Introduction

Infections are among the most common causes of hospitalization among older people. The large volume of antibiotics prescribed has contributed to the emergence of highly resistant pathogens among geriatric patients. Multidrug resistance (MDR) was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories [1]

The high prevalence of MDR pathogens in hospital could take physicians in a new era where no effective antibiotics could be available. The Review on Antimicrobial Resistance estimated that anti microbic resistance could result in the global loss of 10 million lives per year by 2050, with substantial economic ramifications [2].

Frailty is particularly prevalent in older people. This condition could be traditionally defined as a geriatric syndrome associated with a decreased reserve to acute events, including infections [3]. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of older people, which might predispose to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases [4]. This state of uncontrolled development of chronic and degenerative diseases could be the cause of an increased rate of intra-hospital infections, as observed in frail older people. This highlights how it is necessary to carry out a comprehensive geriatric assessment (CGA) to evaluate the real state of frailty in older persons affected by infectious diseases and for clinical-decision making in frail older people often affected by MDR. For example, a recent meta-analysis highlights the impact of frailty in older adults hospitalized with COVID-19, showing that frail COVID-19 patients have an increased risk of short-term mortality compared to non-frail patients affected by COVID-19 [5]. A large meta-analysis indicated that 7% of hospitalized COVID-19 patients had a bacterial co-infection that increases to 14% in studies that only included ICU (intensive care unit) patients [6].

Since the association between frailty and infections in older people affected by COVID-19 is largely unknown, the aim of the present study was to investigate the possible association between higher multidimensional prognostic index (MPI) values and the prevalence of infectious diseases, including antibiotics’ cost and the prevalence of MDR pathogens.

Materials and methods

Study population

We included patients consecutively hospitalized in Internal Medicine or Geriatrics Wards in the University Hospital (Policlinico) ‘P. Giaccone’ in Palermo, Sicily, Italy with an age ≥ 65 years, a diagnosis of SARS-CoV-2 infection confirmed by positive nasal-pharyngeal swab. The only exclusion criterion was the inability to understand the aims of the study. The study was approved by the Local Ethical Committee during the session of the 28th April 2021 (number 04/2021), in the context of the COMEPA (COVID-19 Medicina Policlinico Palermo) study [7].

Multidimensional prognostic index

The Brief-MPI is a prognostic tool that had a good agreement with the standard version of the MPI. [8] The Brief-MPI includes eight domains, as the full version consequently keeping its multidimensional value:

  • Activities of daily life, derived from the activities of daily living (ADL)

  • Instrumental activities of daily living, derived from the instrumental ADL (IADL)

  • Cognitive assessment, using the Short Portable Mental Status Questionnaire (SPMSQ)

  • Mobility assessment, evaluated using the Barthel mobility index

  • Nutritional assessment, evaluated with the Mini-Nutritional Assessment Short Form

  • Comorbidities as evaluated using the Cumulative Illness Rating Scale (CIRS)

  • Number of drugs in use.

  • Cohabitation status.

The first seven domains had a dichotomic response (yes/no or right/wrong). The value of cohabitation status was 0 for individuals who lived with the family, 0.5 for institutionalized, and 1 for those who lived alone. Each domain received a risk rating (low risk = 0, moderate risk 0.5 high risk = 1).

Laboratory tests and antibiotic costs

The presence of pathogens during hospitalization was detected for patients with symptoms such as fever, higher inflammatory index, suspicious of infectious diseases using all the laboratory tests available such as blood cultures, urine culture test, skin swabs tests, and other tests. Antibiotics’ costs, during hospitalization, were analyzed using data from European Medicines Agency (EMA) and World Health Organization (WHO) databases.

Outcomes

The main outcome of our investigation was to explore the prevalence of any co-infection in a population of older people hospitalized with COVID-19, according to the presence of multidimensional frailty. Moreover, we considered as secondary outcomes antibiotics’ cost and the presence of MDR, again by presence or not of multidimensional frailty.

Statistical analyses

Data are reported as means with standard deviations (SDs) for continuous variables and as percentages for categorical parameters, by Brief-MPI values categorized in three groups according to a classical division [9] (< 0.33 [robust], 0.33–0.66 [pre-frail], > 0.66 [frail]). Data were reported as means and standard deviation values (SD) for quantitative measures and as percentages were used for discrete variables, such as percentage of females and living alone. Levene’s test was used to test the homoscedasticity of variances and, if its assumption was violated, Welch’s ANOVA was used. P-values were calculated using the Jonckheere–Terpstra test for continuous variables and the Mantel–Haenszel Chi-square test for categorical variables by Brief-MPI groups.

The strength of the association between the Brief-MPI and the presence of any pathogen was analyzed using a logistic regression analysis, adjusted for age, sex, ward (internal medicine vs. geriatrics). The data were then reported as odds ratios (ORs) with their 95% confidence (CIs).

Significance was accepted if P < 0.05, and all tests were two-tailed. All analyses were performed by using SPSS 25.0 for Windows (SPPS Inc).

Results

Of the 246 participants who initially took part in COMEPA study, 134 were excluded being younger than 65 years, leaving 112 subjects eligible for this study. All 112 patients were hospitalized with COVID-19 with a mean age of 77.6 years (SD = 10.3) and prevalently males (= 55.4%).

