Infectious Diseases in Clinical Practice:
Clinical Outcomes in Patients With Ceftriaxone-Resistant Streptococcus pneumoniae Pneumonia
Wenzler, Eric PharmD, BCPS*; Goff, Debra A. PharmD, FCCP*; Bazan, Jose A. DO†; Bauer, Karri A. PharmD, BCPS*
From the Departments of *Pharmacy and †Internal Medicine, Division of Infectious Diseases, The Ohio State University Wexner Medical Center.
Correspondence to: Karri A. Bauer, PharmD, BCPS, Infectious Diseases, The Ohio State University Wexner Medical Center, 410 W 10th Ave, Room 368 Doan Hall, Columbus, OH 43210. E-mail: Karri.Bauer@osumc.edu.
D.A.G. serves on the advisory boards of Astellas, Nanosphere, Cubist, Forest, and Merck and has received grants from Cubist and Merck. K.A.B. has attended speakers’ bureau for Merck, Astellas, and Forest and has received grants from Cubist and Merck.
The other authors have no funding or conflicts of interest to disclose.
Multiple in vitro studies have demonstrated Streptococcus pneumoniae resistance to β-lactams, including ceftriaxone. The clinical impact of resistance has not been fully evaluated in patients with pneumonia caused by drug-resistant strains of S. pneumoniae.
Adult inpatients 18 or older and younger than 89 years with a diagnosis of pneumonia plus a respiratory culture positive for S. pneumoniae between January 2007 and September 2012 were evaluated. Patients with pneumonia due to ceftriaxone-resistant (minimum inhibitory concentration >1 µg/mL) S. pneumoniae (CRSP) were compared with those with ceftriaxone-susceptible S. pneumoniae (CSSP). Statistical significance was ascertained using 2-tailed χ2 or Fisher exact test.
Thirty patients were evaluated: 10 with CRSP and 20 with CSSP. No patient with CRSP had prior ceftriaxone exposure. Seven CRSP patients (70%) achieved a clinical cure compared with 14 CSSP patients (70%) (P = 1.00). Time to clinical cure for CRSP was 4 (1–5) days compared with 8 (3–12) days for CSSP (P = 0.51). Length of stay and infection-related length of stay were 17 days (9–23) and 9 days (7–13) for patients with CRSP, respectively, compared with 15 (8–20) days and 8 (7–13) days for patients with CSSP (P = 0.46, 0.74). No patient with CRSP died or was readmitted for pneumonia. Of the 10 CRSP isolates, 100% were resistant to azithromycin, 90% to penicillin, and 70% to cefepime.
Although differences in clinical outcomes were not observed, isolates resistant to ceftriaxone were more likely to be multidrug resistant. As the proportion of pneumococcal isolates with elevated minimum inhibitory concentrations to β-lactams continues to rise, treatment options may become more limited.
Pneumonia has become the first infectious disease targeted by the Centers for Medicare & Medicaid Services to improve quality of care and patient outcomes. Pneumonia accounts for significant morbidity, mortality, and health care costs with an average length of stay (LOS) of 5.2 hospital days per patient, resulting in greater than $3.5 billion in health care costs annually in the United States.1,2Streptococcus pneumoniae is one of the most commonly isolated pathogens associated with pneumonia.2 Recently, increasing rates of antimicrobial resistance including multidrug resistance, defined as nonsusceptibility to at least 1 agent in 3 or more antimicrobial categories, have been demonstrated.3 In 2008, 28% of pneumococcal isolates were resistant to at least 1 antibiotic, whereas 11% were multidrug-resistant.4 Over the past several decades, treatment failures due to resistance have been reported with infections due to S. pneumoniae, including meningitis and otitis media. However, the clinical impact of resistance has not been fully elucidated in patients with pneumonia caused by multidrug-resistant strains of S. pneumoniae.4
Ceftriaxone, a third-generation cephalosporin, is commonly used in the treatment of pneumonia due to S. pneumoniae. Resistance to β-lactams, including ceftriaxone, is mediated by successive alterations in essential penicillin binding proteins.5 Nationally, resistance rates to ceftriaxone among S. pneumoniae isolates approach 10%.6 At the Ohio State Wexner Medical Center (OSUWMC), increasing rates of ceftriaxone-resistant S. pneumoniae (CRSP) have been observed. The emergence of resistance to ceftriaxone is of significant concern as patients with pneumonia are often treated with this agent before pathogen identification or susceptibility data. Currently, there are limited studies comparing clinical outcomes in patients with pneumonia due to CRSP (minimum inhibitory concentration [MIC], >1 µg/mL) and ceftriaxone-susceptible S. pneumoniae (CSSP).7
MATERIALS AND METHODS
This study was a retrospective nonequivalent comparative study conducted at OSUWMC, a 1250-bed tertiary care academic medical center located in Columbus, Ohio. The study period was from January 1, 2007, to September 30, 2012. The study was approved by the Office of Responsible Research Practices institutional review board with a waiver of consent granted. The primary objective of the study was to compare clinical cure between patients with CRSP pneumonia to those with CSSP pneumonia. Secondary objectives included time to clinical cure, LOS, infection-related LOS, in-hospital mortality, and 30-day readmission for pneumonia. Susceptibility to ceftriaxone, penicillin, azithromycin, sulfamethoxazole/trimethoprim, tetracycline, cefepime, moxifloxacin, and vancomycin was defined according to the Clinical Laboratory and Standards Institute8 as determined by Microscan WalkAway System (Siemens Diagnostics, Tarrytown, NY).
