1 CPL Associates LLC, 3980 Sheridan Drive, Suite 501, Amherst, NY 14226-1727; 2 The University at Buffalo School of Pharmacy, Buffalo, NY, USA
Received 24 February 2003; returned 15 April 2003; revised 21 May 2003; accepted 29 May 2003
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Abstract |
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Patients and methods: This non-randomized multicentre study included 100 consecutively identified patients with pneumonia caused by fluoroquinolone-susceptible (n = 50) or fluoroquinolone-resistant (n = 50) strains of P. aeruginosa. Medical records were examined for demographic, clinical and treatment variables including antibiotics received in the 30 days before the index respiratory or blood culture; AUICs were calculated for each patient using reported or derived MICs. Multivariate logistic and linear regressions were used to identify factors associated with successful clinical and microbiological outcomes.
Results: The study population was primarily elderly, frequently in a critical care unit, with low serum albumin and with a high probability of failure and mortality. Patients with pneumonia caused by fluoroquinolone-resistant P. aeruginosa were more likely to have received antibiotics within 7 days before the infection (P = 0.027); the antibiotic regimen was more likely to be of a weak potency (mean AUIC of 58 versus 169, P = 0.001) and to include levofloxacin (P < 0.0001) than what was administered to patients who became infected with a fluoroquinolone-susceptible strain. Regardless of susceptibility, a mean of between 2 and 3 weeks of directed antibiotic therapy was administered to each patient.
Conclusions: Pneumonia caused by fluoroquinolone-resistant P. aeruginosa is frequently associated with prior exposure to levofloxacin. Treatment of P. aeruginosa pneumonia is difficult and usually consists of combination regimens with multiple modifications.
Keywords: AUIC, predictive, outcomes
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Introduction |
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Although bacterial resistance is a complex, multi-factorial phenomenon, it is primarily associated with antibiotic use.35 Pharmacodynamic studies have characterized relationships between antibiotic concentration, antibacterial activity and bacterial resistance.614 The area under the 24 h plasma concentrationtime curve (AUC24) has been integrated with the MIC of a pathogen into a relationship described as the area under the inhibitory curve (AUIC).14 Routine exposure with antimicrobial regimens having low AUIC values is associated with the emergence of resistance.13,15
This association has been confirmed in epidemiological benchmarking studies. The impact of fluoroquinolone use on the susceptibility of P. aeruginosa was examined in 109 U.S. hospitals. The rate of P. aeruginosa resistance was <17% among the 76 hospitals that used ciprofloxacin as their primary fluoroquinolone, whereas hospitals that used ofloxacin as their primary fluoroquinolone had a >28% rate of fluoroquinolone-resistant P. aeruginosa (P = 0.04).16 A subsequent study of 174 U.S. hospitals included data on levofloxacin use. Preliminary results, presented at ICAAC, demonstrate that for every $US300 per occupied bed (OB) per year spent on ofloxacin or levofloxacin, fluoroquinolone-resistant P. aeruginosa increased 5.4% per year, a statistically significant and non-sustainable rate when considering the long-term usefulness of an agent.17 A similar increase in ciprofloxacin expenditures did not result in a statistically significant increase in P. aeruginosa resistance.17 Ciprofloxacin is a more potent agent against P. aeruginosa than either ofloxacin or levofloxacin.18
Determining the relationship between a specific antimicrobial agent and bacterial resistance cannot be fully appreciated without knowledge of prescribing patterns for various patient populations and disease states. This study was conducted to characterize specific antibiotic regimens used before patients developed a pneumonia caused by fluoroquinolone-susceptible or fluoroquinolone-resistant strains of P. aeruginosa. In addition, we sought to identify the antibiotic regimens used to treat the documented infections. Finally, we planned to determine microbiological, clinical and pharmacoeconomic outcomes and compare these results for the fluoroquinolone-resistant versus fluoroquinolone-susceptible cases.
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Patients and methods |
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Inclusion criteria
Patients were required to have a respiratory or blood culture positive for P. aeruginosa, as well as having a temperature >38°C (100.4°F) or <36.1°C (97°F), or leucocytosis (WBC > 10 x 109 leucocytes/L), or >10% bands at baseline. Patients were also required to have clinical evidence of pneumonia: chest radiographic examination demonstrating a new or progressive infiltrate, consolidation, cavitation, or pleural effusion; rales or dullness to percussion on physical examination of the chest, new onset of purulent sputum, or change in character of sputum. Isolation of P. aeruginosa had to be from a blood culture or an appropriately obtained respiratory sample, either: sputum (Gram stain results demonstrating >25 WBC and <10 epithelial cells/low powered field); endotracheal or transtracheal aspirate; bronchial brushing or lavage; or biopsy. The infection had to be of sufficient severity or complexity to warrant at least 3 days of antibiotic therapy.