Overall using MPI, 35 (31.3%) patients were categorized as robust, 51 (45.5%) as pre-frail and 26 (23.2%) as frail. Table 1 shows that frailer people were significantly older (p < 0.0001), whilst they did not differ in terms of females (p = 0.19). As shown in Fig. 1, a higher prevalence of positive blood culture (15.4% vs. 5.7%, p = 0.02) was reported in frailer patients compared to robust ones, like urine culture test (46.2% vs. 5.7%, p < 0.0001) or other type of swabs (p = 0.03), whilst no associations was demonstrated for skin swabs (p = 0.36). Moreover, analyzing MDR pathogens, 50% of them were Klebsiella Pneumoniae Carbapenemase-Producing (KPC) followed by Escherichia Coli Beta Lattamase-Producing (ESBL) with a prevalence of 14%.

Table 1 Descriptive characteristics at the baseline by multidimensional prognostic index values
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Fig. 1
figure 1

Prevalence of pathogens by multidimensional prognostic index values

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In an adjusted logistic regression analysis, higher MPI values were associated with a significantly higher odds of any positivity to pathogens (MPI > 0.66: prevalence: 61.5%, OR = 15.56, 95% CI 3.39–71.50) compared to a prevalence of 8.6%, if MPI was < 0.33. For four months a total of 86,000 euros was spent for all the antibiotics, with a median of 262 euro for patient. Overall, 67 (59.8%) patients received at least one antibiotic and 5 (4.5%) received four antibiotics because of repeated infections. Robust patients (MPI < 0.33) had an antibiotics average cost of 94 € versus pre-frail and frail patients (MPI ≥ 0.33) for which the cost was 1084 €, showing an association between higher MPI values, use and costs of antibiotics.

Discussion

To the best of our knowledge, this is one of the first studies that tried to analyze the association between multidimensional frailty and bacterial co-infections in a population of older people hospitalized with COVID-19. Overall, our study demonstrated that higher MPI values were associated with a significantly higher presence of any positivity to pathogens compared to lower values, indicating a strong association between frailty, defined in a multidimensional way, and infectious diseases.

Our research demonstrated a higher prevalence of urine and blood cultures in frailer subjects compared to their counterparts. Several risk factors that are associated with frailty such as dehydration, reduced mobility and cognitive impairment can make our patients more prone to urinary tract infections that are also more difficult to treat [10]. Using laboratory tests, our study demonstrated the high presence of MDR pathogens in older hospitalized patients: three quarters of the patients who reported a positivity for pathogens had MDR in their lab tests. An European survey consisting of 471 million individual records or isolates covering 7585 study-location-years obtained from surveillance systems, hospital systems, systematic literature reviews, and other sources showed that 541,000 deaths were associated with bacterial antimicrobial resistance (AMR) and 133,000 deaths attributable to bacterial AMR in the whole WHO European region in 2019 [11].

Susceptibility to infection increases with age and when infections occur they often present atypically, otherwise, diagnostic uncertainty is much more pronounced in the geriatric population [12]. Our research indicates even the importance of cost’s management: a total of 86,000 euros was spent for all the antibiotics for four months of follow-up. Moreover, 30 patients (about a quarter of all population) needed more than one antibiotic during their hospitalization. An Asiatic cross-sectional survey of 402 people showed the lack of knowledge about antibiotics ‘ role, whereby more than half of the respondents incorrectly believed that antibiotics can treat viral infections (53.5%) and colds and coughs (53.7%) [13].

In our study the most detected MDR pathogen was Klebsiella Pneumoniae KPC overall confirming a negative issue who’s spreading in all hospital all over the world. It Italy, a particularly critical resistance rates are observed for Klebsiella pneumoniae to amoxicillin-clavulanic acid (57.2%) and piperacillin-tazobactam (45.8%), to third generation cephalosporins (> 50%) and to carbapenems (28.7% for meropenem) [14]. A recent review showed that in the context of COVID-19, frail older adults accounted for approximately 51% of hospitalized patients with confirmed cases and elevated risk of in-hospital mortality [5]. An American survey based on 50,419 respiratory samples demonstrates how even though the overall median age of the SARS-CoV-2-positive patients was 45 years, the bacterial co-infections were significantly higher in the older age group (60 + years) when compared to any other age group [15].

Possible limitations of our study were that we used a brief version of MPI motivated by hygienic reasons. Moreover, we included only 112 patients, all with COVID-19, without a possible comparison with patients non-affected by this infectious disease. Moreover, the cross-sectional nature of the study is another important limitation since we cannot rule out a reverse causation, i.e., the infectious diseases can increase the presence of frailty and not vice versa.

In conclusion, our study shows an association between higher MPI values and infections in a population of older people affected by COVID-19. The constant raising of pathogens resistance it’s a dangerous event who needs more attention by our clinical government and these values could be a cheaper and easier way to prevent negative issue as hospitalization or death in older people. Future studies analyzing the importance of frailty, as defined in multidimensional way, are needed to analyze its importance for clinical-decision making in antibiotics’ choice.