|Year : 2020 | Volume
| Issue : 1 | Page : 24-31
Mortality from acinetobacter infections as compared to other infections among critically ill patients in South India: A prospective cohort study
Ajoy Oommen John1, Hema Paul2, Saranya Vijayakumar3, Shalini Anandan3, Thomas Sudarsan4, Ooriyapadickal Cherian Abraham1, Veeraraghavan Balaji5
1 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Hospital Infection Control Committee, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Medicine, Division of Critical Care, Christian Medical College, Vellore, Tamil Nadu, India
5 Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||26-Dec-2019|
|Date of Decision||18-Feb-2020|
|Date of Acceptance||30-Apr-2020|
|Date of Web Publication||25-Jul-2020|
Dr. Ajoy Oommen John
Department of Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Acinetobacter baumannii has become a common pathogen causing hospital-acquired infections (HAIs). Although acquiring any nosocomial infection is associated with increased mortality, we do not know if the acquisition of Acinetobacter infection confers a worse prognosis as compared to non-Acinetobacter-related HAI. The aim of the current study is to compare the clinical outcomes of ventilator-associated pneumonia (VAP) and central line associated blood stream infections (CLABSIs) caused by A. baumannii with those caused by other bacterial pathogens. Materials and Methods: This prospective cohort study was conducted among critically ill adults admitted to a tertiary care hospital in South India from January 2013 to June 2014. We enrolled patients who developed new-onset fever ≥48 h after admission and fulfilled pre-specified criteria for VAP or CLABSI. The patients were followed up until the primary outcomes of death or hospital discharge. Results: During the study period, 4047 patients were admitted in the intensive care units, among which 129 eligible HAI events were analysed. Of these, 95 (73.6%) were VAP, 34 (26.4%) were CLABSI, 78 (60.4%) were A. baumannii-related HAI (AR-HAI) and 51 (39.6%) were non-A. baumannii-related HAI (NAR-HAI). Mortality among AR-HAI was 57.6% compared to 39.2% in NAR-HAI (P = 0.04) which on multivariate analysis did not achieve statistical significance, although the trend persisted (odds ratio [OR] = 4.2, 95% confidence interval [CI]: 0.95–18.4, P = 0.06). The acquisition of VAP due to A. baumannii was associated with poor ventilator outcomes even after adjusting for confounders (adjusted OR = 3.5, 95% CI: 1.07–11.6, P = 0.04). Conclusion: In our cohort of critically ill adults with VAP and CLABSI, AR-HAI was associated with poor ventilator outcomes and a trend towards higher mortality. These findings add to the evidence suggesting that A. baumannii is a dangerous pathogen, perhaps even more so than others.
Keywords: Acinetobacter baumannii, central line-associated blood stream infections, hospital-acquired infection, ventilator-associated pneumonia
|How to cite this article:|
John AO, Paul H, Vijayakumar S, Anandan S, Sudarsan T, Abraham OC, Balaji V. Mortality from acinetobacter infections as compared to other infections among critically ill patients in South India: A prospective cohort study. Indian J Med Microbiol 2020;38:24-31
|How to cite this URL:|
John AO, Paul H, Vijayakumar S, Anandan S, Sudarsan T, Abraham OC, Balaji V. Mortality from acinetobacter infections as compared to other infections among critically ill patients in South India: A prospective cohort study. Indian J Med Microbiol [serial online] 2020 [cited 2020 Aug 11];38:24-31. Available from: http://www.ijmm.org/text.asp?2020/38/1/24/290680
| ~ Introduction|| |
Hospital-acquired infection (HAI) is associated with substantial increase in direct healthcare associated costs and mortality.Acinetobacter baumannii are becoming an increasingly common cause of HAI, especially in the intensive care units (ICUs). A 2008 report from the National Healthcare Safety Network found that A. baumannii accounted for 8.4% of the ventilator-associated pneumonias (VAPs) and 2.2% of all catheter-related blood stream infections (BSIs). Studies have also demonstrated an increasing incidence of Carbapenem-resistant strains of A. baumannii, estimating to almost 50% increase in the incidence of drug-resistant isolates, with increased mortality and length of hospital stay. However, a debate exists regarding the attributable mortality from Acinetobacter infection which stems from the difficulty in determining whether the cause of death was due to the underlying illness or due to the super-added infection. As a pathogen, it usually targets mucous membranes, and its ability to form biofilms over invasive devices makes the critically ill patient an easy target. However, differentiation of infection from colonisation adds further complications to the debate of attributable mortality.
