Introduction
Antimicrobial resistance (AMR) rate increase constitutes a global threat and is projected to be one of the leading causes of death by 2050 1 accounting for 10 million deaths each year. Some contributors of AMR include improper and excessive use of antimicrobials in both, humans and animals, coupled with inadequate infection control and prevention measures. Reference Septimus2
Carbapenem-resistant Enterobacterales (CRE) are a growing problem for public health. Detection and control of CRE infections are a challenging issue, mainly in low- and middle-income countries (LMIC). During COVID-19, countries in Latin America reported clinical emergence of carbapenemase-producing Enterobacterales that had not been previously characterized locally, increased prevalence of carbapenemases that had previously been detected, and co-production of multiple carbapenemases in some isolates. Reference Thomas, Corso and Pasterán3
Argentina is the third country in the world with the higher levels of CRE, Reference Lee, Ko and Hsueh4 being 43.5% carbapenem-resistant of the whole K. pneumoniae isolates in 2020.
A recent study—which included 822 CRE isolates from 183 hospitals—detected at least one carbapenemase gene in 97.3% of the isolates. Main genes were blaNDM (41.6%) and blaKPC (39.4%), and 8.7% of the strains presented a combination of genes. 5
Most multidrug-resistant organisms (MRO) are linked to healthcare-associated infections (HAI). According to a report from the World Health Organization (WHO), HAI are among most frequent adverse events in health care 6 ; it is estimated that 15 out of every 100 patients will experience a HAI in LMIC. The significant burden of MRO infections underscores the importance of implementing measures for their control and prevention. 6
Most healthcare institutions in Argentina lack Infection Prevention and Control (IPC) programs. Argentina is included in the 54% of countries worldwide with a national IPC program and operational plan and the availability of national guidelines for infection prevention. 6 Nonetheless, approximately only 0.4% of hospitals in Argentina report their HAIs rates to the National Surveillance Program in 2018. 7,8
Antimicrobial stewardship programs (ASP) constitute another key tool in the battle against AMR. Their primary objective is to achieve optimal patient outcomes for those with suspected infections, while minimizing the unintended consequences of antimicrobial use. Reference Schuts, Hulscher and Mouton9
Most basic components required to establish ASP are not available in Argentina 10,Reference Fabre, Secaira and Cosgrove11 : limited formal hospital leadership support, inadequate staffing and tools to perform AS work more efficiently, limited awareness of AS principles by HCWs, and limited training opportunity. This situation halts the establishment and articulation of both programs, with heterogeneous results nationwide.
The main objective is to achieve an optimal result in the CRE infection rate after the implementation of an IPC program and ASP in a large teaching hospital in Argentina.
Material and methods
Retrospective, observational study from January 2018 to December 2021 in a tertiary care teaching hospital in Buenos Aires province. The institution has been accredited from the Joint Commission International since 2013.
The hospital has 220 beds, with 64 critical care beds distributed as follows: (1) adult intensive care unit (ICU) 21 beds, (2) pediatric ICU 10 beds, (3) coronary unit 15 beds, and (4) neonatal ICU 18 beds.
Beginning in 2018, the ICP staff consists of three infection control nurses and two infectious diseases specialists. The ASP has clinical pharmacist, six infectious diseases specialists (four adults and two pediatrics), one member of each of the following: Department of Quality & Patient Safety and the Microbiology Department. Both programs are coordinated by the head of the Infection Prevention and Control Department, which are supervised by the Medical Director.
Programs were evaluated on annual basis using validated tools (WHO infection prevention and control assessment framework and Antibiotic stewardship program assessment tool CDC).
Afterwards, a risk matrix was used to establish priorities. Actions aimed at CRE control and prevention include the following:
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1. HAI surveillance. Active surveillance occurs through daily rounds in the hospital by IPC professionals. A registry of patients placed under isolation precautions and/or with invasive devices is maintained. For the definition of episode of HAI infection, the definition of the national surveillance program VIHDA was used (Appendix 1).
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2. Carbapenem-resistant Enterobacterales (CRE) surveillance. Upon admission, nurses obtained a rectal swab to screen for CRE in patients transferred from other institutions, those with chronic hemodialysis, or those with a history of infection or colonization by MRO. Screening is repeated weekly in Intensive Care Units (ICUs) and Bone Marrow Transplant Unit (BMT) for patients with previous negative results.
CRE colonization was divided into two categories: 1. CRE detected <72 h after admission (community or other hospital); 2. CRE identified >72 h after admission (nosocomial). The surveillance included screening by rectal swabs and any clinical sample with CRE during the hospitalization without signs and symptoms of infection. CRE infection was defined as cultures nondoubled in patients with systemic signs of infections.