Exclusion criteria
Patients less than 18 years of age or those having clinical AIDS (in addition to HIV, having an AIDS indicator condition), neutropenia (WBC < 1 x 109 leucocytes/L), or cystic fibrosis were excluded.
Data collection
Site investigators were asked to enter consecutive patients who fulfilled all inclusion/exclusion criteria. A case report form was then completed for each enrolled patient. Medical records were examined for patient-specific variables such as underlying medical pathology, antibiotics received in the 30 days before the culture, follow-up cultures, and outcome parameters. The patients movement between types of hospital units (ICU, step-down, general floor) was documented. Patients were followed until the test-of-cure visit (1014 days after receiving the last dose of antibiotics used to treat the P. aeruginosa infection), discharge, or death, whichever was reached first.
Calculation of AUIC
AUIC values were predicted using AUIC software (M.H. Adelman & J.J. Schentag, 19982001; available at www.schentag-ce.com). MIC values used in the computations were obtained from susceptibility testing carried out by the clinical laboratory at each study site. Derived MIC breakpoints19 were used for 31 resistant isolates where only an R, rather than the specific MIC, was reported. The AUIC software employs MIC50 distributions for imputing MIC values below breakpoint in a four-step approach (R/I/S/VS). Resistance is defined as a value >MIC90, intermediate is defined as a value MIC90 but >MIC50, susceptible is defined at the MIC50, and very susceptible is defined as the lowest MIC value found in the literature.
CLCR, updated each time a serum creatinine was obtained, was estimated using the method described by Jeliffe20 as adapted by Paladino et al.21 and Canaday et al.22 A serum creatinine value of 88.4 µmol/L was used in the calculation if one was not provided (n = 5). Consistent with standard practice, if the reported value was <88.4 µmol/L, the CLCR was estimated using 88.4 µmol/L. Total body drug CL was computed using population data.23 For combination therapy, AUIC values for individual agents with activity against P. aeruginosa were summed to provide a daily measure of exposure.24 The number of AUICs calculated per patient varied depending on the number of serum creatinine measurements (and consequent estimated CLCR), the number of MIC values, and the number of antibiotics administered; ranging from 1 to more than 60 AUICs per patient. To account for an entire period of drug therapy, the average daily AUIC was calculated by taking the total of daily AUICs divided by the number of days of treatment.
Clinical outcome evaluations
Patients were evaluated for their clinical response on the final day of anti-pseudomonal antibiotic therapy and at the test of cure visit or at discharge from the hospital, whichever was reached first. Clinical success was declared if complete resolution or clear improvement in all pre-therapy signs and symptoms were observed. Clinical failure resulted when persistence or progression of signs and symptoms of infection were noted, including: fever or leucocytosis; radiographic abnormalities; development of new pulmonary or extra-pulmonary clinical findings consistent with active infection; or death due to pneumonia or bacteraemia. Clinical relapse occurred when worsening or reappearance of some signs or symptoms followed an initial favourable response either during treatment or off therapy. Outcomes were unable to be determined when classification was precluded due to extenuating circumstances such as worsening co-morbidity (independent of bacterial infection) or patient lost to follow-up (e.g. transferred to another facility, or death occurring for non-infection-related reasons, during the study period).
Microbiological response
A positive baseline respiratory and/or blood culture provided the basis for evaluating microbiological results on the final day of anti-pseudomonal therapy and at the test-of-cure visit or at discharge, whichever was reached first. Eradication was declared if P. aeruginosa was eliminated from the initial infection site during or upon completion of therapy. Eradication was presumed if the patient was improved clinically and there was an absence of appropriate material for culture (e.g. sputum) or if further sampling of blood cultures was not clinically indicated. Failure to eradicate the P. aeruginosa from the initial infection site, with or without continued presence of signs of infection, resulted in a rating of persistence. Development of a new lower respiratory tract infection (documented by fever, chest radiogram, and/or auscultatory findings) or new bacteraemia during therapy or within 714 days after therapy had been completed, due to a new pathogen, was scored as superinfection. Development of a positive sputum culture with a bacterial strain other than P. aeruginosa, appearing >48 h after initiation of therapy, persisting in at least two repeated cultures, and not associated with fever, leucocytosis, persistence or progression of pneumonia, or evidence of infection at a distant site, was considered colonization. The microbiological response was unable to be determined if it was not possible to collect further cultures because of death, or the lack of opportunity, or the patient withdrew from the study, or the inability to obtain an adequate sputum sample in a patient with pneumonia who had failed clinically.
