52-60. Dance, D. A. B., Wuthiekanun, V., Chaowagul, W. & White, N. J. (1989). The antimicrobial susceptibility of Pseudomonas pseudomallei. Emergence of resistance in vitro and during treatment. Journal of Antimicrobial Chemotherapy 24, 295-309. Jarlier, V., Nicolas, M.-H., Fournier, G. & Philippon, A. (1988). Extended broad-spectrum ^-lactamases conferring transferrable resistance to newer /J-lactam agents in Enterobacteriactae: hospital prevalence and susceptibility patterns. Reviews of Infectious Diseases 10, 867-78. livennore, D. M., Chau, P. Y., Wong, A. I. W. & Leung, Y. K. (1987). 0-Lactamase of Pseudomonas pseudomallei and its contribution to antibiotic resistance. Journal of Antimicrobial Chemotherapy 20, 313-21. Sanders, C. C. & Sanders, W. E. (1985). Microbial resistance to newer generation /2-lactam antibiotics: clinical and laboratory implications. Journal of Infectious Diseases 151, 399-406. White, N. J., Dance, D. A. B., Chaowagul, W., Wattanagoon, Y., Wuthiekanun, V. & Pitakwatchara, N. (1989). Halving of mortality of severe metioidosb by ceftazidime. Lancet U, 697-701.
Correspondence
325
Table. Resolution of symptoms in response to antibiotic therapy Responses to first line
Overall response to staged antimicrobials*
Qprofloxatan + azlocillin micTobiologically documented infection clinical infection overall
10 27 37
5 (50%) 15 (55%) 20 (54%)
8 (80%) 24 (88%) 33 (89%)
Netilmicin + azlocillin microbiologically documented infection clinical infection overall
12 24 36
2 (16%) 11 (46%) 13 (36%)
12 (100%) 20 (83%) 32 (88%)
•See text
first or second episode and also no difference vancomycin (Smith et at., 1988), or benzyl between those undergoing bone marrow trans- penicillin (Kelsey et at., 1990), and supports plantation and those not. No serious drug the work of Philpott-Howard et at. (1990) who related adverse events were noted. Two infec- found comparable efficacy between the comtion related deaths occurred, one due to cytc- binations of azlocillin with either ciprofloxacin megalovirus and one suspected aspcrgillosis. or gentamicin. The use of ciprofloxacin in Bacteriological evidence of infection was conjunction with a ureidopenicillin such as obtained in 22 (30%) febrile episodes; 78% of azlocillin extends the Gram-negative cover of these were associated with culture of the combination without the potential risks of Gram-positive organisms, 22% with aminoglycoside toxicity. Gram-negative organisms. Four of the Ideas for empirical treatment may change Gram-positive isolates were resistant to cipro- with increasing use of ciprofloxacin for floxacin (all were coagulase-negative staphylo- prophylaxis during the period of neutropenia. cocci) but all Gram-negative isolates were Warren et at. (1990) report exclusively sensitive. Gram-positive breakthrough bacteraemias and From this we conclude that ciprofloxacin suggests the initial use of vancomycin and an plus azlocillin is safe and as effective as netil- ureidopenicillin in the empirical treatment of micin plus azlocillin for the empirical treat- febrile neutropenics. Septicaemias with ciproment of infections due to both Gram-positive floxacin resistant Gram-negatives remain a and Gram-negative bacteria in neutropenic theoretical possibility; surveillance cultures may alert clinicians to the colonization of patients. Deficiencies in the use of ciprofloxacin as patients with such organisms and enable treatmonotherapy for empirical treatment of infec- ment to be directed accordingly. tions have been encountered with the emerD. S. HYATT* gence of resistant coagulase-negative T. R. F. ROGERS' staphylococci (Oppenhcim et at., 1989) and D. M. MCCARTHY* also streptococci (Smith et at., 1986); its use in D. S. SAMSON* combination with a penicillin may be expected 'Department of Medical Microbiology to extend the therapeutic range against Charing Cross and Westminster Medical School, Gram-positive organisms. Development of 17 Horstferry Road. London SW1P 2AR; resistance in P. aeruginosa has also been ''Department of Haematology reported (Scully et at., 1986) and it may be Charing Cross Cross Hospital. Fulham Palace Road, prudent to combine ciprofloxacin with another London W6. UK anti-pseudomonal agent, such as a ureidopenicillin; synergistic activity between ciprofloxReferences acin and azlocillin has been observed in vitro against P. aeruginosa, Acinetobacter calcoace-Barnes, R. A. & Rogers, T. R. (1988). Response ticus var. anitratus and Staphylococcus aweus rates to a staged antibiotic regimen in febrile neutropenic patients. Journal of Antimicrobial (Moody, Peterson & Gerding, 1985). Chemotherapy 22, 759-63. Our work confirms the value of ciproflox- Hiopoulos, G. M., Gardella, A. & Moellering, R. C. acin in neutropenic patients as suggested (1984). In vitro activity of ciprofloxacin, a new carboxyquinolone antimicrobial agent earlier by its use in combination with either
