a Duke University Medical Center, Box 3306, Durham, NC 27710 and Campbell University School of Pharmacy, Buies Creek, NC, USA; b Duke University Medical Center, Durham, NC, c Bethesda Memorial Hospital, Boynton Beach, FL, USA; d Aventis Pharmaceuticals, Bridgewater, NJ, USA
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Abstract |
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Introduction |
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Quinupristindalfopristin (Synercid), the first injectable streptogramin antibiotic, demonstrates in vitro activity against a variety of Gram-positive organisms including staphylococci, streptococci and enterococci (except Enterococcus faecalis).4 In particular, quinupristindalfopristin is active in vitro against S. aureus, with an MIC90 of 1.0 mg/L.4 Quinupristindalfopristin also demonstrates consistent in vitro activity against MRSA, and therefore has a potential role in the treatment of infections due to these organisms.4,914 However, published reports on the treatment of staphylococcal infections with quinupristindalfopristin are few.
The primary objective of this study was to evaluate the efficacy and safety of quinupristindalfopristin for the treatment of infections caused by MRSA in patients participating in a worldwide emergency-use protocol. A secondary objective was to observe the influence of resistance phenotypes on treatment outcome.
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Materials and methods |
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Before any study-related procedures were carried out, written informed consent was obtained from each patient or his/her agents (except where exempted by local regulations). The recommended quinupristindalfopristin treatment regimen was 7.5 mg/kg iv every 8 h for a duration judged to be appropriate based on the severity of infection, the anatomical site involved, the comorbidities and the patient's initial response to treatment. Clinical and microbiological assessments were performed at baseline, during study drug treatment, within 24 h after the last study drug infusion (end-of-treatment visit) and 721 days post-treatment (test-of-cure visit). Clinical and laboratory adverse events judged to be related to treatment or that led to treatment discontinuation were recorded.
Pathogen identification and antimicrobial susceptibility to comparative antibiotics were determined by broth microdilution or agar macrodilution methods according to NCCLS guidelines18 (for all centres in the USA), or locally defined susceptibility test methods. No central testing laboratory was used. S. aureus resistance to methicillin was defined as MIC 16 mg/L. The resistance phenotype of MRSA isolates to macrolidelincosamidestreptogramin type B (MLSB) antibiotics was inferred from their resistance to erythromycin and clindamycin as follows: MLSB-susceptible (MLSBS), susceptible to both erythromycin and clindamycin; MLSB-inducibly resistant (MLSBI), erythromycin resistant, clindamycin susceptible; MLSB-constitutively resistant (MLSBC), resistant to both erythromycin and clindamycin. The MIC breakpoints for resistance used were erythromycin
8 mg/L and clindamycin
4 mg/L. Baseline isolates were not routinely tested for susceptibility to quinupristindalfopristin.
Assessment of efficacy outcomes
The clinical response to quinupristindalfopristin was assessed for each infection at the test-of-cure assessment (or end-of-treatment if the patient did not progress to test-of-cure). Definitions were as follows. Cure: resolution of all signs and symptoms related to the original infection(s), with no new signs or symptoms; improvement: in patients not cured, resolution or reduction of the majority of signs and symptoms relating to the original infection, with no new or worsened signs or symptoms; failure: either (i) no resolution and no reduction of a majority of signs and symptoms, (ii) a worsening of one or more signs and symptoms, or (iii) new signs or symptoms associated with the original infection or a new infection; indeterminate: inability to assess the patient's signs and symptoms because of lack of information, or interference in the assessment by concomitant medical or surgical conditions. Indeterminate responses were classed as failures for the calculation of success rates in the all-treated population (see below), but were not included in the calculation for the evaluable population.
The bacteriological response of each isolate was determined by an internal steering committee, based on culture results obtained within 3 days before or after the day of the clinical response assessment, and was assigned as one of the following. Eradicated: culture obtained from original site(s) and no growth of MRSA; presumed eradicated: no culture obtained, but the clinical response was cure or improvement; persistence: culture obtained, growth of MRSA; presumed persistence: no culture obtained, but clinical response was failure; indeterminate: no culture obtained, and clinical response was indeterminate.