Rectal swabs are initially processed using selective and differential chromogenic media (SUPERCARBA®). Subsequently, positive samples are processed with a rapid colorimetric biochemical test (Blue-Carba®) and immunochromographical tests in order to detect carbapenemase-producing Enterobacterales. The identification is thereafter complimented with automated methods to determine antimicrobial susceptibility. Culture results are reviewed daily by professional IPCs to report the presence of CRE in clinical specimens and implement isolation.
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3. Hand hygiene compliance monitoring. The institution adheres to the WHO Multimodal Hand Hygiene Improvement Strategy. From 2018 to 2020, it was comprised of direct observations including both the moments and technique proposed by the WHO. From 2021, video observation was added to direct observation in critical care units in order to reduce the Hawthorne effect. Observations were performed throughout one week every three months in all units with at least 50 opportunities per unit. The acceptable standard was set at a lower limit of an 80% compliance rate.
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4. Hospital hygiene (HH) monitoring. Compliance was monitored monthly, randomly, while patients were hospitalized and at discharge. The observer marked—using invisible fluorescent ink—frequently touched surfaces of patient’s rooms, and, 24–48 h later, the room was inspected with a special lantern recording the remaining marks. The rate of hospital hygiene effectiveness was determined by the percentage of marks no longer visible. At the beginning, the designated observer was the coordinator of Environmental Health Services and in 2021 IPC professionals replaced him.
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5. Compliance with contact isolation precautions. Since 2020, appropriate signage, availability of personal protective equipment, proper hand hygiene, and appropriate donning and doffing of supplies were evaluated by IPC professionals monthly in all the hospital units, including emergency department.
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6. Compliance with care bundles for the prevention of device-associated infections. IPC specialists and bedside nurses verified adherence to care bundles for the maintenance of central catheter, urinary catheter, and mechanic ventilation daily. The information was registered using MEG® Audit Tool, a cloud-based digital quality management system that allows for bedside registry of data.
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7. Compliance with guidelines was audited by clinical pharmacist every three months and reported to prescribers twice annually. Infectious disease practitioner and clinical pharmacist performed a daily antimicrobial prescription audit of hospitalized patients (prioritizing ICU patients) and gave recommendations—feedback—to prescribing physicians.
Clostridioides difficile infection, urinary tract infection, catheter bloodstream infection, community and hospital-acquired pneumonia, skin and soft tissue infections, surgical antibiotic prophylaxis, spontaneous bacterial peritonitis, infections in immunocompromised patients, prosthetic joint infection, and empirical treatment for ICU patients.
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8. Antimicrobial consumption. The quantification of antimicrobials vials prescribed in adults per semester started in 2018 with the incorporation of the pharmacist. In 2020, antimicrobial ordered is reviewed every month, stratified by inpatient hospital service and drug.
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9. Education. The IPC and ASP group developed an educational slide deck addressing key IPC practices, antibiotic guidelines, and update them annually. All newly hired and existing healthcare workers must review these slides each year. Virtual education started in 2020.
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10. Feedback. Information on HAI is presented weekly to critical areas and the Medical Board, monthly at Morbidity and Mortality meetings, and every three months at Infection Control Committee meetings.
Table 1 summarizes the IPC and ASP strategies.
Table 1. IPC and ASP programs
Quantification of the results of the interventions is done using the following indicators:
• Incidence density (ID) of infection by ERC: number of infections by ERC in patients hospitalized for more than 72 h per 1,000 patient days.
ID of nosocomial colonization by ERC: number of colonization (nondoubled) by MRO in patients hospitalized for more than 72 h per 1,000 patient days.
Incidence of community or other hospital colonization by ERC: number of colonizations (nondoubled) by MRO detected <72 h of admission per 1,000 discharges.
ID of ventilator-associated pneumonia (VAP): number of VAP per 1,000 ventilator days.
ID of central line-associated bloodstream infection (CLABSI): number of CLABSI per 1,000 central line days.
ID of catheter-associated urinary tract infection (CAUTI): number of CAUTI per 1,000 catheter days.
Hand hygiene compliance rate: number of appropriate hand hygiene episodes/total number of opportunities per 100.
Hospital hygiene compliance rate: number of disappeared marks/total number of marks made per 100.
Contact isolation compliance rate: number of contact isolations complied with/total number of isolation opportunities per 100.
Bundle compliance rate: number of bundles complied with (discriminated by invasive device)/total number patients eligible for a bundle per 100.
Antimicrobial consumption: Defined Daily Doses (DDD) per 100 patient days. The indicator is expressed as total antimicrobial consumption, and consumption of carbapenems, colistin, piperacillin-tazobactam, and third- and fourth-generation cephalosporins.