Patients were adult inpatients 18 or older and younger than 89 years with a diagnosis of pneumonia plus a respiratory culture positive for S. pneumoniae. Respiratory samples obtained included expectorated sputum of acceptable quality with purulence and a Gram stain consistent with S. pneumoniae, bronchoalveolar lavage with 105 colony-forming units/mL or greater or a protected specimen brush with 103 colony-forming units/mL or greater.
Demographic data and clinical outcomes were collected from the patient’s electronic medical record. Data collected included age, sex, Charlson Comorbidity Index,9 Pneumonia Severity Index (PSI) class (calculated as the worst physiological score within 24 hours of culture positivity),10 prior hospitalization within 90 days, prior antibiotic therapy within 90 days, intensive care unit (ICU) admission, ICU LOS, and antibiotic therapy and susceptibilities. Pneumonia was defined as presence of new or increasing pulmonary infiltrate(s) on chest radiograph or chest computed tomography scan consistent with pneumonia and 3 or more clinical signs or symptoms consistent with a lower respiratory tract infection (ie, new or increased cough, purulent sputum or change in sputum character; auscultatory findings consistent with pneumonia [eg, rales, egophony, consolidation]; dyspnea, tachypnea, or hypoxemia [O2 saturation <90% on room air or Po2 <60 mm Hg]; oral temperature >38°C [>38.5°C rectally or tympanically] or hypothermia [<35°C]; white blood cell [WBC] count >10,000 cells/µL or <4500 cells/µL, >15% immature neutrophils [bands] irrespective of WBC count).11 Community-acquired pneumonia (CAP) was defined as pneumonia that occurred in patients 48 hours or less after admission or that was incubating at the time of admission who did not meet the definition for health care–associated pneumonia (HCAP).12 Hospital-acquired pneumonia (HAP) was defined as pneumonia that occurs 48 hours or more after admission that was not incubating at the time of admission. Health care–associated pneumonia was defined as pneumonia in any patient who was hospitalized in an acute care hospital for 2 or more days within 90 days of the infection; resided in a nursing home or long-term care facility; received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection; or attended a hospital or hemodialysis clinic. Ventilator-associated pneumonia (VAP) was defined as pneumonia that arose more than 48 to 72 hours after endotracheal intubation.13 Clinical cure was defined as the resolution of all signs and symptoms consistent with a lower respiratory tract infection, WBC less than 10,000 cells/µL, and absence of oral temperature of more than 38°C for 24 consecutive hours. Time to clinical cure was defined as the time from antibiotic administration directed at pneumonia to resolution of signs and symptoms of pneumonia. Length of stay was defined as the difference between admission and discharge date. Infection-related LOS was calculated as the difference between antibiotic initiation and discontinuation or discharge, whichever was sooner.
Differences between groups were explored using a Wilcoxon rank sum test for continuous variables and a χ2 test for categorical variables. A 2-tailed α of 0.05 or less was considered statistically significant. Categorical data are presented as frequency (%), and continuous data with skewed distribution are presented as median (interquartile range) as appropriate. All data analyses were performed using SPSS Statistics, IBM Software, Version 20.0 (SPSS Inc, Chicago, IL).
During the study period, 10 patients with CRSP were identified and compared with 20 patients with CSSP. The 20 patients with CSSP were randomly selected from a database of patients with CSSP during the same period. There were no differences in baseline demographics or clinical characteristics as described in Table 1. There was no difference between the study groups with respect to age or PSI risk class. Overall, 30-day mortality rate as predicted by PSI risk class was the same between the 2 groups (Table 2). Five patients (50%) with CRSP had a polymicrobial infection compared with 9 CSSP patients (45%). The effect of a polymicrobial infection on patient outcomes was likely minimal, given that the majority of patients were treated with broad-spectrum antibiotics. Twenty-five patients (83%) received a β-lactam empirically, 16 (53%) of whom received piperacillin/tazobactam. Clinical cure was achieved in 70% of patients in both groups (Table 3). One patient (10%) with CSSP was readmitted for pneumonia within 30 days after leaving against medical advice with no antibiotics. Of the CRSP isolates, 10 (100%) were resistant to azithromycin, 9 (90%) to penicillin, 9 (90%) to sulfamethoxazole/trimethoprim, 9 (90%) to tetracycline, and 7 (70%) to cefepime (Fig. 1). Of the CSSP isolates, 9 (45%) were resistant to azithromycin, 5 (25%) to penicillin, 11 (55%) to sulfamethoxazole/trimethoprim, 6 (30%) to tetracycline, and 2 (10%) to cefepime. No resistance to vancomycin or moxifloxacin was observed in either group. Ten patients (50%) with CSSP had an S. pneumoniae isolate with an MIC of 0.25 µg/mL or less, 1 (5%) had an MIC of 0.047 µg/mL, and 9 (45%) had an MIC of 1 µg/mL. Three CRSP patients (30%) had an MIC of more than 2 µg/mL, and 7 (70%) had an MIC of 2 µg/mL.
