a Department of Haematology, b Medical Microbiology and c Hospital Pharmacy, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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Abstract |
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Introduction |
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To investigate if there is a place for the use of glycopeptides on empirical grounds, i.e. based solely on the presence of (persistent) fever, in the absence of methicillin-resistant Gram-positive bacteria, we conducted a prospective, double-blinded trial in which neutropenic patients with persistent axillary temperature >38°C after 7296 h of imipenem monotherapy were randomized between addition of teicoplanin or placebo.
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Materials and methods |
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After giving informed consent, consecutive adult patients (>18 years) with haematological disorders and neutrophil count <500 cells/mm3, or <1000 cells/mm3 and decreasing as a result of chemotherapy, were randomized between the addition of either teicoplanin 400 mg daily or placebo when their axillary temperature remained 38°C or higher after 7296 h of monotherapy with iv imipenem 500 mg qid. Computer-assisted randomization was performed by the hospital pharmacy. On the first day, teicoplanin or placebo was administered twice. In responsive patients the assigned treatment (placebo as well as teicoplanin) was continued for five afebrile days; non-responders after 72 h were considered failures and received further treatment, which often consisted of (non-blinded) teicoplanin in combination with antifungal or antiviral drugs as clinically indicated.
Patients with the following characteristics were excluded from randomization: (i) identification of microorganisms not susceptible to teicoplanin or imipenem in clinical isolates, the latter because it was felt unethical to treat patients in the placebo arm with inactive drugs only; (ii) high suspicion of fungal infection based on clinical and radiological grounds; (iii) sign and symptoms of central iv line infection even in the absence of a microbiological diagnosis, because these infections are mostly caused by methicillin-resistant microorganisms; (iv) clinical deterioration, which made randomization unethical in the opinion of the attending physician; (v) known allergy to imipenem or teicoplanin; (vi) renal failure necessitating control of blood levels of the glycopeptide; (vii) concomitant severe cardiac, hepatic or neurological disease. Interim analyses blinded to the clinical investigators were performed to exclude excess mortality in the placebo arm, but no check for excess morbidity because of practical restraints and because this was part of the evaluation.
Definitions and evaluation
At the outset, fever necessitating empirical imipenem therapy was defined as an otherwise unexplained single axillary temperature reading of >38.5°C or temperature >38°C for 24 h. After initiation of treatment, temperature of at least 38°C on two consecutive readings 48 h apart was considered persistent fever. Response was a fall in temperature below 38°C within 3 days from randomization and lasting for at least 48 h, in the absence of a change of the assigned regimen. Persistent fever and change or addition of antibiotics on clinical or microbiological grounds were called a failure. At the end of the neutropenic episode or at discharge from hospital, the overall response was evaluated, i.e. whether or not the patient had survived. For patients who did not survive, it was defined whether death was due to infection or to other causes. When granulocytes increased >500 cells/mm3 for three consecutive days, regeneration of the bone marrow was presumed.
When bacteria not susceptible to imipenem were isolated or when other exclusion criteria were met after the randomization but before the first dose of the trial medication, the patient was excluded from evaluation; demonstration after the first dose leading to a change of the assigned study drugs was considered a failure. Febrile episodes were subdivided into: microbiologically documented infection (MDI), when a causative microorganism was isolated; clinically documented infection (CDI), when clinical or radiological signs and symptoms of a localized infection were present but no causative organism was identified; and fever of unknown origin (FUO), in the absence of criteria for either MDI or CDI. A positive blood culture without signs of localized infection represented a bacteraemia (in the case of CoNS at least two positive blood cultures were considered necessary). Relapse was the recurrence of the same infection or FUO within 14 days of randomization, before the end of neutropenia; superinfection was the occurrence of a new infection during that period. A patient could be randomized only once during the same neutropenic episode.