Education: number of persons received education or capacitation.
Statistical analysis
Categorical variables were presented as numbers and percentages. Continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR) according to data distribution.
To compare results of continuous variables, t test or Mann-Whitey test was performed, in line with type of distribution. Categorical variables results were analyzed using χ2 or Fisher’s exact test.
Numerators and denominators of infection episodes were registered using Epicontrol version 7, a computerized epidemiology and infection control surveillance record system.
Incidence rates were assessed with a Poisson regression model with patient days as the offset variable. Assumptions of the model were checked and satisfied. Pairwise comparisons by year and semester were evaluated with the Tukey method for multiple comparisons. Alpha was set at the 0.05 level.
Analysis was performed with R Studio v. 2023.03.1
Results
Synergy between an ICP and ASP achieved controlled rate of CRE infections finding the lowest levels during 2020 (0.08 episodes/1,000 patient days) (Figure 1). Colonization rate remained stable throughout the study period (Table 2).
Figure 1. Incidence density of carbapenem-resistant Enterobacterales infection.
Table 2. Results indicators
CRE, Carbapenem-resistant Enterobacterales; VAP, ventilator-associated pneumonia; CLABSI, Catheter-associated bloodstream infection; CAUTI, Catheter-associated urinary tract infection.
There was a significant reduction in VAP rates between 2019 and 2021 (7.18 vs. 4.62 episodes per 1,000 ventilator days; p = 0.02). Notably, the rate had doubled in 2020, likely related to the COVID-19 pandemic (Table 2). There was no difference in CLABSI and a nonstatistical increase in the ID of CAUTI. Compliance with care bundles increased gradually during the study period achieving rates >85% by 2021.
Hand hygiene adherence rate was over 80% during 2018 to 2020 (Table 3). Thereafter, there was a reduction in the compliance rate, most likely linked to the modification in the observation method (Figure 2). Hospital hygiene adherence rate was consistently over 90%.
Table 3. Process indicators
Antimicrobial consumption in DDD/100 PD.
Figure 2. Hand hygiene compliance rate.
Note: Adherence to hand hygiene moments and technique. The blue star marks the point in time when observations via cameras was added to direct observation.
Compliance with contact isolation was 76% in 2018 and 69% in 2019. Given the extension of isolation precautions during the COVID-19 pandemic, data from 2020 and 2021 were not included (Table 2).
Antimicrobial consumption increased slightly during the study period (15%). Among high-impact antimicrobials, however, only colistin consumption increased (Table 3).
The number of persons who received education and training in prevention and infection control was stable during the study period. We included computerized tools on topics such as hand hygiene (moments and technique) and isolation precautions, which were mandatory for the entire hospital staff and allowed the continuity of training despite the pandemic.
Discussion
To our knowledge, we are the first to show the results of 4 years ASP and PCI working jointly to fight AMR in Argentina.
Our study shows that it is possible to achieve a stable CRE infection rate by implementing our strategy despite Argentina´s situation—high CRE incidence—and COVID-19 pandemic.
We believe that these results were the consequence of some differential components of the programs which are seldom found together in our country: first, management support was crucial in the priorization of these programs in means of funds designation and unique coordination; second, screening CRE on admission and in high-risk areas with prompt identification and isolation’ third, inclusion of a clinical pharmacist in 2018, allowing us to quantify the ASP actions, finally, encouraging interdisciplinary work groups with healthcare personnel to audit and maintain adherence to hand hygiene, hospital hygiene, and bundles for the prevention of device-associated infections and the use of antimicrobials in order to establish continuous improvement strategies over time.
National rates of HAI are higher than those reported in our study (VAP 11,28 infections/1,000 ventilator days; CLABSI 5,57 infections /1,000 central line days), highlighting the importance of allocating resources and prioritizing IPC and ASP programs in healthcare facilities.
During the peak of COVID-19 pandemic, as in most institutions, Reference Weiner-Lastinger, Pattabiraman and Konnor19–Reference Lastinger, Alvarez and Kofman22 HAI rates increased in our facility. However, having a working and robust ICP program allowed us to control the situation and even reduce the rates of VAP and CLABSI during the study period.
Hand and hospital hygiene compliance rates were consistently high. We attribute this outcome to the commitment of our staff, their effective teamwork, and the cultivation of a safety-centric culture. We further enhanced monitoring measures by adding an external audit for hospital hygiene and video cameras for hand hygiene. This strategy was included in new campaigns, training, and education. Continuous training of hospital hygiene staff together with audit and feedback have proved to be key factors in the continued success of this standard. At the very beginning, it was hard to convince staff of the importance of both programs. Today, the main issue is to sustain already implemented measures.