The by-patient bacteriological response was derived from the bacteriological responses for the primary infection site(s) and the blood, if applicable. In the case of multiple indications, the worst outcome was used. Bacteriological success was defined as a response of eradication or presumed eradication.
The overall response was defined as success if a clinical response of either cure or improvement together with a by-patient bacteriological response of eradicated or presumed eradicated were observed.
Assessment of evaluability
For a patient to be considered clinically evaluable, the following were required: (i) documented infection with MRSA isolated any time before, or within 2 days after, the start of quinupristindalfopristin therapy, and either documented treatment failure or intolerance to all other clinically appropriate antibiotics; and (ii) signs and symptoms of infection consistent with the specified indications. For bacteraemia of unknown source, two positive blood cultures obtained within 7 days before, or 2 days after, initiation of therapy were required; (iii) clinical response of cure, improvement or failure (i.e. not indeterminate); (iv) quinupristindalfopristin administration for 5 days; (v) mean quinupristindalfopristin daily dose of
15 mg/kg; (vi) not
10% of scheduled quinupristindalfopristin doses missed; (vii) no scheduled dose missed on three consecutive days; (viii) no more than one course of quinupristindalfopristin therapy during the study; (ix) test-of-cure assessment performed 321 days after the last dose of quinupristindalfopristin, or, for patients who discontinued study treatment, end-of-treatment assessment performed between 1 day before and 2 days after the last dose of quinupristindalfopristin.
For a patient to be bacteriologically evaluable, the following were required: (i) they must have been clinically evaluable; (ii) bacteriological specimens had to establish the diagnosis within the period from 96 h before starting treatment to day 2 of treatment; and (iii) test-of-cure procedures had to be completed such that the bacteriological response could be assessed, using cultures obtained within 3 days before or after the clinical response assessment.
Patient populations
The two patient populations were defined as follows. (i) All-treated population: all patients who received any amount of study medication and for whom data were available were included in the all-treated population. Each patient in the all-treated population also had at least one isolate of MRSA. Patients with indeterminate clinical and/or bacteriological responses were retained in the denominator as failures for the calculation of success rates for this population. (ii) Evaluable population: consisted of patients who met both the clinical and bacteriological evaluability criteria. All patients receiving study medication were eligible for safety analysis.
Superinfection.
Superinfection was defined as a Grampositive pathogen not present at baseline but present at the primary infection site at the test-of-cure assessment along with clinical evidence of continued infection. Some superinfecting organisms were tested for susceptibility to quinupristindalfopristin. NCCLS-approved interpretive criteria were not in place at the time of the study, so the provisional MIC breakpoint for resistance to quinupristin dalfopristin of 4.0 mg/L was used.19
Statistical methods.
Descriptive statistics were used to characterize the patient population, clinical response and incidence of adverse reactions. A two-tailed 95% confidence interval (CI) was calculated for the primary and selected secondary efficacy outcome variables. CIs were also derived for indications with 10 or more patients.
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Results |
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A descriptive summary of study drug administration is contained in Table II. Quinupristindalfopristin was administered every 8 h to the majority (76/90, 84.4%) of patients at a mean (± S.D.) daily dose and duration of 20.2 ± 2.9 mg/kg for 28.5 ± 22.3 days. The duration of quinupristindalfopristin treatment varied for different infection sites. For those patients with bone and joint infection who completed the study, the mean duration of quinupristindalfopristin treatment was 45.2 ± 30.6 days, while the corresponding values for patients with skin and skin structure infection and respiratory tract infection were 24.7 ± 18.2 days and 18.2 ± 9.1 days, respectively. The mean interval from the date of hospitalization to the initiation of quinupristindalfopristin was c. 3 weeks.