Statistical analysis
Patient populations and results were analysed by 2 testing. With the included patient numbers a difference between study arms of 28% was demonstrable with a P value of <0.05 and a power of 85%. Data were analysed on an intention-to-treat basis.
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Results |
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In 115 patients, 125 randomizations took place. Eleven patients (8.8%, seven teicoplanin and four placebo) were excluded because of major protocol violation, i.e. essential data missing (two), absence of neutropenia (three), treatment with antibiotics in addition to imipenem (two) and recurrence of fever while on imipenem, administration of open teicoplanin, presence of CoNS before randomization, and randomization on the first day of fever (once each), leaving 114 evaluable episodes, of which 56 were assigned to teicoplanin and 58 to placebo. Characteristics of the study population are given in Table I. The majority (103; 90%) had oral antibacterial prophylaxis with ciprofloxacin or co-trimoxazole; in addition, 73 (64%) received oral roxithromycin or iv penicillin as antistreptococcal prophylaxis; 25 received iv amphotericin B 0.3 mg/kg, 15 were given oral fluconazole and seven itraconazole as antifungal prophylaxis. Most patients had a Hickman line (83; 73%), 58 (51%) were treated in rooms with laminar air flow, 13 (11%) received a growth factor, mostly G-CSF. Most items were well matched but the age was slightly higher in the teicoplanin arm and the majority of acute lymphoblastic leukaemias was assigned to the placebo arm; these differences were not statistically significant. Furthermore, the populations were well distributed with respect to type and localization of infection but the teicoplanin arm had a double number of lower respiratory tract infections (12 versus six MDI + CDI) whereas all Hickman line infections occurred in the placebo arm. This latter difference was of borderline significance (P = 0.06).
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Table II shows that 44.6% and 46.6% of patients became afebrile within 72 h after randomization without there being a difference between those given teicoplanin and those given placebo. In the placebo group more relapses were seen, including four FUOs and two infections with CoNS, whereas in the teicoplanin group more superinfections occurred, including three (versus one) fungal infections, two (versus one) Hickman line infections, two (versus two) herpes labialis, one tuberculosis arising at regeneration and one candida vaginitis. These differences were not statistically significant.
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Of the six fungal infections in the teicoplanin arm (three at the onset of fever and three as superinfection later on) four proved fatal. The one fungal infection in the placebo arm also had a fatal outcome whereas a patient with a fungal superinfection survived. Other causes of death in the teicoplanin arm were candida septicaemia and respiratory distress syndrome; in the placebo arm, one patient died as a result of tumour progression and two as a result of cardiac events that were not related to the infectious episode.
Microbiological data
Table III enumerates the 34 microorganisms that were isolated in 30 febrile episodes and were considered to cause the infection at the time of randomization. Although most patients received prophylactic antibiotics, more than half of the clinical isolates still showed Gram-positive bacteria that appeared to be resistant to the prophylactic antibiotic in most cases; incidentally, Gram-negative bacilli were found mainly in patients not taking prophylaxis. All CoNS with one exception were resistant to cloxacillin and imipenem but all were susceptible to teicoplanin. The seemingly poor response of CoNS even in the teicoplanin arm (1/4) was due to the fact that, according to the protocol, isolation of CoNS was a reason to stop the trial medication. With the exception of CoNS, Gram-positives responded well in both arms (5/6 in the teicoplanin arm and 3/3 in the placebo arm) but Gram-negatives apparently did not (neither of two Pseudomonas aeruginosa infections on teicoplanin because of concomitant infection with fungi and Pneumocystis carinii, respectively, and one of two on placebo because of imipenem-resistant S. maltophilia).
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Discussion |
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Teicoplanin is shown in several studies to have equal antibacterial efficacy, better tolerance and easier administration in comparison with vancomycin.19,20 Therefore, there are no reasons to suspect that use of vancomycin instead of teicoplanin would change the outcome. A large multicentre study with the same basic design as the present one but with vancomycin instead of teicoplanin is in progress (A. Cometta, personal communication) and will, it is hoped, confirm our results.
