Rapid Responses to:
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lactam monotherapy versus 
Rapid Responses: Rapid Responses published:
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The dangers of broad spectrum antibiotics
- Stephanie J Dancer (27 May 2003)
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Beta lactum monotherapy is not adequate to treat to all cases of febrile neutropenia
- SATYA P YADAV, Sydney, NSW 2145, Australia (29 May 2003)
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Reply to rapid responses
- Mical Paul (6 June 2003)
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Risk of aminoglycoside nephrotoxicity in neutropenic fever may be overestimated
- RICHARD P COOKE, Richard J Grace, Pamela A Gover (18 June 2003)
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In case of septic shock, beta lactam monotherapy would be dangerous
- Joseph C Watine (24 June 2003)
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Stephanie J Dancer, Consultant Microbiologist Scottish Centre for Infection & Environmental Health, Clifton House, Clifton Place, Glasgow G3 7LN
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EDITOR - The meta-analysis regarding b lactam monotherapy versus b lactam-aminoglycoside combination therapy misses an important point.1 The broad spectrum monotherapy endorsed is far more likely to select for antimicrobial resistance than a combination regimen. Prescribers do not always realise that giving a patient antibiotics not only affects that patient and his environment, but also anyone else who comes into contact with that patient and his environment.2 Antibiotics seriously disturb the normal intestinal flora. This disturbance facilitates bacterial overgrowth with emergence of resistant microorganisms. These organisms themselves can cause serious infections, but they will also encourage the transfer of resistance factors to other bacteria. The more broad spectrum an agent, the more effect it will have on the intestinal flora. Carbapenems are associated with an increase in hospital-acquired infections due to Stenotrophomonas maltophilia.3 This particularly resistant Gram-negative organism will also overgrow in response to treatment with third-generation cephalosporins, along with a host of other pathogens, namely Clostridium difficile, multiply resistant coliforms, methicillin-resistant Staphylococcus aureus (MRSA), yeasts and enterococci.2 These may spread to other patients, cause outbreaks and contaminate the environment long-term. The risk of selecting resistant organisms is reduced by using a combination of antibiotics, particularly b lactam-aminoglycoside combinations.4 Such combinations also demonstrate synergistic bactericidal activity.4 Whilst there may be little difference in outcome to an individual patient, antibiotic prescribers have a duty to consider the future treatment of infection, because we appear to be running out of therapeutic options. The ecological benefits of narrow spectrum â lactam- aminoglycoside regimens become even more attractive when managers realise the cost-savings they represent.5 (1) Paul M, Soares-Weiser K, Leibovici L. â lactam monotherapy versus â lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003; 326:1111-5. (2) Dancer SJ. The problem with cephalosporins. J Antimicrob Chemother 2001; 48:463-78. (3) Sanyal SC, Mokaddas EM. The increase in carbapenem use and emergence of Stenotrophomonas maltophilia as an important nosocomial pathogen. Chemother 1999; 11:28-33. (4) Barriere SL. Therapy of choice for the empiric treatment of the febrile neutropenic patient. Drug Intell Clin Pharm 1986; 20:767-9. (5) Lemmen SW, Hafner H, Kotterik S, Lutticken R, Topper R. Influence of an infectious disease service on antibiotic prescription behaviour and selection of multiresistant pathogens. Infection 2000; 28:384-7. Competing interests: None declared |
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SATYA P YADAV, oncology fellow The Children's Hospital at Westmead, Sydney, NSW 2145, Australia
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It was very interesting to read the paper written by Mocal Paul,Karla & Leonard on antibiotic efficacy in Febrile neutropenia. The points which point to flaws in the study are: 1) All the 47 trials cannot be pooled together for analysis as the cut off for treating febrile neutropenia varies from absolute neutrophil count of 1500 to 500.Many of them may not have needed antibiotics.They have included studies over last 20 yr and a lot has happened in the field of antibiotics in these 20 years. They have included 6 unpublished studies which may or maynot be of international standard. 2)All cause fatality is not a true reflector of the success or failure of treatment of febrile neutropenia as many other factors would affect that. Overall mortality of 6% is too much for febrile neutropenia if its alone the cause. 3) Outcome in the form of treatment failure is not valid as in both the arms the failure rate is close to 40% which is too much by current standards of treatment of febrile neutropenia. May be the reason for that is inadequate coverage for gram positive bacteria on most treatment regimen in all trials included. 4) As all studies cannot be pooled together so it cannot be concluded that beta lactum monotherapy for febrile neutropenia is adequate. Competing interests: None declared |
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Mical Paul, Consultant in Infectious Diseases Infectious Diseases Unit; Rabin Medical, Centre, Beilinson Campus; Petah-Tikva, 49100 Israel.