Statistical analysis
Multivariate logistic and linear regressions were used to identify factors significantly associated with the probability of clinical success, microbiological success (documented or presumed eradication), infection-related costs, and the number of infection-related hospital days (ICU and non-ICU). Independent variables considered include: study site, age, prior length of hospitalization, underlying medical conditions, baseline susceptibility of P. aeruginosa, prior antimicrobial treatment, infection site, AUIC for the antimicrobial agent(s) used before the culture, and the AUIC for the antimicrobial regimens used to treat the P. aeruginosa infections.
Institutional Review Board
The protocol was reviewed and approved by a properly constituted Institutional Review Board/Ethics Committee at each participating institution. As this was a non-interventional, data collection only study, expedited review was common; informed consent from each patient (or the patients legally authorized representative) was required at very few sites.
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Results |
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Demographic data and baseline clinical characteristics are shown in Table 1. As this was a non-randomized study, there are some disparities in the patient types. Of particular note, patients infected with fluoroquinolone-susceptible P. aeruginosa were more often in an intensive care unit at the time of infection (P = 0.001) and had more nosocomially-acquired infections (P = 0.037). There was a trend for a slightly lower serum albumin in patients infected with fluoroquinolone-resistant P. aeruginosa (P = 0.077).
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As shown in Table 1, patients infected with fluoroquinolone-resistant P. aeruginosa were more likely to have received an antibiotic in the 30 days before developing the infection (P = 0.027), especially a fluoroquinolone (P = 0.006), which was levofloxacin most frequently (P < 0.0001). No patients infected with fluoroquinolone-susceptible P. aeruginosa received levofloxacin; seven of the 50 patients received ciprofloxacin (P = 0.182). Regimens are further characterized by antibiotic class, and combinations used, in Table 2.
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Antimicrobial regimens administered before culturing P. aeruginosa differed in ultimate potency against the pathogen. Strains that were susceptible had been exposed to a mean AUIC of 169, whereas strains that were resistant had been exposed to a mean AUIC of only 58 (P = 0.001).
Antibiotics used to treat P. aeruginosa
There were no conspicuous differences among the regimens employed to treat the infections caused by P. aeruginosa (Table 3). The AUIC values for the various regimens did not differ between groups. The mean ± S.D. AUIC of antibiotic regimens used to treat fluoroquinolone-susceptible strains was 203 ± 125 and the mean ± S.D. AUIC of antibiotic regimens used to treat fluoroquinolone-resistant strains was 179 ± 247 (P = 0.5). Monotherapy was used to treat eight of 50 (16%) patients in each group. A fluoroquinolone was used in 15 of 50 cases (30%) of fluoroquinolone-resistant infections; each instance in combination with one or more antibiotics and before the culture result. In nine patients, the fluoroquinolone was subsequently discontinued. In five patients fluoroquinolone therapy was continued to treat or provide empiric coverage for other Gram-negative pathogens. However, in one patient fluoroquinolone therapy was continued, and in a further two patients a fluoroquinolone was added after an initial unsatisfactory response, as part of combination therapy to treat the fluoroquinolone-resistant P. aeruginosa, each achieving eventual success.
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As shown in Table 4, patients infected with fluoroquinolone-susceptible P. aeruginosa did less well at the end of the initial treatment regimen than those infected with fluoroquinolone-resistant P. aeruginosa, 66% versus 92%, respectively (P = 0.001). However, there was no difference at the conclusion of all treatment, including modified regimens, 74% versus 88%, respectively (P = 0.074). Patients infected with fluoroquinolone-resistant P. aeruginosa were more likely to be discharged, 82% versus 38%, respectively (P = 0.005) and more likely to survive, 92% versus 74%, respectively (P = 0.012) than patients infected with fluoroquinolone-susceptible P. aeruginosa. This will be addressed in the Discussion.