The mortality from VAPs has been estimated between 13% and 30%, with a similar mortality rate from nosocomial BSIs. Therefore, we know that the acquisition of any of the above nosocomial infections is associated with an increase in mortality. However, it is not known if the acquisition of Acinetobacter-related infection confers a worse prognosis as compared to the acquisition of a non-Acinetobacter-related HAI.
In this study, we aim to compare the clinical outcomes among critically ill patients with HAI-related VAP and central line-associated BSIs (CLABSIs) caused by A. baumannii, with HAI caused by other bacterial pathogens.
| ~ Materials and Methods|| |
This prospective cohort study was undertaken in a 2500-bed, university-affiliated, private teaching hospital in semi-urban India. The hospital is serviced by patients from all over India. Most patients admitted in the critical care units, medical ICU (MICU), medical high-dependency unit (MHDU) and surgical ICU (SICU) arrived through the accident and emergency department, although the SICU also had post-operative patients admitted for stabilisation before shifting to the wards.
This study included consecutive adult patients above the age of 18 years admitted in the MICU, MHDU and SICU for a consecutive 18 months who fulfilled the pre-defined classification criteria for VAP and CLABSI.
Infections with coagulase-negative Staphylococci and patients for whom subsequent evaluation demonstrated an alternate aetiological focus other than the lung or the central venous catheter were excluded from the study.
Any patient who developed fever, 48 h after admission to the ICU, was evaluated by the principal investigator to determine whether the fever was due to VAP or CLABSI. The patients' clinical progress and investigations were followed up to determine if they fulfilled the pre-defined criteria for diagnosis of VAP or CLABSI. During this entire process, all investigations and clinical management plans were made by the treating physicians, with no involvement from the study team. If a patient fulfilled the criteria of VAP or CLABSI, then they were classified as study participants and were recruited after obtaining informed consent from the family members. The patient's demographics, clinical details, disease severity on admission and blood investigations were entered into the clinical research form.
The study participants whose clinical isolates grew Acinetobacter baumannii calcoaceticus complex (Acb complex) were classified as Acinetobacter-related HAI (ARHAI). The study participants whose clinical isolates grew other non-Acinetobacter organisms such as Klebsiella, E. coli, Pseudomonas, S. aureus and Proteus were classified as non-Acinetobacter-related HAI (NARHAI). The accurate identification of Acb complex at the species level as A. baumannii was confirmed using MALDI-TOF. If the culture grew more than one organism of which one was A. baumannii, the patient was still classified as belonging to the ARHAI group. The patients were followed up until death or discharge from the hospital.
During the course of hospital stay, if the patient developed another episode of fever and fulfilled criteria for VAP or CLABSI, then the details were entered as a separate event and followed up accordingly. Hence, a single patient could have more than one HAI event during the course of hospital stay.
Central line-associated blood stream infection case definition
CLABSI was defined according to the National Healthcare Safety Network criteria, as follows: (i) recognised pathogen, identified from one or more blood culture specimens and (ii) organism(s) identified in blood is not related to infection at any other site and (iii) an eligible central line is present on the day of the positive blood culture or the day before.
An eligible central line was defined as one that had been in place for two or more consecutive calendar days.
Ventilator-associated pneumonia case definition
If the patient is clinically suspected to have VAP, then the Clinical Pulmonary Infection Score (CPIS) was calculated. A score more than 6 is considered highly suggestive of VAP. Appropriate tracheal aspirate and blood cultures were taken as per the normal protocol in the ICU. The patient was reassessed again at 72 h and a repeat CPIS score was calculated. The results of the ET aspirate were also followed up by this time. A patient is classified as having VAP if day 1 and day 3 CPIS is >6 and the ET aspirate culture is positive or day 1 CPIS <6 and day 3 CPIS >6 and the ET aspirate culture is positive. Bacterial growth of >105 colony-forming unit/ml is considered positive for ET aspirate cultures.