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I have read with interest the points raised by Dr. Dancer and Dr. Yadav. Dr. dancer raises the important issue of reducing bacterial resistance emergence with the use of combination antibiotic therapy vs. broad-spectrum monotherapy. Development of bacterial resistance should indeed be a major factor underlying decisions concerning antibiotic selection. Actually, the cost of resistance, considering both the individual patient and the environment, surpasses probably several folds other costs associated with antibiotic use. Despite many reviews discussing this potential advantage of combination therapy, data to support it are surprisingly meager. There is a rationale underlying the concept, strengthened perhaps by our experience with other infections, such as M. tuberculosis and HIV. A mathematical model predicts reduced resistance development with combination therapy, assuming no colonization, and unless resistance to the two drugs is carried on the same plasmid (1). Few in-vitro and animal studies have shown this (2-4). However, projection of all these models to clinical effect is not straightforward, since interactions in-vivo will depend on dosing, timing, pharmacokinetic and pharmacodynamic properties of the antibiotics. I am not aware of clinical trials proving that beta-lactam- aminoglycoside combinations reduce resistance development, despite the underlying rationale. Elphick et al. showed in a meta-analysis comparing beta-lactam-aminoglycoside combination therapy to beta-lactam monotherapy that combination therapy was associated with a significantly lower carriage rate of resistant Pseudomonas aeruginosa at 2-8 weeks post- therapy, but not at end of treatment (5). Another clinical trial showed that replacing ceftazidime with cefepime-amikacin as empirical regimen for febrile neutropenia lowered Enterobacteriaceae resistance rates (6), while other clinical trials could not demonstrate a reduction of resistant isolates with combination therapy (7-8). In our meta-analysis we tried to compare resistance induction following combination vs. monotherapy using available data. Superinfections were reported in the trials and did not differ between the two regimens. Colonisation rates were only rarely reported. In 2 studies assessing 152 patients, colonisation with resistant Gram-negatives occurred among 1 vs. 5 patients with combination and monotherapy, respectively. Both were assessed at end of therapy. What can be inferred from these data? Looking at the superinfection comparison we know that for the individual patient, at the time of the infectious episode, consequences of resistant isolate selection do not differ between the treatment regimens. With respect to other possible adverse effects of resistance development, such as environmental effects and further infections for the individual patient, we remain in the dark. There is no debate that antibiotic use should be restricted to the minimum needed. While using combination treatment may decrease resistance development to each of its components, it still mandates use of two antibiotic classes (9). Studies comparing antibiotic regimens should perform and report surveillance cultures to improve our understanding of resistance development following antibiotic use. Dr. Yadav addressed potential flaws in our analysis. The studies, included in the review, defined neutropenia as less than 500-1000 neutrophils/ mm3 (full text table 1). We performed a subgroup analysis of patients with severe neutropenia (<100 neutrophils/mm3), which did not show that results differ in this patient group (full text table 2). Unpublished trials were included to prevent publication bias. Sensitivity analyses show that results obtained from unpublished material do not differ form results obtained from the published studies (full text figure 7). We have decided to compare all-cause and not infection-related mortality because infection-related mortality may be biased. It is difficult, if not impossible, to establish the exact cause of death in cancer patients, frequently treated with multiple medications and chemotherapy, with neutropenia, and severe infections. All-cause mortality is indeed diluted. However, this is the reason for randomisation. If the randomisation is proper, mortality should distribute randomly among the patients. If the treatment regimen makes a difference, the mortality part related to infection will differ between the study groups. The consequence of comparing all-cause mortality is that a large sample size is needed to detect a difference in infection-related mortality. We agree that treatment failure should not be the main outcome assessed. However, this was the primary outcome in all existing trials. 1. Bonhoeffer S, Lipsitch M, Levin BR. Evaluating treatment protocols to prevent antibiotic resistance. Proc Natl Acad Sci U S A 1997;94(22):12106-11. 2. Wu YL, Scott EM, Po AL, Tariq VN. Ability of azlocillin and tobramycin in combination to delay or prevent resistance development in Pseudomonas aeruginosa. J Antimicrob Chemother 1999;44(3):389-92. 3. Gruneberg RN, Emmerson AM. Prevention of emergence of bacterial resistance with the combination of sulphamethoxazole and trimethoprim. Eur J Clin Microbiol 1982;1(3):155-8. 4. Pechere JC, Marchou B, Michea-Hamzehpour M, Auckenthaler R. Emergence of resistance after therapy with antibiotics used alone or combined in a murine model. J Antimicrob Chemother 1986;17 Suppl A:11-8. 5. Elphick HE, Tan A. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software. 