|Year : 2019 | Volume
| Issue : 1 | Page : 16-23
Appropriateness of antimicrobial therapy for culture-proven blood stream infections
Monica Selvan, R Deepashree, Prasanna Bhat, R Akshatha, Sunil Jayakar, Apurba Sankar Sastry
Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Web Publication||12-Aug-2019|
Dr. Apurba Sankar Sastry
Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Blood stream infections (BSIs) are responsible for significant morbidity and mortality. Numerous studies have pointed to the importance of early and prompt institution of empirical antimicrobial therapy in reducing morbidity and mortality in BSI. The antibiotic spectrum must be narrowed as soon as possible, considering the clinical condition of the patient, the pathogens identified in cultures and the sensitivity profile obtained from the antibiogram. When no evidence of bacterial infection is present, antibiotic therapy must be suspended. However, it is often observed that the clinician does not adhere to the guideline and continues with the same empirical treatment.
MATERIALS AND METHODS: The study was conducted at Department of Microbiology, in a tertiary care hospital from April 2017 to September 2017. Two hundred patients with microbiologically documented BSIs were included in the study. They were followed up to find the appropriateness of change in empirical treatment carried out according to culture sensitivity report, and antimicrobial consumption was also calculated.
RESULTS: We observed that there was an increased use of antipseudomonal penicillins plus beta-lactamase inhibitors, amikacin and carbapenems which was due to higher prevalence of multidrug-resistant Gram-negative bacilli among blood culture isolated. We also found that in most of the patients, the empirical treatment was inappropriately modified at day four after availability of culture reports, i.e., inappropriately escalated or de-escalated or continued while there was no indication to do so.
CONCLUSION: Treatment inappropriate group was associated with higher treatment failure as compared to treatment appropriate group. Studies of the other factors associated with inappropriate treatment such as changes in resistance patterns, antimicrobial-related adverse effect and of the long-term clinical outcomes are warranted.
Keywords: Antibiotics, antimicrobial policy, antimicrobial stewardship program, de-escalation, escalation, extensively drug resistant, multidrug resistant, treatment, VRSA
|How to cite this article:|
Selvan M, Deepashree R, Bhat P, Akshatha R, Jayakar S, Sastry AS. Appropriateness of antimicrobial therapy for culture-proven blood stream infections. J Acad Clin Microbiol 2019;21:16-23
|How to cite this URL:|
Selvan M, Deepashree R, Bhat P, Akshatha R, Jayakar S, Sastry AS. Appropriateness of antimicrobial therapy for culture-proven blood stream infections. J Acad Clin Microbiol [serial online] 2019 [cited 2020 Feb 26];21:16-23. Available from: http://www.jacmjournal.org/text.asp?2019/21/1/16/264251
| Introduction|| |
Blood stream infections (BSIs) are responsible for significant morbidity and mortality. Numerous studies have pointed to the importance of early and prompt institution of empirical antimicrobial therapy in reducing morbidity and mortality in BSI. The choice of empirical antimicrobial agent depends on the infecting organism (s) suspected and the local hospital antibiogram., In de-escalation strategy, broad-spectrum empirical antimicrobials are used early (if local antibiogram suggests a high prevalence of multidrug-resistant [MDR] pathogens); conversely in escalation strategy, narrow-spectrum antimicrobials are instituted empirically (in hospitals with low prevalence of MDR pathogens). Regardless of the agent used in empirical therapy, its appropriateness has to be reviewed at 72–96 h, after the availability of culture and antimicrobial susceptibility test (AST) report, Depending on the AST report, the empirical antimicrobials can either be: continued continuation approach or brought down, by using narrowspectrum antimicrobials deescalation approach or escalated to broadspectrum antimicrobials escalation approach.,,
Many studies have shown that physicians do not adhere to the antimicrobial policy guidelines for change of empirical therapy following AST report. In most cases, empirical therapy is either continued without change or may be changed irrationally based on clinical judgement without taking the culture sensitivity reports into consideration.,, With thorough literature search, it was noted that there have been only few studies from India and only one study from Pondicherry conducted on evaluating the appropriateness of monitoring the change in antimicrobial practice following culture sensitivity report. Hence, this study was designed to analyse the action taken by the clinician to revise the antimicrobial therapy once the culture and sensitivity reports become available. Furthermore, the impact of the initiation of targeted and appropriate therapy in terms of clinical outcome at day 30 follow-up was studied.
| Materials and Methods|| |
This is a prospective observational study conducted in a 2100-bedded tertiary care hospital with 21 intensive care units, located in South India, after obtaining the approval (JIP/IEC/2017/0160) of its institutional ethics committee, which waived the need for informed consent from the patients.
During the study period, all adult patients with microbiologically documented BSIs based on the laboratory records of blood culture investigations were included as study sample.
The following cases were excluded from the study: (i) those reported as contaminants, (ii) polymicrobial BSIs, (iii) patients with age <18 years, (iii) length of stay less than three days after start of empirical therapy, (iv) antimicrobials started for another clinically documented infection at a different sites, (iii) patients already put on definitive therapy based on previous blood culture reports, (v) blood culture-proven fungal infections and (vi) repeat isolates from the same patient (positive follow-up blood culture containing the same pathogen during antimicrobial treatment as the original pathogen was classified as persistent and was not counted as a new infection).