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Table III contains a description of the types of infections treated with quinupristindalfopristin in this trial. Bone and joint infections constituted 40/90 (44.4%) and 13/27 (48.1%) of the all-treated and clinically and bacteriologically evaluable patient populations, respectively. These included osteomyelitis (n = 24), prosthetic joint infection (6), septic arthritis (6) and post-surgical mediastinitis (4). Skin and skin structure infections made up 15/90 (16.7%) and 6/27 (22.2%) of patients in each population, respectively. Respiratory tract infections [10/90 (11.1%) and 6/27 (22.2%), respectively] included pneumonia (n = 8) and pleurisy (2). As previously stated, each patient required a baseline culture positive for MRSA to be included in the evaluation. Staphylococcus epidermidis and vancomycin-resistant E. faecium were also isolated as a causative pathogen in one patient each. MRSA bacteraemia was identified in 43 patients (47.8%) in the all-treated group. Of patients clinically and bacteriologically evaluable, MRSA was isolated from blood cultures of patients with bone and joint, respiratory tract, and skin and skin structure infections, central-catheter-related bacteraemia and endocarditis.
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The clinical responses were also determined for all-treated and evaluable patients according to resistance markers for MLSB antibiotics, and are summarized in Table IV. Although numbers are small for two groups, the presence of the MLSBC phenotype did not appear to affect the clinical response.
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Discussion |
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Several studies have reported increased morbidity and mortality associated with MRSA compared to methicillin-susceptible S. aureus (MSSA) infections. For example, the European Prevalence of Infection in Intensive Care Study, involving >10000 patients from 1417 intensive care units in 17 Western European countries, found that patients with MRSA infections were less likely to survive than those with MSSA.22 For lower respiratory tract infections, the risk of mortality was three times higher in patients with MRSA compared with those with MSSA. A casecontrol study of S. aureus primary bacteraemia in the USA concluded that MRSA infection resulted in an approximately three-fold increase in direct costs compared with MSSA.23 Many MRSA strains are resistant to all clinically available antibiotics with the exception of the glycopeptides vancomycin and teicoplanin. In cases of treatment failure or intolerance to these agents, few proven alternative therapeutic options are available.
The in vitro activity of quinupristindalfopristin has been studied extensively.4,914 Jones and colleagues4 examined its activity against 10216 clinical isolates of MSSA and MRSA from the USA and Canada. The MIC50 and MIC90 reported for quinupristindalfopristin for MRSA were 0.5 and 1.0 mg/L, respectively, and did not differ significantly from those reported in methicillin-susceptible isolates. Over 99% of these isolates were considered to be susceptible to quinupristindalfopristin. Similar MIC50 and MIC90 values have been reported recently in a study of 251 MRSA isolates.10 A worldwide evaluation of MRSA susceptibility to quinupristindalfopristin has shown in vitro resistance rates of <1%.14 MRSA isolates with reduced susceptibility to vancomycin have also been reported to be susceptible to quinupristindalfopristin in vitro.13,24
Previously published data regarding the use of quinupristindalfopristin in the treatment of MRSA infections are limited. Successful outcomes were reported in three of nine patients with catheter-related bacteraemia caused by S. aureus in a phase II dose-finding trial of either 5 or 7.5 mg/kg quinupristindalfopristin administered every 8 h.25 However, it was unclear from this report how many of these were MRSA. In a comparative study involving quinupristindalfopristin in the treatment of hospitalized patients with complicated skin and skin structure infections, only nine patients assigned to the quinupristindalfopristin treatment group had MRSA infection.26 A bacteriological success rate of 77.8% was reported in these patients, with an overall response rate for all infections caused by S. aureus in this study of 70/109 (64.2%). The efficacy rate for quinupristindalfopristin in combination with aztreonam for nosocomial pneumonia caused by MRSA was 6/20 (30.0%), compared with 8/18 (44.4%) for patients treated with a combination of vancomycin plus aztreonam.27 However, these results should be interpreted cautiously because of the small number of patients. The bacteriological success rate for patients with S. aureus bacteraemia in global phase III studies of quinupristin dalfopristin has been reported to be 8/14 (57.1%).28
In the present study, quinupristindalfopristin therapy was associated with a satisfactory overall response of 71% in the all-treated population and 67% in the evaluable population. Such response rates must be interpreted in light of the severity of illness, the high prevalence of significant comorbidities, and the study population which included only treatment failures or treatment-intolerant patients. Our experience is comparable to that previously reported for treatment with either vancomycin or teicoplanin. Average clinical response rates of c. 78% for vancomycin and teicoplanin were reported in a meta-analysis of 11 randomized trials, involving over 1000 patients, published between 1987 and 1995.29 For those patients that could be identified as having deep-seated infection, including bone and joint infection, endocarditis and central catheter infection, the response rates were much lower than for the patient population as a whole (44% when vancomycin and teicoplanin results were combined). The highest clinical response rates in the present study were observed for patients with skin and skin structure infection, urinary tract infection, and other infections. The clinical response rate for bacteraemic patients in the all-treated population was only slightly lower than that for the entire population. Lower success rates were documented for patients with endocarditis and bacteraemia of unknown source. For patients with endocarditis, only about half in the all-treated population were considered to be clinical successes. Furthermore, both of the bacteriologically evaluable patients with endocarditis were clinical failures. Published data regarding the successful use of quinupristin dalfopristin in the treatment of MRSA endocarditis are limited to a single case report.30 Our limited experience suggests that quinupristindalfopristin as monotherapy may not be able to consistently sterilize cardiac vegetations, but further data are needed.