Three days after randomization, about half of the patients were afebrile but there was no difference between teicoplanin and placebo. A relatively low response rate is consistent with our previous experience18 and that of others21 when nonresponders to initial broad-spectrum antibiotics were given vancomycin or teicoplanin. That an equal number of placebo patients became afebrile suggests that many neutropenic patients respond more slowly than expected to the initial imipenem, although in about a third the drop of fever could be caused by the simultaneous regeneration of granulocytes. Evaluation of the efficacy of antibiotics up to 4 days after the start of empirical therapy is probably too early. A significant proportion of patients might still respond later or show a spontaneous' improvement. Again, empirical stepping-up with glycopeptides in patients who obviously have no life-threatening infection and who have survived the initial period of high risk seems not to be indicated. In the majority of the nonresponders there was no identifiable cause for the lack of response and it is possible that their fever did not have an infectious origin. Besides, a number of patients seemed to need other antimicrobial drugs instead of glycopeptides. Especially when the lower respiratory tract was involved the response rate to antibacterial drugs was poor, mainly because these infections were often caused by fungi. In these patients, institution of antifungal drugs without further delay appears mandatory. It is widely accepted that antifungals should be strongly considered when neutropenic patients remain febrile despite 1 week of broad-spectrum antibiotics.22,23 In patients with pulmonary abnormalities this period could be shortened by omitting a therapeutic trial with glycopeptides.
Aspergillosis was considered the primary cause of infection in three nonresponders from the teicoplanin arm, and during follow-up three superinfections with Aspergillus spp. occurred in teicoplanin responders. With the small numbers concerned, this did not differ significantly from the placebo arm, where one primary and one secondary aspergillosis were diagnosed. The higher incidence in the teicoplanin group could be a coincidence not directly related to the use of teicoplanin but a causal relationship cannot be excluded as antibiotics such as teicoplanin contribute to the emergence of fungal infections. This could be an additional argument not to initiate glycopeptide therapy on empirical grounds.
Several other studies provide arguments against the use of glycopeptides as initial empirical therapy in febrile neutropenia1316,24 even after bone marrow transplantation.25 The present data strongly suggest that glycopeptides should not be used on empirical grounds for continuation therapy in nonresponders either. This corresponds with the experience of others, who found no benefit for vancomycin or teicoplanin for neutropenic patients in the absence of Gram-positive infection.21,2628 Our results suggest that glycopeptide use can be further reduced because Gram-positive infections with streptococci and S. aureus are highly susceptible to ß-lactam antibiotics in most institutions provided that MRSA (methicillin-resistant S. aureus) is not prevalent (which is the case at our institution). When MRSA is found in surveillence cultures of neutropenic patients, special precautions such as isolation are necessary and glycopeptides have to be applied, probably from the first day of fever onwards.29 A variable proportion of CoNS are susceptible to cloxacillin and imipenem in vitro and some may argue that even CoNS are no indication for glycopeptides unless resistance to other antibiotics used for primary intervention is proven. However, it seems that glycopeptides cannot and should not be withheld in this situation. The susceptible bacteria are often only a subpopulation and resistant bacteria are quickly selected. In this study, most isolated CoNS were resistant to imipenem and cloxacillin; the few patients with CoNS or Hickman line infection who seemed to respond initially to placebo relapsed later.
By limiting glycopeptides to the known and preferably bacteriologically documented indications, the direct and indirect costs of antibiotic therapy in neutropenic patients can be reduced and, most importantly, the emergence of resistance to glycopeptides will probably be delayed, prevented or even reversed.30,31
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Acknowledgments |
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Notes |
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Present address. Internal Medicine, Delfzicht Ziekenhuis, Jachtlaan 50, 9934 JD Delfzijl, The Netherlands.
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References |
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Received 25 October 1999; returned 29 December 1999; revised 19 January 2000; accepted 28 January 2000