There are limited studies evaluating the clinical outcomes in patients with CRSP pneumonia compared with patients with CSSP pneumonia. We observed an overall clinical cure rate of 70% with no difference observed between groups. The lack of difference in clinical cure can be explained by the observation that few patients empirically received ceftriaxone. All patients had pneumonia that required hospitalization and thus received aggressive empirical antibiotic therapy, which reduced the likelihood that a patient would receive a drug to which the pathogen was resistant. This is evident by the fact that more than half of the patients were admitted to the ICU, and the median PSI class (IV) was significantly higher than that reported in previous studies.11,14 We observed no significant differences in secondary outcomes including time to clinical cure, LOS, infection-related LOS, in-hospital mortality, and 30-day readmission for pneumonia. Interestingly, no patient with CRSP pneumonia had prior ceftriaxone exposure within the 90 days before inclusion in the study. This lack of observed difference in clinical outcomes between the two groups may be analogous to previous studies that have also not demonstrated a negative impact on outcomes in patients with penicillin-resistant invasive pneumococcal infections treated with β-lactams.15,16 This inconsistency between in vitro resistance and clinical outcomes prompted the Clinical Laboratory and Standards Institute to revise the breakpoints for penicillin in 2008.17 Choi et al18 conducted a retrospective study evaluating the clinical impact of antibiotic therapy in patients with both penicillin-susceptible and nonsusceptible S. pneumoniae bacteremia based on the revised breakpoints. The authors determined that ceftriaxone resistance was an independent risk factor for 30-day mortality after controlling for age, underlying diseases/conditions, and initial severity of illness.18 In contrast, Moroney et al7 found no measurable consequences on clinical outcomes in 20 patients with invasive pneumococcal disease resistant to cefotaxime who received discordant antibiotic therapy. In our study, half the patients in the CRSP group were empirically treated for a median of 5 days with an antibiotic to which their S. pneumoniae isolate was resistant and no difference in clinical outcomes was observed in this group.
Recent studies have demonstrated increasing resistance among S. pneumoniae isolates along with mixed clinical outcomes in patients with invasive disease. Importantly, studies have shown that the MIC to all β-lactams has increased as the penicillin MIC has increased over the last decade.19 According to the Centers for Disease Control and Prevention, national S. pneumoniae resistance to ceftriaxone is approximately 10%. At OSUWMC, similar rates of ceftriaxone resistance among S. pneumoniae exist. This increasing rate of resistance is of paramount importance as ceftriaxone is considered standard of therapy for pneumococcal pneumonia.12 Also, once S. pneumoniae is identified, antimicrobial stewardship programs often recommend de-escalation of broad-spectrum antibiotics to ceftriaxone. Importantly, we observed the propensity for S. pneumoniae isolates resistant to ceftriaxone to be multidrug-resistant, including to penicillin, azithromycin, and cefepime. This finding is in concordance with previous studies that have demonstrated an association between penicillin resistance and resistance to other antibiotics.4 In the absence of effective stewardship, an increasing rate of antibiotic resistance, including to ceftriaxone, could be observed that would further limit available options for the treatment of pneumococcal pneumonia.
There are several limitations to our study. Our study was performed retrospectively at a single center and represented a small sample size, increasing the possibility of type II error. We included inpatients with HCAP, CAP, HAP, and VAP. We were also not able to correlate patient vaccination status with clinical outcome. Finally, serotyping of the isolates could not be performed to determine the impact on resistance profiles.
We report one of the few studies evaluating clinical outcomes in patients with CRSP pneumonia compared with those with CSSP pneumonia. Interestingly, no patient with a ceftriaxone-resistant isolate had previously received ceftriaxone. Although we did not observe differences in clinical outcomes, the increasing prevalence and potential clinical consequences of multidrug-resistant S. pneumoniae warrant further investigation. Antimicrobial stewardship programs and infectious disease clinicians should be cognizant of the increasing rate of ceftriaxone resistance among S. pneumoniae isolates. As the proportion of invasive pneumococcal disease with elevated MICs to β-lactams continues to rise, the adverse clinical impact could potentially become more apparent.
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ceftriaxone; streptococcus pneumoniae; pneumonia; stewardship
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