The primary outcome was in-hospital mortality. For the purpose of this study, patients who were discharged against medical advice were included as 'death'.
We compared the duration of ICU stay and duration of hospital stay among patients with NARHAI with those of ARHAI.
Factors affecting duration of mechanical ventilation
We assessed factors affecting duration of mechanical ventilation among our patients who were mechanically ventilated. The duration of mechanical ventilation was expressed in terms of ventilator-free days (VFDs). This was defined as number of days between successful weaning from mechanical ventilation and day 28 after initiation of mechanical ventilation (VFD = 28 − number of days on the ventilator). If the patient required mechanical ventilation beyond 28 days or if the patient died during the course of hospital stay, the number of VFD was taken as 0. Successful weaning was defined as a continuous period of 48 h or more off mechanical ventilation.
Antimicrobial susceptibility testing
Antimicrobial susceptibility testing (AST) was performed for all the study isolates for different class of antimicrobials such as cephalosporins, β-lactam-β-lactamase inhibitors, carbapenems, fluoroquiolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole and colistin. The breakpoints were interpreted as per CLSI guidelines.
A prior study published from our ICU showed VAP-related mortality rates to be 52.7%. We calculated that a total of 93 patients in each arm would yield a power of 80% at an alpha error of 5% to detect a 20% difference in mortality between the two groups. We calculated t-test, Chi-square test and ANOVA as appropriate for all analyses. Odds ratio (OR) and confidence intervals (CI) were calculated, and a 'P' < 0.05 was considered statistically significant. Data was entered using Epi Data version 3.1 (Lauritsen JM and Bruus M. EpiData (version 3.1). A comprehensive tool for validated entry and documentation of data. The EpiData Association, Odense Denmark, 2004.) and the data was analysed using SPSS version 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.).
The study was approved by the institutional review board and ethics committee (IRB min no. 8159/13).
| ~ Results|| |
During the study period, a total of 4047 patients were admitted in the ICUs (MICU/MHDU/SICU), out of which 129 patients fulfilled the case definitions for VAP or CLABSI as defined earlier.
Among these 129 patients, 78 (60.5%) had ARHAI and the remaining 51 (39.5%) had NARHAI. At baseline, the patients in this cohort were found to have a mean age of 40 years, with a mild male predominance (57.7% and 67.9% in ARHAI and NARHAI, respectively). The two groups were found to have comparable median APACHE III scores at presentation (70 and 66, respectively, in ARHAI and NARHAI) and comparable median Charlson comorbidity index (1 and 0 in ARHAI and NARHAI, respectively). The baseline characteristics of the patients are described in [Table 1].
Of 78 patients with ARHAI, 68 (87.2%) had VAP, while only 24 (45.3%) among the 53 patients with NARHAI had VAP. Most of the VAP (71.5%) were caused by ARHAI [Figure 1]. The most common non-Acinetobacter organisms were Klebsiella and Pseudomonas. The distribution of NARHAI is shown in [Figure 2].
|Figure 1: Proportion of ventilator-associated pneumonia and central line-associated blood stream infection due to Acinetobacter-related hospital-acquired infection and non-Acinetobacter-related hospital-acquired infection (central line-associated blood stream infection n = 34, ventilator-associated pneumonia n = 95)|
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Of the 78 patients with ARHAI, 45 died (57.6%), while only 20 of 51 patients (39.2%) with NARHAI died (P = 0.04). Multivariate analysis was done after adjusting for confounders such as severity of illness (using APACHE scores), underlying disease condition (using the syndromic diagnosis at admission), age and duration of ICU stay. This analysis showed a trend towards higher mortality among those with ARHAI compared to those with NARHAI although this difference did not achieve statistical significance (OR = 4.2, 95% CI: 0.95–18.4, P = 0.06) [Table 2].
