Use of meropenem 3 g once daily for outpatient treatment of infective exacerbations of bronchiectasis
Elizabeth S. R. Darleya,*,
Karen E. Bowkera,
Andrew M. Loveringa,
John E. Harveyb and
Alasdair P. Macgowana
a Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol, Department of Medical Microbiology, and
b Department of Respiratory Medicine, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK
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Abstract
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Meropenem administered as a single iv 3 g dose once every 24 h was used to treat nine ambulatory patients with infective exacerbations of bronchiectasis. Serum meropenem concentrations were measured before dosing and at 30 min after each 30 min infusion. Mean pre-dose concentrations were <0.1 mg/L and mean post-dose concentrations 93.9 ± 29.5 mg/L (95% confidence interval (CI) 86.2101.6, n = 59). A pathogen was cultured from sputum in six patients and eradicated (<100 cfu/g sputum) in all but one by day 6 of therapy. Previous work on animals has shown that a bacteriostatic effect is seen with meropenem when t > MIC is greater than 2030% of the dose interval. In these nine patients, this could be achieved and was associated with successful outcome for pathogens for which MICs are
0.5 mg/L. Therefore, once-a-day meropenem therapy may be a useful option for outpatient treatment for isolates for which MICs are
0.5 mg/L.
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Introduction
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Carbapenems, unlike other ß-lactam antibiotics, are known to exhibit both concentration-dependent killing and a post-antibiotic effect (at concentrations of <50 mg/L and <75 mg/L, respectively) against Gram-negative organisms.1 Linear kinetics has been demonstrated with meropenem in man following infusions of up to 2 g and may be expected with even higher doses.2 The pharmacodynamic properties of meropenem indicate that twice-daily dosing may be more appropriate than the recommended 8-hourly dosing schedule, a theory supported by in vitro models comparing the bactericidal effect of a simulation of 3 g/day given as three doses, two doses or one dose.3 A bacteriostatic effect has been shown in animal studies when the meropenem concentration exceeds the MIC (t > MIC) for at least 20% of the dose interval, dependent on the organism and isolate tested.4 Together, these factors raise the question of whether high dose, once-daily meropenem would be as efficacious as conventional doses, allowing selected patients who might otherwise require a period of admission for iv antibiotic therapy to be treated on an outpatient basis.
The use of meropenem 3 g once daily in the treatment of a patient with an infective exacerbation of bronchiectasis caused by Pseudomonas aeruginosa has previously been reported.5 Following the success of this dosing regimen, a further eight patients have been treated for respiratory infections on an outpatient basis. Here we report the results of this treatment.
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Materials and methods
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Adult bronchiectatic patients were referred for once daily meropenem by the respiratory department after treatment of an infective exacerbation had failed with conventional oral therapy. Having excluded patients with abnormal liver or renal function, or a history of ß-lactam allergy, four male and five female patients, average age 60.4 ± 11.8 years (95% confidence interval (CI) 51.369.5) were treated. All were considered well enough to remain at home for the duration of treatment and were keen to do so. The study was carried out with approval from the Local Research Ethics Committee.
Patients were given 3 g meropenem reconstituted in 100 mL of 0.9% saline as a 30 min infusion, at the same time each day, for 710 days. Serum for meropenem assay was collected immediately pre-infusion and 30 min post-infusion for each dose given. When necessary, serum was frozen overnight before performing the assay by HPLC according to the method previously described by Lovering et al.6 A post-dose mean and the likely expected range within 95% CI were calculated from the results. Sputum was cultured initially by standard methods to identify a pure or heavy growth of a respiratory pathogen before the start of treatment. Thereafter, sputum was collected daily until the treatment was completed (scanty growth of mixed respiratory flora was ignored). Each sample was homogenized 50:50 with Sputasol (Oxoid, Basingstoke, UK). Neat sputum, 1/10 and 1/100 dilutions in sterile saline were plated on to pseudomonas-selective agar (Oxoid), blood agar base (Oxoid) supplemented with 8% whole horse blood (TCS Microbiology, Buckingham, UK) or chocolate blood agar (as above), according to the pathogen, using a spiral plater (Don Whitley Scientific, Shipley, UK). Counts were made of potential pathogens isolated. MIC was determined for all isolates of Pseudomonas spp. cultured on first isolation (method as described by Holt et al.).7 The MICs for the two other pathogens isolated, Haemophilus influenzae and a penicillin-sensitive Streptococcus pneumoniae were not determined; however, the MIC90 of meropenem for both these species has previously been shown to be 0.13 mg/L.8
The half-life of meropenem has previously been calculated to be 79.6 ± 19.5 min (95% CI 63.395.9) in a pharmacokinetic study on surgical patients of a comparable age to the bronchiectatic patients.6 The assumption was made that the linear kinetics observed when meropenem is given in doses of up to 2 g could be applied to a 3 g dose. This half-life (and the shortest and longest possible half-life from the 95% CI range) was applied to plot time against concentration for the predicted minimum, maximum and mean post-dose levels that could be expected following a 3 g dose. Having determined the MIC for the four isolates of Pseudomonas spp., the minimum and maximum period of time that the concentration would exceed the MIC could be calculated and compared with the clinical outcome in these patients.
