Concerns have been raised that increased antibiotic use to treat patients with coronavirus disease 2019 (COVID-19) has accelerated the development of antimicrobial resistance. Reference Li, Wang and Yang1 Despite <10% of these patients having bacterial coinfection, >70% of hospitalized COVID-19 pneumonia patients receive antibiotics. Reference Calderón-Parra, Muiño-Miguez and Bendala-Estrada2 Furthermore, severely ill COVID-19 patients are prone to develop fungal infections, given the concomitant use of immunosuppressive agents and unnecessary or prolonged board-spectrum antibiotics in intensive care units (ICUs). Reference Arastehfar, Carvalho and van de Veerdonk3 Policies to limit inappropriate antibiotic use are urgently needed.
Limited data are available concerning antibiotic stewardship programs (ASPs) during COVID-19 pandemic. Procalcitonin (PCT)-based strategies have been studied among hospitalized COVID-19 patients and revealed that PCT-guided antibiotic decisions can significantly reduce antibiotic use. Reference Peters, Williams and Un4 In a recent study, using PCT and Clinical Pulmonary for Infection Score (CPIS) significantly reduced inappropriate antibiotic use and lowered the incidence of multidrug-resistant organisms and invasive fungal infections (MDRO-IFIs) among severely-to-critically ill COVID-19 pneumonia patients. Reference Sathitakorn, Jantarathaneewat and Weber5 However, it remains unclear whether such a strategy can be used in all COVID-19 patients, regardless of severity of illness. We conducted a quasi-experimental multicenter study to evaluate the role of PCT-CPIS score in reducing inappropriate antibiotic use and incidence of MDRO- IFI among mildly-to-critically ill COVID-19 patients.
Methods
From March 1, 2020, to February 28, 2022, we performed a quasi-experimental study to evaluate the role of PCT-CPIS score in reducing inappropriate antibiotic use among COVID-19 patients in 2 hospitals. The first hospital (Thammasat University Hospital or TUH) is a 600-bed tertiary-care university hospital consisting of a cohort unit where mildly-to-moderately ill COVID-19 patients receive care, with 4 ICUs where severely-to-critically ill COVID-19 patients receive care. At the same time, 2 other ICUs were part of a separate pilot study and were excluded. Reference Sathitakorn, Jantarathaneewat and Weber5 Care in these units was directed by ICU physicians and infectious disease (ID) physicians. The second hospital (Lerdsin hospital) is a 500-bed government hospital consisting of a cohort unit where mildly-to-moderately ill COVID-19 patients receive care and 1 ICU where severely-to-critically ill COVID-19 patients receive care. Care in these units is directed by ID physicians. The study periods consisted of a 1-year preimplementation period of PCT-CPIS protocol (period 1: March 1, 2020, to February 28, 2021) and a 1-year postimplementation period of PCT-CPIS protocol (period 2: March 1, 2021, to February 28, 2022). During period 1, no antibiotic protocols for COVID-19 patients were available at either hospital. Before period 2, the PCT-CPIS protocol was discussed and approved by physicians in 2 hospitals. During period 2, upon admission, the researchers calculated the CPIS score (COVID-19 version) Reference Schurink6 and ordered admission PCT for all COVID-19 patients. For those with a CPIS score <6 and a PCT <0.5 μg/L, no antibiotics were initiated. On hospitalization day 3, PCT-CPIS score were reassessed. If the patient’s CPIS was <6 and the PCT was <0.5 μg/L or the PCT dropped by ≥80% from admission level, antibiotics were discontinued (Supplementary Fig. 1). In these ICUs, routine evaluations of bacterial coinfections at all sites were performed at admission and during hospitalization if the patients were not responding to therapy. These evaluations included sputum Gram stain and culture, urine culture, blood culture, and chest radiograph. The protocol was monitored by researchers to ensure strict compliance by treating physicians.
Fig. 1. Inappropriate antibiotic use, incidence of multidrug-resistant organisms (MDROs) and invasive fungal infections (IFIs), and incidence of MDR Acinetobacter baumannii in 2 medical centers.
The primary outcome was the role of PCT-CPIS in reducing inappropriate antibiotic use among COVID-19 patients. The secondary outcomes were antibiotic duration, length of hospital stay (LOS), 30-day mortality, and MDRO IFIs incidence. Antibiotic appropriateness was defined according to Kunin et al Reference Kunin, Tupasi and Craig7 and was justified by the hospital’s ASP team. Criteria for PCT and COVID-19 pneumonia severity were defined as previously described. Reference Lee, Kwa and Apisarnthanarak8,Reference Wei9 The CPIS score for pneumonia was defined according to Singh et al Reference Singh, Rogers, Atwood, Wagener and Yu10 and was modified for use in COVID-19 pneumonia patients. Reference Schurink6 The inclusion criteria were adults (aged ≥18 years) with COVID-19 infection. Patients who received antibiotics<24 hours or for other indications (eg, surgical prophylaxis) were excluded. This study was approved by the TUH Institutional Review Board.
All analyses were performed using SPSS version 26 software (IBM, Armonk, NY). We used χ2 tests to compare categorical variables. Mann–Whitney U tests were used for continuous data. All P values were 2-tailed, and P < .05 was considered statistically significant. A trend analysis was performed to evaluate the overall pattern of changes on outcomes of interest over time using segmented regression analysis of interrupted time series (ITS).