The median duration of ICU stay among patients with ARHAI and NARHAI was 18 and 17 days, respectively, with no statistically significant difference (P = 0.2) between them. The median duration of hospital stay was 26 and 27 days among ARHAI and NARHAI, respectively, without any statistically significant difference (P = 0.94).
Mortality between ventilator-associated pneumonia and central line-associated blood stream infection
We performed a subgroup analysis among the patients who developed VAP (95 patients) and CLABSI (34 patients), to determine if there were any differences in mortality. We found no significant differences in mortality even after adjusting for potential confounders.
Factors affecting duration of mechanical ventilation
We also performed an analysis to evaluate the factors which affected the ventilator-related outcomes. We categorised the patient's ventilator outcomes as 'poor outcome' if they died during hospital stay, or remained ventilator dependent on day 28 of mechanical ventilation (VFD = 0). 'Good outcome' was defined as those patients who survived and had <28 days of mechanical ventilation. This analysis was only performed among the subgroup of patients who developed VAP. The patients who had poor ventilator outcomes were older and had higher median APACHE III scores.
Acinetobacter-related hospital-acquired infection versus non-Acinetobacter-related hospital-acquired infection
We found that the patients admitted with diseases requiring surgical intervention, following which they developed the HAI, as well as those with neoplastic processes, had a significantly worse ventilator outcome when compared to those with infections and poisoning or drug overdose (P ≤ 0.001). A larger proportion of patients who had a poor ventilator outcome after VAP had ARHAI (78%). This difference in ventilator outcomes based on the type of organism causing the VAP (ARHAI vs. NARHAI) showed a trend to significance on univariate analysis.
After adjusting for possible confounders using a multivariable regression model, we found that ARHAI, higher APACHE III scores at admission and admission with a surgical or neoplastic process were significant predictive factors for poor ventilator outcomes [Table 3].
Antimicrobial susceptibility profile
Among the isolates of A. baumannii identified in this study, 145 were tested for carbapenem susceptibility. Of which, 143 (98.6%) were carbapenem resistant, while only two (1.3%) were carbapenem susceptible. A subset of 75 isolates were tested for colistin susceptibility and one isolate (1.3%) was found to be resistant, while the remaining 74 (98.6%) were found to be susceptible. The proportion of A. baumannii isolates who were resistant to BL/BLI, fluoroquinolones and aminoglycosides was 97%, 85.9% and 96%, respectively. Therefore one A. baumannii isolate was pan-drug resistant, while the remaining were either multidrug resistant or extremely drug resistant according to prior published definitions. The antimicrobial susceptibility profile of A. baumannii is shown in [Table 4].
|Table 4: Secondary outcomes: Factors affecting ventilator outcomes among those who developed a ventilator-associated pneumonia (95 patients)|
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| ~ Discussion|| |
In this study, among the adults admitted in the MICU and SICU, patients who developed ARHAI and those who developed NARHAI had similar demographic characteristics, Charlson comorbidity scores and APACHE III scores at the time of admission. The time taken to acquire the HAI as well as the duration of time, the device had been in situ prior to acquisition of the HAI was also similar between both thegroups. The patients with ARHAI differed from those with NARHAI in that significantly more of them had been admitted with infections (48.7% vs. 15.1%). It was also noted that most of the patients who developed VAP were AR-HAI, with the converse being true for those with CLABSI.
On univariate analysis, we found a statistically significant increase in crude in-hospital mortality among those with ARHAI. After adjustment for confounding variables using binary logistic regression analysis, we found that there was only a trend towards increase in mortality. We also found that patients with VAP caused by A. baumannii had significantly prolonged duration of mechanical ventilation and death during mechanical ventilation when compared to those with non-Acinetobacter-related VAP. There has been a long-standing belief that Acinetobacter infections do not result in higher mortality.
Infections from A. baumannii primarily occur among critically ill patients, and a debate has existed regarding the attributable mortality from these infections. A retrospective matched cohort study concluded that pneumonia caused by A. baumannii was not associated with any significant difference in mortality or length of stay. A similar study by Blot et al. also concluded that there was no significant increase in mortality due to A. baumannii bacteraemia, albeit with more hemodynamic instability, longer duration of ICU stay and longer ventilation dependence.