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Results and discussion
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Pretreatment sputum culture yielded P. aeruginosa in four cases, one patient had H. influenzae and one S. pneumoniae (penicillin sensitive). No additional pathogens were cultured from sputum during the meropenem treatment period. The results of sequential quantitative sputum counts for each patient are shown in Table I
. In three cases no pathogen was identified from the initial sputum despite clinical signs of an infective exacerbation. In five of the six cases where pathogens were isolated, there was a rapid decline in the daily viable counts/mL sputum (initial counts of 106109 cfu/mL). By day 6 the pathogen was undetectable in the sputum of these patients and a subjective improvement in symptoms was reported in eight of the nine treated cases. In the four cases of Pseudomonas spp. infection the MIC was 0.06 mg/L for one isolate, 0.12 mg/L for two and 1.0 mg/L for one (patient 8). In the last case the P. aeruginosa persisted in significant numbers until the tenth day of treatment and this was thus considered a microbiological treatment failure. Unfortunately, this isolate was lost on subculture before the MIC determination could be repeated.
Eight of the nine patients agreed to have two blood tests each day for pre- and post-dose assay. Each patient provided 820 serum samples over the course of treatment (Table II
). Overall, the pre-dose concentration was <0.1 mg/L on each occasion and the 30 min post-dose concentration was in the range 42.5172.0 mg/L, average 93.9 ± 29.5 mg/L (95% CI 86.2101.6, n = 59). Three of the four patients with Pseudomonas spp. infection had serum samples collected for pre- and post-dose assay. Patient 1 had a mean pre-dose concentration of 135.6 ± 25.9 mg/L (95% CI 117.1154.2), patient 5 a mean pre-dose concentration of 77.4 ± 143 mg/L (95% CI 72.996.8) and patient 8 a mean pre-dose concentration of 84.9 ± 29.5 mg/L (95% CI 86.2101.6). The T > MIC for an isolate of a given MIC was then calculated by plotting concentration against time using the mean pre-dose concentration and the mean calculated half-life for meropenem. Thus T > MIC for an isolate for which the MIC was 0.25 mg/L is 51% (range 4362), T > MIC for an isolate for which the MIC was 0.5 mg/L is 45% (range 3955) and T > MIC for an isolate for which the MIC was 1 mg/L is 40% (range 3449). The range given in each case is taken from two further calculations using the extremes of values within the 95% CI for the calculated half-life and expected post-dose (i.e. plotting the lowest peak with the shortest half-life and plotting the highest peak with the longest half-life). Considering the individual case of patient 8, in whom the Pseudomonas sp. was not eradicated, a T > MIC of 32.6% was calculated using the MIC of 1 mg/L and mean peak of 84.9 mg/L.
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Table II. Meropenem serum concentrations (mg/L) before and 30 min after a 3 g infusion over 30 min Patient number
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In total, eight of the nine patients referred for once-daily meropenem were effectively treated. The failure to eradicate the infection in patient 8 can be compared with animal studies, which demonstrated that a bacteriostatic effect can be expected only when the time that serum meropenem concentration exceeds the MIC is greater than 20%, dependent on the species and the isolate.4 The treatment failure in patient 8 may therefore be attributed to the relatively high MIC for the pathogen (1 mg/L), as the serum meropenem concentrations were not lower than those observed in other patients. Although the mean time that the concentration exceeds the MIC is 40%, it may actually be as low as 34% for an organism for which the MIC is 1 mg/L. In this particular case, the time interval during which the drug concentration was below the MIC must have been c. 1215 h (i.e. 60%), and in all cases the mean pre-dose meropenem concentration was below the lower limit of detection of <0.1 mg/L. However, when comparing these results with the animal model it is important to note that the inoculum load in the mice was 107 cfu in thigh or lung, but in the case of our bronchiectatic patients, the initial inoculum load varied between 7.1 x 106 and 4.6 x 109 cfu/mL sputum. Furthermore, the reported endpoint of the mouse model was a static effect at 24 h, but the endpoint of this study was bacterial killing.
A post-antibiotic effect would probably have prolonged the effect of meropenem for a relatively short period, but this was not investigated in this study.
Patients with chronic respiratory disease, such as bronchiectasis, tend to acquire increasingly resistant pathogens as the course of their disease progresses and the number of antibiotic courses prescribed accumulates. At this point, treatment is often limited to iv antimicrobial agents, which usually warrants a period of admission to hospital. In patients who are otherwise well enough to remain at home this may have a significant impact on their quality of life and also incurs the risk of acquiring nosocomial super-infection. Furthermore, the potential cost benefits of treating patients outside hospital cannot be overlooked. For example, 90 bed-days were saved simply by managing these nine patients as outpatients.
These results show that meropenem, given as a once-daily dose of 3 g, has a useful role in the outpatient management of respiratory infections. This dose was well tolerated by patients and was equally acceptable to nursing staff who were involved in administering the infusion. However, when a pathogen for which the MIC is relatively high is cultured, e.g. a Pseudomonas sp., it is recommended that the MIC should be determined and known to be
0.5 mg/L before proceeding with outpatient treatment with 3 g once-daily meropenem.
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Notes
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* Corresponding author. Tel: +44-117-959-5651; Fax: +44-117-959-3154.

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References
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Received 9 April 1999;
returned 6 August 1999; revised 17 September 1999;
accepted 2 October 1999