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
No. of episodes
326
Correspondence Philpott-Howard, J. N., Barker, K. F., Wade, J. J., Kaamartlri, R. S., Smedley, J. C. & Mufti, G. J. (1990). Randomized multicentre study of dprofloxacin and aziocillin versus gentamidn and aziocillin in the treatment of febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 26, Suppl. F, 89-99. Scully. B. E , Neu, H. C , Parry, M. F. & Mandell, W. (1986). Oral dprofloxadn therapy of infections due to Pseudomonas aeruginosa. Lancet i, 819-22. Smith, G. M., Leyland, M. J., Farrell, I. D. & Geddes, A. M. (1986). PreUminary evaluation of dprofloxacin, a new 4-quinolone antibiotic, in the treatment of febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 18, Suppl. D, 165-74. Smith, G. M., Leyland, M. J., Farrell, I. D. & Geddes, A. M. (1988). A clinical, microbiological and pharmacokinetic study of dprofloxacin plus vancomycin as initial therapy of febrile episodes in neutropenic patients. Journal of Antimicrobial Chemotherapy 21, 647-55. Warren, R. E., Wimperis, J. Z., Baglin, T. P., Constantine, G. E. & Marcus, R. (1990). Prevention of infection by dprofloxacin in neutropenia. Journal of Antimicrobial Chemotherapy 26, Suppl. F, 109-23.
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
Antimicrobial Agents and Chemotherapy 25, 331-5. Kelsey, S. M., Wood, M. E^ Shaw, £ , Jenkins, G. C. & Newland, A. C. (1990). A comparative study of intravenous dprfloxacin and benzylpenidllin venus netilmicin and piperacillin for the empirical treatment of fever in neutropenic patients. Journal of Antimicrobial Chemotherapy 25, 149-257. Klastersky, J., Glauser, M. P., Schimpff, S. C , Zinner, S. H., Gaya, H. and the European Organisation for Research on Treatment of Cancer Antimicrobial Therapy Project Group (1986). Prospective randomised comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenk patients. Antimicrobial Agents and Chemotherapy 29, 263-70. Moody, J. A., Peterson, L. R. & Gerding, D. N. (1985). In vitro activity of dprofloxacin combined with aziocillin. Antimicrobial Agents and Chemotherapy 28, 849-50. Oppenheim, B. A., Hartley, J. W., Lee, W. & Burnie, J. P. (1989). Outbreak of coagulate negative staphylococcus highly resistant to dprofloxacin in a leukaemia unit British Medical Journal 299, 294-7.
Correspondence References
trial of dproBoxadn ptas azlodnin versos netttmicin pins aztocflUn for the empirical treatment of fever in nentropenic patients Sir, Patients suffering prolonged neutropenia commonly experience multiple episodes of fever, most of which will respond to staged empirical antibiotic therapy (Barnes & Rogers, 1988). Initial empirical treatment of febrile episodes usually involves using a combination of bactericidal antibiotics, such as an extended spectrum penicillin with an aminoglycoside (Klastersky et al., 1986). This aims to provide cover for both the common Gram-positive and Gram-negative infections seen in neutropenic patients; although the former are increasing in prevalence the latter continue to present the
highest risk of early mortality. Ciprofloxacin is a 4-quinolone with broad spectrum bactericidal activity comparable to the aminoglycosides against many Gram-negative organisms, including Pseudomonas aentginosa (Eliopoulous, Gardella & Moellering, 1984). It is, however, much less toxic and serum levels do not need to be monitored. We undertook a prospective, randomized study comparing the efficacy and safety of parenteral ciprofloxacin 200 mg bd, plus azlocillin S g tds, with that of netitmicin 5-7-5 mg/kg/day plus azlocillin in the empirical treatment of fever in neutropenic patients. All patients received gut decontamination with colistin (1-5 mega units bd) and neomycin (500 mg qds). Inclusion criteria were: adult patient > 18 years and temperature > 38°C for 2 h or longer in the first or second pyrexial episode during a period of neutropenia (neutrophil count < 0-5 x lO'/L) following chemotherapy for remission induction or bone marrow transplantation for acute or chronic leukaemia. In the absence of either a response to first line therapy (ciprofloxacin plus azlocillin or netilmicin plus azlocillin) after 72 h, or the results of bacteriological cultures being used to modify therapy, antibiotic treatment was changed to vancomycin