The relatively long and highly variable interval between hospitalization and initiation of quinupristindalfopristin therapy in this study probably reflects both the nosocomial acquisition of infection and the initiation of quinupristin dalfopristin therapy after one or more treatment failures with other antibacterial agents. The data regarding community-acquired as opposed to nosocomially acquired MRSA infections were not specifically collected in this study and thus cannot be addressed.
Response rates in our study were apparently not affected by MLSB resistance phenotype, suggesting that the efficacy of quinupristindalfopristin was not significantly reduced by the presence of resistance to streptogramin type B antibiotics. This result is consistent with in vitro findings that the synergism between the two components of quinupristindalfopristin is retained for bacterial strains that show resistance to the quinupristin component on its own.31 Although S. aureus strains with MLSB resistance are still susceptible to quinupristindalfopristin, its bactericidal activity may be affected by the MLSB resistance phenotype.32 Quinupristindalfopristin has been reported to show reduced in vitro bactericidal activity against S. aureus strains that are constitutively resistant to macrolides (MLSBC phenotype).33 This finding might be significant for treating indications such as endocarditis when bactericidal activity is important. In recent in vivo rat models of endocarditis, optimized to closely simulate human pharmacokinetics, with erythromycin-resistant MRSA, combination therapy with quinupristindalfopristin plus cefepime and quinupristindalfopristin plus cefamandole was superior to either antibiotic alone,3436 but clinical data are not available.
The adverse event profile is similar to that reported in other quinupristindalfopristin emergency-use patients.37 A substantial majority of the adverse events observed in the present study reflect the high severity of illness in the population studied. Adverse clinical events of note included nausea, arthralgia and myalgia. The aetiology of these arthralgias and myalgias is presently under investigation, but they are reversible upon treatment discontinuation. In earlier comparative trials of quinupristindalfopristin, a high proportion of patients receiving the drug via peripheral venous catheters experienced local adverse events, and administration by a central venous route has therefore been recommended.37 Venous adverse events were not analysed in the present study because the great majority of patients received the study medication via a central catheter.
In summary, the data from this study indicate that quinupristindalfopristin is a therapeutic option for patients with certain MRSA infections, including strains with the MLSBC phenotype. The presence of multiple comorbidities in many patients, combined with the mortality rate of 25.8% in the all-treated population, illustrates the severity of illness of the population treated. Furthermore, all patients had failed, or were judged not suitable for, alternative antibiotic therapy, and thus the response rates obtained under such circumstances for selected infections were excellent. Efficacy rates for skin and skin structure and for bone and joint infections were generally favourable. However, response rates were lower for patients with endocarditis, in which rapidly bactericidal therapy may be needed; the effectiveness of quinupristin dalfopristin against MRSA strains of the MLSBC phenotype for this important infection remains to be fully assessed. Combination antimicrobial therapy may prove necessary in endocarditis patients. Additional comparative clinical trials with vancomycin and newer classes of agents with activity against Gram-positive pathogens are needed to further define the role and impact of quinupristindalfopristin in the treatment of MRSA infections.
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Appendix |
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Acknowledgments |
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Notes |
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Synercid Emergency-Use Study Group Investigators are listed in the Appendix.
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References |
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Received 25 May 2000; returned 20 July 2000; revised 31 August 2000; accepted 11 September 2000