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As expected, the microbiological outcomes closely mimicked the clinical outcomes. At the end of initial therapy, 55% of the fluoroquinolone-susceptible P. aeruginosa isolates were eradicated or presumed eradicated, compared to 88% of the fluoroquinolone-resistant strains (P = 0.003). However, there was no difference at the conclusion of all treatment, including modified regimens, as 24% of the fluoroquinolone-susceptible P. aeruginosa isolates and 12% of the fluoroquinolone-resistant strains persisted (P = 0.145).
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Discussion |
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Regardless, a number of interesting observations can be made, and several results confirm findings from pharmacological (e.g. AUIC),615 microbiological [e.g. mutant prevention concentration (MPC)],2528 and epidemiological studies.16,17,29,30 These diverse studies consistently demonstrate that resistant pathogens are more likely to follow treatment with less potent compounds, especially at lower AUIC values. In this study, antibiotic regimens (regardless of class) administered before culture were more likely to be associated with a resistant strain if the AUIC was <100. Levofloxacin was administered before culturing fluoroquinolone-resistant strains of P. aeruginosa more frequently than ciprofloxacin, which is a more potent antimicrobial versus P. aeruginosa.18 Moreover, a study of the MPC found that levofloxacin was more likely to select for resistant strains of P. aeruginosa than ciprofloxacin.27
Although numerous surveillance programmes monitor antimicrobial susceptibility, few include antimicrobial usage and thus are unable to detect whether any association exists between antibiotic use and bacterial resistance. Two programmes coordinated by our laboratory, the National Nosocomial Resistance Surveillance Group (NNRSG) and the Benchmarking Program have examined this relationship since 1993. The NNRSG and the Benchmarking Program each consist of a large collaborative network of clinical pharmacists and physicians with an interest in antimicrobial stewardship and microbial resistance.
The relationship between fluoroquinolone expenditures/OB and susceptibility of P. aeruginosa to fluoroquinolones was described previously.16,17 A decrease in P. aeruginosa susceptibility to ciprofloxacin was associated with increasing ofloxacin (P = 0.0001) or levofloxacin (P = 0.036) expenditures/OB but not with increasing ciprofloxacin expenditures/OB (P = 0.22).16,17 An association between levofloxacin use and P. aeruginosa resistance was also found by the Centers for Disease Control and Prevention (CDC) Project ICARE,16,17,29,30 as well as by researchers at individual institutions.30,31
Many patients receiving an antibiotic regimen with an AUIC > 125 developed a fluoroquinolone-susceptible infection. There are several possible explanations for this. The mean duration of prior antibiotic therapy was only 3 days, probably not sufficient to stem a brewing infection. This study was comprised of elderly patients with a mean serum albumin of <30 g/L; 78% of the patients in the susceptible group were located in a critical care unit.
Combination regimens, including as many as four antibiotics, were used in the treatment of 84% of patients. Modification of regimens was common, implying that these infections are not easily treated. Details of the consequences of infections caused by fluoroquinolone-resistant P. aeruginosa are rarely found in the literature. In one study of hospitalized patients, baseline cultures were tested for resistance to ceftazidime, ciprofloxacin, imipenem and piperacillin.1 Of 489 patients, 144 had a resistant organism at baseline (29.4%) whereas another 30 patients (6.1%) began with susceptible strains but had resistance emerge later. There were no differences in mortality rates (7.5% versus 7.6%), mean length of stay (LOS) (7 days for each), or mean per-patient hospital charges ($US14 415 versus $US15 358) between patients with susceptible isolates and those with resistance at baseline, respectively. However, a significant difference was found between patients with resistance that emerged after the first culture versus the other two groups. Mortality rose to 27% (P < 0.05) and LOS was extended to 24 days (P < 0.05).1 Using U.S. average daily hospital costs, patients who developed P. aeruginosa resistance during or after treatment for initially susceptible infections had a mean estimated hospital cost of $US67 728 and an incremental cost of $US52 370.2
In our study, more susceptible strains were nosocomially-acquired than resistant strains. Carmeli et al. and others have suggested that a nosocomial infection is a more powerful determinant of outcome than a resistant pathogen.1,32 An international panel noted that deaths caused by resistance are a fraction of deaths caused by nosocomial infections.32 This may provide a further explanation for our findings, as it was not expected that outcomes of infections caused by susceptible strains would be worse than those from resistant strains. Additional credence to this can be inferred from the fact that potency (as measured by AUIC) of the antibiotic regimens used to treat the documented P. aeruginosa infections did not differ whether the strain was susceptible or resistant to fluoroquinolones.
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Summary |
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Acknowledgements |
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Footnotes |
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References |
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