Global antimicrobial consumption remained stable, despite certain variation among antimicrobial families. Argentina regretfully lacks hospital comparators, and antimicrobial consumption is reported to be between 11 and 36 DDD per 1,000 inhabitants per day. Reference Marin, Giangreco and Dorati23
ANLIS Malbrán—Argentina´s Institute of Reference for antimicrobial resistance—reported 32.4% of carbapenem-resistant K. pneumoniae from 43.495 nosocomial isolates. Reference Pasteran, Echegorry and Olivieri12 Such situation urges the need to restrict unnecessary antimicrobial use and to optimize infection prevention and control measures. Reference Zhou, Nagel, Kaye, LaPlante, Albin and Pogue13
A recent publication determined that the multi-resistance load could be reduced by 85% with the implementation of an ICP that emphasizes hand hygiene and hospital hygiene, with strong support from an ASP. Reference Lee, Ko and Hsueh4 Such a strategy is cost-effective and not resource-prohibitive. This evidence is reinforced by a metanalysis, Reference Baur, Gladstone and Burkert14 which showed that ASP, when implemented alongside infection control measures, are more effective than implementation of ASP alone on reduction of AMR. Studies co-implementing a hand hygiene program with an ASP have reported a reduction of 66% in antibiotic resistance versus 17% in studies without co-implementation of hand hygiene interventions, supporting the so-called “butterfly effect” of hand hygiene. Reference Baur, Gladstone and Burkert14
As established by Dik and colleagues, Reference Dik, Poelman, Friedrich, Niesters, Rossen and Sinha15 controlling the prevalence of AMR infections can only be achieved through a holistic approach exemplified by the tripartite model of antimicrobial stewardship, infection prevention, and diagnostic stewardship.
Although Argentina is among the 54% of countries with a national IPC program, Reference Lee, Ko and Hsueh4 only selected institutions have robust systems in place to implement and disseminate IPC practices. Even where IPC and ASP programs are in place, they are often not able to function appropriately and sustainably in an enabling environment. Additionally, they often function independently and not synergistically. Moreover, particularly in LMICs, facilities frequently lack full-time IPC professionals, an allocated IPC budget, routine microbiological laboratory support, and appropriate workload, staffing, and bed occupancy. 10
It is common knowledge that colonization by MRO increases the risk of subsequent infection by these organisms. Reference Thatrimontrichai and Apisarnthanarak16–Reference Smith, Lautenbach and Omulo18 Thus, colonized patients comprise a high-risk group for infection by MRO, as well as an important source for transmission of MRO in the hospital setting. Surveillance of MRO microorganisms constitutes an opportunity to break the chain of transmission Reference Smith, Lautenbach and Omulo18 . The application of containment strategies for colonized patients and verification of compliance likely bolstered the success of CRE control.
Our study has limitations. First, it was carried out in a single institution, which has an established safety culture. Hence, the results might not be applicable to other healthcare institutions. However, we are certain that our results demonstrate that coordinated actions of both programs have a favorable impact on AMR. Second, the COVID-19 pandemic may have acted as a confounder, altering the course of the study variables. In the pandemic setting, synergy between both programs allowed us to easily return to prepandemic rates of HAI.
We did not analyze individual factors in relation to the results. However, we strongly believe that attaining high levels of compliance with process indicators such as hand hygiene, hospital hygiene, isolation precautions, and care bundles in articulation with antimicrobial stewardship measures was critical in CRE control.
Conclusions
Our study suggests that achieving a reasonable CRE infection rate in LMICs hinges on the sustained and beneficial impact of both IPC and AS programs when implemented collaboratively by an interdisciplinary team. Success would have been unlikely without likely our senior leadership’s commitment to both critical programs. Further studies in LATAM are needed to support our results and demonstrate the importance of a synergistic approach in controlling CRE.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/ash.2023.439.
Acknowledgments
We would like to thank the collaboration of the Departments of Infectious Diseases, Microbiology, Pharmacy, and Quality and Safety whose work is crucial for the success of the ICP and ASP: María Eugenia Harispe, Guillermina Kremer, Rocío Gago, Maria Laura Pereyra, Roxana Sadorín, Alejandra Quevedo, Ivana Martinelli, Viviana Vilches, María Marcó del Pont, Macarena Uranga, Magdalena Princz.
Financial support
None reported.
Competing interests
Wanda Cornistein received speaker honoraria from MSD, PFIZER, ROCHE, and BD in the last year. The other authors declared no potential conflicts of interest with respect to research, authorship, and/or publication of this article.
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