The argument for A. baumannii being a less potent pathogen than other organisms is finding less support from published literature. The SCOPE National surveillance programme on nosocomial BSIs in United States hospitals found similar crude mortality rates with A. baumannii-related BSI compared to BSI caused by other organisms. A comparison of mortality rates among patients with A. baumannii bacteraemia with those of Klebsiella bacteraemia found an increased mortality of 22.7% among the Acinetobacter group even after adjusting for potential confounders. A large single-centre retrospective matched cohort study which compared 52 cases of nosocomial bacteraemia with matched controls found an excess mortality with Acinetobacter bacteraemia, even after adjusting for disease severity and risk-exposure time. Finally, a systematic review of published case–control and cohort studies found attributable in-hospital mortality rates that ranged from 7.8% to 23% among patients with Acinetobacter-related infections. However, there was significant heterogeneity among the studies in the review.
Although the current study findings did not show increase in mortality among patients with Acinetobacter-related infections, it may be construed as an argument against its pathogenicity; we believe it is equally important to note the crude difference in mortality between ARHAI and NARHAI (57.6% vs. 39.2%). The additional 18% mortality in our cohort of patients with ARHAI suggests that the acquisition of an Acinetobacter-related infection in ICU is at least as bad, if not worse than being infected with any of the other 'proven' pathogens. This finding is in concurrence with other studies. Furthermore, we believe that the difference in mortality may have become more evident with a larger sample size. The results of these studies show that A. baumannii is a significant pathogen as any of the other Gram-negative organisms encountered in the ICU.
The current study findings of poor ventilator outcomes among A. baumannii-related VAP patients are not surprising given our evolving understanding of the ability of A. baumannii to form biofilms over the surface of endotracheal tubes. This is believed to be the cause for the high levels of colonisation seen in the lower respiratory tract.
Kollef et al. found that the occurrence of late-onset VAP due to a certain 'high-risk' pathogen (Pseudomonas sp., Acinetobacter sp. and Xanthomonas maltophila) was an independent risk factor for mortality (adjusted OR = 5.4, 95% CI: 2.8–10.3; P = 0.009). A retrospective study by Yang et al. from Taiwan compared 14-day mortality among patients with A. baumannii-related VAP and bacteraemic Acinetobacter- related non-ventilated hospital-acquired pneumonia. This study showed surprising result that adjusted mortality was lower among ventilated patients with Acinetobacter-related infection (OR = 0.021, 95% CI: 0.075–0.538, P = 0.001). The authors attributed this difference to better airway management and more intensive monitoring and treatment among those on ventilator. Another retrospective study among mechanically ventilated patients in Malaysia compared patients with respiratory isolates positive for A. baumannii versus those with negative cultures. No significant increase in mortality was found, but there was a significantly longer duration of hospital stay among those with A. baumannii positive cultures.
In this study, majority (96%) of the A. baumannii isolates fulfilled the definition of multidrug resistance. Debate has also existed with regard to whether the acquisition of multidrug resistance confers increasing pathogenicity to the organism, thus accounting for the increased mortality seen among patients in ICUs. However, a recent study in Thailand found no statistically significant difference in mortality rates between imipenem-resistant and imipenem-susceptible isolates on multivariate analysis.,
Trend analysis of antibiotic susceptibility rates of A. baumannii based on unpublished data from the same hospital showed significant changes over the past 6 years (2014–2019). The most important trends were decreased susceptibility rates to commonly used antibiotics as well as increasing resistance rates to last resort antibiotics [Supplementary Figure 1] and [Supplementary Figure 1].