and ceftazidime; in patients persistently febrile after a further 48 h intravenous amphotericin B was added. Safety of drug treatment was monitored by careful clinical observations including evaluation of possible central nervous system effects and by tests of renal, hepatic and hacmatological function. Seventy-three episodes were evaluable out of an initial 78 recorded. Episodes not evaluable were the result of the patient not being neutropenic prior to or during the study period, or being placed on an inappropriate combination of antibiotics. Thirty-seven patients received ciprofloxacin plus azlocillin and 36 netilmicin plus azlocillin. Overall outcomes based on clinical and microbiological responses to antibiotics in the absence neutrophil recovery are shown in the Table. There was a greater frequency of response to initial therapy in the ciprofloxacin and azlocillin group but overall responses to staged antimicrobial therapy were comparable. The 16% response rate to azlocillin and netilmicin in microbiologically documented infections was low and was caused by the isolation of seven netilmkan-resistant Gram-positive organisms necessitating an early change in therapy. There were no differences in response rates between those patients experiencing their
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
Bakken, J. S., Sanders, C. C. & Thomson, K. S. (1987) Selective ceftazidime resiitasce in Escherichia coli: association with changes in outer membrane protein. Journal of Infectious Diseases 155, 1220-5. Bayer, A. S., Peters, J., Parr, T. R., Chan, L. & Hancock, R. E. W. (1987). Role of ^-lactamase in in vivo development of ceftazidime n^jftgriof in experimental Pseudomonas aentginosa endocarditis. Antimicrobial Agents and Chemotherapy 31, 253-8. Dance, D. A. B. (1991). Melioidoas: the tip of the iceberg? Clinical Microbiology Reviews 4, 52-60. Dance, D. A. B., Wuthiekanun, V., Chaowagul, W. & White, N. J. (1989). The antimicrobial susceptibility of Pseudomonas pseudomallei. Emergence of resistance in vitro and during treatment. Journal of Antimicrobial Chemotherapy 24, 295-309. Jarlier, V., Nicolas, M.-H., Fournier, G. & Philippon, A. (1988). Extended broad-spectrum ^-lactamases conferring transferrable resistance to newer /J-lactam agents in Enterobacteriactae: hospital prevalence and susceptibility patterns. Reviews of Infectious Diseases 10, 867-78. livennore, D. M., Chau, P. Y., Wong, A. I. W. & Leung, Y. K. (1987). 0-Lactamase of Pseudomonas pseudomallei and its contribution to antibiotic resistance. Journal of Antimicrobial Chemotherapy 20, 313-21. Sanders, C. C. & Sanders, W. E. (1985). Microbial resistance to newer generation /2-lactam antibiotics: clinical and laboratory implications. Journal of Infectious Diseases 151, 399-406. White, N. J., Dance, D. A. B., Chaowagul, W., Wattanagoon, Y., Wuthiekanun, V. & Pitakwatchara, N. (1989). Halving of mortality of severe metioidosb by ceftazidime. Lancet U, 697-701.
Correspondence
325
Table. Resolution of symptoms in response to antibiotic therapy Responses to first line
Overall response to staged antimicrobials*
Qprofloxatan + azlocillin micTobiologically documented infection clinical infection overall
10 27 37
5 (50%) 15 (55%) 20 (54%)
8 (80%) 24 (88%) 33 (89%)
Netilmicin + azlocillin microbiologically documented infection clinical infection overall
12 24 36
2 (16%) 11 (46%) 13 (36%)
12 (100%) 20 (83%) 32 (88%)
•See text
first or second episode and also no difference vancomycin (Smith et at., 1988), or benzyl between those undergoing bone marrow trans- penicillin (Kelsey et at., 1990), and supports plantation and those not. No serious drug the work of Philpott-Howard et at. (1990) who related adverse events were noted. Two infec- found comparable efficacy between the comtion related deaths occurred, one due to cytc- binations of azlocillin with either ciprofloxacin megalovirus and one suspected aspcrgillosis. or gentamicin. The use of ciprofloxacin in Bacteriological evidence of infection was conjunction with a ureidopenicillin such as obtained in 22 (30%) febrile episodes; 78% of azlocillin extends the Gram-negative cover of these were associated with culture of the combination without the potential risks of Gram-positive organisms, 22% with aminoglycoside toxicity. Gram-negative organisms. Four of the Ideas for empirical treatment may change Gram-positive isolates were resistant to cipro- with increasing use of ciprofloxacin for floxacin (all were coagulase-negative staphylo- prophylaxis during the period of neutropenia. cocci) but all Gram-negative isolates were Warren et