Results
In total, 192 patients were identified in period 1 and 214 patients were identified in period 2. Their median age was 62 years (range, 18–94 years). The most common underlying diseases were hypertension (201 of 406, 49.5%) and diabetes mellitus (132 of 406, 32.5%). All COVID-19 patients were categorized as mildly ill (40 of 406, 9.9%), moderately ill (59 of 406, 14.5%) severely ill (211 of 406, 52.0%), or critically ill (96 of 406, 23.6%). Demographics and baseline characteristics of participants are summarized in Table 1.
Table 1. Demographics and Baseline Characteristics of Participants Compared the Preimplementation Period (Period 1) Group Versus the Postimplementation Period (Period 2) Group
Note. BMI, body mass index; ATB, antibiotics; MDROs, multidrug-resistant organisms; IFIs, invasive fungal infection; ESBL, extended-spectrum β-lactamase; ARDS, acute respiratory distress syndrome.
a Units unless otherwise specified.
b COVID-19 severity was defined based on diagnosis and treatment protocol for novel coronavirus pneumonia. Reference Wei9
c Aspergillosis.
d Upper gastrointestinal bleeding, acute pulmonary embolism, volume overload.
Compared to period 1, the overall inappropriate antibiotic use was significantly reduced during period 2: 122 (63.5%) of 192 versus 67 (31.3%) of 214 (P < .01). Overall, inappropriate use was significantly reduced among severely-to-critically ill COVID-19 patients between the 2 periods: 118 (80.8%) of 146 versus 63 (39.1%) of 161 (P < .01). But it was not reduced among mildly-to-moderately ill COVID-19 patients: 4 (8.7%) of 46 versus 4 (7.5%) of 53 (P = .83). In period 2, there was a significantly lower incidence of MDRO-IFIs: 48 (25.0%) of 192 versus 36 (16.8%) of 214 (P = .04). We also detected lower incidence of MDR Acinetobacter baumannii during period 2: 31 (16.1%) of 192 versus 20 (9.3%) of 214 (P = .04). We detected a significantly shorter total antibiotic duration (7 days vs 0 days; P < .01) and LOS (13 days vs 10 days; P < .01) in period 2. The 30-day mortality was not significantly different between the 2 periods (Table 1). In the subgroup analysis, we did not detect any significant reduction in MDRO-IFI incidence in mildly-to-moderately ill COVID-19 patients (Table 1). Using segmented regression analysis of ITS, we detected a significant reduction in inappropriate antibiotic use, MDR Acinetobacter baumannii and MDRO-IFI incidence (Fig. 1). However, we did not detect significant changes in the trends of the outcomes (Fig. 1).
Discussion
Our study yielded several notable findings. Despite directed care by ICU and/or ID physicians, PCT-CPIS was implemented successfully to reduce inappropriate antibiotic use among severely-to-critically ill COVID-19 pneumonia patients in 2 medical centers. PCT-CPIS was associated with significant reductions in MDRO-IFIs and MDR Acinetobacter baumannii incidence. Furthermore, the PCT-CPIS strategy decreased antibiotic duration and shortened hospital LOS. Our findings suggest that the PCT-CPIS strategy could be beneficial to severely-to-critically ill COVID-19 patients.
Several recent studies have reported that inappropriate antibiotic use during the COVID-19 pandemic was associated with an increased incidence of adverse drug reactions, including acute kidney injury, Reference Calderón-Parra, Muiño-Miguez and Bendala-Estrada2 and MDROs. Reference Li, Wang and Yang1 Notably, the main reported hospital-acquired pathogen in Asia was A. baumannii. Reference Li, Wang and Yang1 In previous studies, PCT-based ASPs have been shown to reduce inappropriate antibiotic use and MDRO-IFI incidence. Reference Peters, Williams and Un4,Reference Sathitakorn, Jantarathaneewat and Weber5 In this quasi-experimental multicenter study, we found a benefit of PCT-CPIS–based strategies to reduce inappropriate antibiotic use among severely-to-critically ill COVID-19 pneumonia patients but not for mildly-to-moderately ill patients. This strategy may also help further reduce MDRO-IFI incidence.
This study had several limitations. First, the small sample size, particularly among mildly-to-moderately ill COVID-19 patients, may not have been sufficient to demonstrate a significant reduction in outcomes. Second, despite being performed in 2 medical centers, the generalization of our findings may not apply to every setting. Third, as a nonrandomized controlled trial with the lack of a comparative arm, potential unmeasured confounders (eg, lack of vaccination data) and/or biases (eg, regression to the mean, historical bias) may have affected our findings.
In conclusion, PCT-CPIS can be implemented successfully to reduce inappropriate antibiotic use in severely-to-critically ill COVID-19 pneumonia patients. PCT-CPIS–based strategies can be integrated into ASPs among severely-to-critically ill COVID-19 patients to limit unnecessary antibiotic exposure.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/ice.2022.201
Acknowledgments
Financial support
This research was supported by Faculty of Medicine, Thammasat University Research Fund under Financial support.
Conflicts of interest
All authors report no conflicts of interest relevant to this article.