Among the BSIs, susceptibility to ceftazidime, cefepime, piperacillin/tazobactam, amikacin, gentamicin, tetracycline and co-trimoxazole has declined. Cefoperazone/sulbactam retained 40% susceptibility over the years, and the reason behind could be due to sulbactam's intrinsic activity against A. baumannii. Decreased susceptibility to carbapenems was observed, and it could be due to rise in the use of meropenem as empiric therapy along with colistin by the clinicians. Among aminoglycosides, netilmicin and tobramycin showed 40% to 45% susceptibility. Minocycline retained 60% susceptibility over the years, whereas tigecycline's susceptibility declined. Though more than 90% susceptibility rates were observed for colistin, gradual increase in resistance is emerging [Supplementary [Figure 1]. The overall susceptibility rate of 25% to 30% was reported for all class of antibiotics except for colistin which showed 92% susceptibility rate against respiratory infections [Supplementary [Figure 2].
Based on thein vitro susceptibility profile from various studies, minocycline, tigecycline, sulbactam and colistin are the most commonly used agents in combination for treating Acinetobacter infections. Minocycline can be considered as an alternative choice, and global studies such as TEST/ATLAS revealed 80% susceptibility against A. baumannii. Despite various studies reporting higher susceptibility rates to tigecycline, the FDA does not recommend tigecycline for treating hospital-acquired VAP, while treatment of bacteraemia with tigecycline is controversial due to its low serum concentration levels. Sulbactam has intrinsic antibacterial activity against A. baumannii due to its selective affinity for the penicillin-binding proteins. However, studies report approximately 50% susceptibility for sulbactam.
Though colistin-based combinations can be considered for treating A. baumannii infections such as BSI and VAP, several controversies have been reported. Due to limited clinical efficacy, colistin is not recommended for the treatment of BSI and VAP. Despite excellent bactericidal activity, low level of colistin was achieved in the epithelial lining fluid (ELF) and with higher doses of nebulised colistin, the concentration can be attained among VAP patients., Based on the PK/PD data, clinical outcome and MIC distribution, CLSI 2020 excluded the susceptible breakpoint for colistin (Humphires, 2019). EUCAST agrees with CLSI that non-polymyxin agents should be preferred over colistin, and this would be effectively helpful in considering colistin as a treatment option in selected cases.
Recently, various novel agents such as cefiderocol and eravacycline were approved and showed goodin vitro activity. However, further clinical trials are warranted to understand the efficacy against BSI and VAP. None of the newly available combinations such as ceftazidime-avibactam, aztreonam-avibactam, imipenem-relebactam and meropenem-vaborbactam have clinical activity against A. baumannii infections except for the β-lactam-β-lactamase enhancer, cefepime-zidebactam.,In vivo studies on cefepime-zidebactam revealed pronounced bacterial killing and show potential clinical utility in the treatment of infections caused by A. baumannii.,
The strengths of this study are (a) the patients were prospectively recruited, (b) each patient was assessed by the same clinician (the principal investigator) to ascertain if they fulfilled the pre-defined definitions for VAP and CLABSI and (c) the criteria for diagnosis of VAP were modified to make it strict – instead of using a single CPIS score, the trend of the score over 48 h because the onset of symptoms with the culture results was considered. We believe that this enhanced the diagnostic confidence prior to study entry.
The limitations of this study are (a) we were unable to achieve the calculated sample size to identify the difference in the primary outcome, (b) we recruited both medical and SICU patients. Both these populations of patients were very different, in that the MICU patients entered the hospital/ICU with a very high APACHE III score as compared to SICU patients, who usually entered the hospital well (with low APACHE III scores at the time of admission), but subsequently entered the ICU after surgical complications and (c) the inherent flaws of the CPIS score in the diagnosis of VAP would still remain despite our best efforts to circumvent them. The new CDC guidelines for diagnosis of VAP were published while this study was close to completion, and hence no changes in the protocol were made (CDC VAP definition, 2020).
| ~ Conclusion|| |
Based on the findings of the current study, In our cohort of critically ill adult patients with VAP and CLABSI, acquiring an Acinetobacter baumanii related HAI resulted in significantly poorer ventilator outcomes and a trend towards higher mortality. Such findings add to the evidence suggesting that A. baumannii is a dangerous pathogen and an argument can be made for early aggressive treatment of mechanically ventilated patients with respiratory isolates positive for A. baumannii.
Financial support and sponsorship
This work was supported by funding from the Fluid Research Grant of Christian Medical College, Vellore.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]