at. (1990) report exclusively sensitive. Gram-positive breakthrough bacteraemias and From this we conclude that ciprofloxacin suggests the initial use of vancomycin and an plus azlocillin is safe and as effective as netil- ureidopenicillin in the empirical treatment of micin plus azlocillin for the empirical treat- febrile neutropenics. Septicaemias with ciproment of infections due to both Gram-positive floxacin resistant Gram-negatives remain a and Gram-negative bacteria in neutropenic theoretical possibility; surveillance cultures may alert clinicians to the colonization of patients. Deficiencies in the use of ciprofloxacin as patients with such organisms and enable treatmonotherapy for empirical treatment of infec- ment to be directed accordingly. tions have been encountered with the emerD. S. HYATT* gence of resistant coagulase-negative T. R. F. ROGERS' staphylococci (Oppenhcim et at., 1989) and D. M. MCCARTHY* also streptococci (Smith et at., 1986); its use in D. S. SAMSON* combination with a penicillin may be expected 'Department of Medical Microbiology to extend the therapeutic range against Charing Cross and Westminster Medical School, Gram-positive organisms. Development of 17 Horstferry Road. London SW1P 2AR; resistance in P. aeruginosa has also been ''Department of Haematology reported (Scully et at., 1986) and it may be Charing Cross Cross Hospital. Fulham Palace Road, prudent to combine ciprofloxacin with another London W6. UK anti-pseudomonal agent, such as a ureidopenicillin; synergistic activity between ciprofloxReferences acin and azlocillin has been observed in vitro against P. aeruginosa, Acinetobacter calcoace-Barnes, R. A. & Rogers, T. R. (1988). Response ticus var. anitratus and Staphylococcus aweus rates to a staged antibiotic regimen in febrile neutropenic patients. Journal of Antimicrobial (Moody, Peterson & Gerding, 1985). Chemotherapy 22, 759-63. Our work confirms the value of ciproflox- Hiopoulos, G. M., Gardella, A. & Moellering, R. C. acin in neutropenic patients as suggested (1984). In vitro activity of ciprofloxacin, a new carboxyquinolone antimicrobial agent earlier by its use in combination with either
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
No. of episodes
326
Correspondence Philpott-Howard, J. N., Barker, K. F., Wade, J. J., Kaamartlri, R. S., Smedley, J. C. & Mufti, G. J. (1990). Randomized multicentre study of dprofloxacin and aziocillin versus gentamidn and aziocillin in the treatment of febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 26, Suppl. F, 89-99. Scully. B. E , Neu, H. C , Parry, M. F. & Mandell, W. (1986). Oral dprofloxadn therapy of infections due to Pseudomonas aeruginosa. Lancet i, 819-22. Smith, G. M., Leyland, M. J., Farrell, I. D. & Geddes, A. M. (1986). PreUminary evaluation of dprofloxacin, a new 4-quinolone antibiotic, in the treatment of febrile neutropenic patients. Journal of Antimicrobial Chemotherapy 18, Suppl. D, 165-74. Smith, G. M., Leyland, M. J., Farrell, I. D. & Geddes, A. M. (1988). A clinical, microbiological and pharmacokinetic study of dprofloxacin plus vancomycin as initial therapy of febrile episodes in neutropenic patients. Journal of Antimicrobial Chemotherapy 21, 647-55. Warren, R. E., Wimperis, J. Z., Baglin, T. P., Constantine, G. E. & Marcus, R. (1990). Prevention of infection by dprofloxacin in neutropenia. Journal of Antimicrobial Chemotherapy 26, Suppl. F, 109-23.
Downloaded from http://jac.oxfordjournals.org/ at University of Lethbridge on September 11, 2015
Antimicrobial Agents and Chemotherapy 25, 331-5. Kelsey, S. M., Wood, M. E^ Shaw, £ , Jenkins, G. C. & Newland, A. C. (1990). A comparative study of intravenous dprfloxacin and benzylpenidllin venus netilmicin and piperacillin for the empirical treatment of fever in neutropenic patients. Journal of Antimicrobial Chemotherapy 25, 149-257. Klastersky, J., Glauser, M. P., Schimpff, S. C , Zinner, S. H., Gaya, H. and the European Organisation for Research on Treatment of Cancer Antimicrobial Therapy Project Group (1986). Prospective randomised comparison of three antibiotic regimens for empirical therapy of suspected bacteremic infection in febrile granulocytopenk patients. Antimicrobial Agents and Chemotherapy 29, 263-70. Moody, J. A., Peterson, L. R. & Gerding, D. N. (1985). In vitro activity of dprofloxacin combined with aziocillin. Antimicrobial Agents and Chemotherapy 28, 849-50. Oppenheim, B. A., Hartley, J. W., Lee, W. & Burnie, J. P. (1989). Outbreak of coagulate negative staphylococcus highly resistant to dprofloxacin in a leukaemia unit British Medical Journal 299, 294-7.