6. Mebis J, Goossens H, Bruyneel P, Sion JP, Meeus I, Van Droogenbroeck J, et al. Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients. Leukemia 1998;12(10):1627-9. 7. Chandrasekar PH, Crane LR, Bailey EJ. Comparison of the activity of antibiotic combinations in vitro with clinical outcome and resistance emergence in serious infection by Pseudomonas aeruginosa in non- neutropenic patients. J Antimicrob Chemother 1987;19(3):321-9. 8. Nichols L, Maki DG. The emergence of resistance to beta-lactam antibiotics during treatment of Pseudomonas aeruginosa lower respiratory tract infections: is combination therapy the solution? Chemioterapia 1985;4(1):102-9. 9. Leibovici L, Berger R, Gruenewald T, Yahav J, Yehezkelli Y, Milo G, et al. Departmental consumption of antibiotic drugs and subsequent resistance: a quantitative link. J Antimicrob Chemother 2001;48(4):535-40. Competing interests: None declared |
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RICHARD P COOKE, Consultant Medical MIcrobiologist Eastbourne District General Hospital, Eastbourne, East Susex. BN21 2UD, Richard J Grace, Pamela A Gover
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Editor - The systematic review by Paul et al on single versus combination antibiotic therapy in neutropenic fever noted a significant risk of renal failure with either multiple or single dose aminoglycoside administration.1 However, in attempting to determine the cause of nephrotoxicity in neutropenic febrile patients, it is often difficult to assess if high aminoglycoside concentrations have caused nephrotoxicity or are elevated as a result of renal impairment due to other reasons.2 Also, previously published meta-analyses on once-daily dosing aminoglycoside regimes have suggested that single-dosing may be less nephrotoxic than multiple doses.3, 4 Nevertheless, because of concerns over aminoglycoside toxicity, many units prefer to use antibiotic monotherapy for neutropenic fever. In our own haematology unit, the risk of nephrotoxicity developing during treatment for neutropenic fever has been recently assessed over a five year period. All patients are usually treated with a combination of beta-lactam and gentamicin (5mg/kg) antibiotic therapy. Gentamicin exclusion criteria include underlying myeloma, previous or concurrent nephrotoxic chemotherapy, age 80 years or over, previous gentamicin trough levels >2mg/l and baseline serum creatinine levels >200µmol/l.5 Gentamicin administration and blood level monitoring are nurse-led following the unit’s protocol. Aminoglycoside therapy is usually limited to 5 days. Liposomal amphotericin is used in preference to standard amphotericin B. Using gentamicin trough levels of >2mg/l as a surrogate marker for impending aminoglycoside nephrotoxicity, 1,289 gentamicin trough samples were assessed. Only 68 (5.3%) were found to be >2mg/l. 57 high trough levels (relating to 50 patients) were able to be investigated further. 48 (84%) of these samples were elevated 24 hours after the first dose of gentamicin which would have been immediately discontinued. Only 14 patients with trough levels >2mg/l had concurrent serum creatinine levels exceeding 200µmol/l (range 211-497, mean 288). Using standard definitions for nephrotoxicity,3,4 gentamicin nephrotoxicity may have occurred in only approximately 1% of treated neutropenic febrile episodes. The risk of nephrotoxicity with once-daily aminoglycoside therapy can be kept to an absolute minimum in neutropenic febrile patients if specific patient exclusion criteria are applied, specialist nursing staff are closely involved in antimicrobial administration and trough level measurements are instituted early. Future studies on the risks of aminoglycoside toxicity in neutropenic fever should, in our view, apply similar criteria. RPD Cooke, Consultant Medical Microbiologist1, RJ Grace, Consultant Haematologist2, PA Gover, Consultant Haematologist2 Departments of Medical Microbiology1 and Haematology2, East Sussex Hospitals NHS Trust, District General Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD 1. Paul M, Soares-Weiser K, Leibovie L. ß lactam monotherapy versus ß lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis. BMJ 2003; 326: 1111-1115 2. MacGowan A, Reeves D. Serum aminoglycoside concentrations: the case for routine monitoring. J Antimicrob Chemother 1994; 34: 829-837 3. Hetela R, Dink T, Cook DJ. Once daily aminoglycoside dosing in immunocompetent adults. Ann Intern Med 1996; 124: 717-725 4. Barza M, Ioannidid JPA, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312: 338-345 5. Cooke RPD, Grace RJ, Gover PA. Audit of once-daily dosing gentamicin therapy in neutropenic fever. Int J Clin Pract 1997; 51: 229- 231 Competing interests: None declared |
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Joseph C Watine, Consultant Hôpital de Rodez, France
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Betalactam-aminoside combination therapy may be given for another reason that was not examined by Paul et al's. Indeed, such combinations can kill most bacteria in less than an hour, whereas betalactams alone take at least 18 hours to do so. It has repeatedly been suggested that such rapid speeds of bactericidal activity are crucial in case of patients with septic shock, or severe sepsis. It is therefore perhaps regrettable that Paul et al.'s, in their statistical analysis, did not separate such patients from other patients at lower risk from death. Competing interests: None declared |
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