Data collection and classification
The hospital records and laboratory registers of the study sample (i.e., patients who met with the inclusion/exclusion criteria) were screened prospectively on a daily basis. The study sample was followed until their discharge or 30 days of institution of antimicrobials whichever is later. The following data were collected.
- Demographic detail: age and sex
- Clinical profile of the patients: clinical profile of the patients to know the source of bacteraemia, acute physiology and chronic health evaluation (APACHE) II score and underlying comorbidity
- Laboratory data: the data on the following laboratory parameters were captured: (i) frequency of culture sent before antimicrobial start, (ii) turnaround time (TAT) of blood culture reporting, (iii) frequency and (iv) type of organisms isolated from blood culture, antibiotic susceptibility pattern of organism isolated in blood
- Data on antimicrobials use: as per the standard reference, and local antibiogram, the antimicrobial classes were categorised according to their spectrum of activity from Rank 1–4 (increasing order of spectrum) as given below in [Table 1]. Data on the following parameters were collected:
- Frequency of monotherapy and combination therapy used
- Frequency of antimicrobials used in terms of days of therapy
- Antibiotic consumption expressed by number of prescriptions (NOPs) used was calculated.
- Approach taken at fourth day to modify empirical treatment: the approach for changing empirical antimicrobial at day four were categorised into escalation, de-escalation and continuation of empirical antimicrobial (as per the criteria given below); each was further classified into appropriate and inappropriate. Therefore, the approach taken at fourth day was categorised into the following six types [Table 2]
- Appropriate de-escalation
- Inappropriate de-escalation
- Appropriate escalation
- Inappropriate escalation
- Appropriate continuation
- Inappropriate continuation
- 30th day clinical outcome: data on 30th day clinical outcome indicators collected such mortality indicators (e.g., deaths) and morbidity indicators (complications developed). All these indicators were classified as infection related only after consensus arrived between the treating physician and the infection control team. The clinical outcome was classified as treatment successful or treatment failure based on the following parameters:
- Treatment successful: (i) discharge without complication or (ii) BSI treated, but still in hospital due to other reason
- Treatment failure: if one among the following is present: (i) infection-related deaths or (ii) infection-related complications developed.
|Table 1: Ranking of antibiotic classes according to their spectrum of activity|
Click here to view
|Table 2: Definitions of types of action indicated/taken at day four after culture report available|
Click here to view
Ranking of antibiotic classes according to their spectrum of activity: [Table 1].
- Rank 1: narrow-spectrum antimicrobials
- Rank 2: broad-spectrum antimicrobials
- Rank 3: extended-spectrum antimicrobials
- Rank 4: restricted antimicrobials.
The collected data were entered into Microsoft excel sheet, and analysis of data was carried out using SPSS version 21 software (Armonk, NY: IBM Corp.). Continuous data were expressed as medians (ranges) and compared using the Mann–Whitney U-test. Categorical data were expressed as percentages and were compared using the Chi-square test. Odds ratio and 95% confidence intervals were calculated. P ≤ 0.05 was considered as statistically significant.
| Results|| |
This study was conducted at Department of Microbiology, a tertiary care teaching hospital located in South India. The study duration was for a period of six months, from April 2017 to September 2017.
As shown in [Figure 1], of 1685 individuals with positive blood culture during the study period (total of 8879 blood culture investigations received), 1523 (17.1%) were categorised into those BSIs developed as 162 were contaminated. The following were further excluded as per the study protocol: (i) polymicrobial blood cultures (n = 21), (ii) <18 years (n = 168), (iii) length of stay less than three days after start of therapy (n = 530), (iv) antibiotic started for another clinically determined infection (CDI) (n = 452) and (v) already on definitive therapy based on culture reports (n = 152). After exclusion and inclusion criteria were met, the analysable patients at day four available for the study were 200. Nine patients were lost to follow-up during the analysis period. 191 patients were available for follow-up at 30th day for determining outcome measure.
The median age was 44.2 years. Male to female ratio was found to be 1.7:1 (127:73). The median APACHE II score at admission and at day four was recorded as 13.94 and 12.73, respectively.
Central line associated infections (22%) (44) & urinary tract infections (21%) (44) accounted for the most common source of bacteremia. Urinary tract infection (UTI) and other kidney diseases accounted for the most common diagnosis found on patient's clinical record 18.5% (37) followed by gastrointestinal diseases 10% (20). Diabetes mellitus 30.5% (61) and hypertension 15.5% (31) were the most common underlying comorbid condition observed. Most blood cultures were automated type 56.5% (113). It was observed that only 36% (72) of times the culture sent before antibiotic start. The median TAT, in days, to blood culture report was 4.2 days.
Total of 622 types of different prescriptions were used for the 200 patients under the study at an average frequency of 3.1 prescriptions per patient, of which 40.2% (250) were monotherapy and 59.8% (372) were combination therapy (≥2 antimicrobials).
The days of therapy (DOTs) of antimicrobial categories along with the NOPs used are depicted in [Table 3]. The total DOTs were recorded as 4218 days and NOPs were 622. Most antimicrobials were used as combined therapy (DOTs 3057 [72.5%] and NOPs 372 [60%]). Monotherapy of was given only in 40% (372) of prescriptions with DOTs 27.5% (1161 days). Rank 2 antimicrobials were the most common to use (accounted for 60.8% of NOPs and 57.9% of DOTs) followed by Rank 3 antimicrobials (22.2% of NOPs and 25.6% of DOTs).
The consumption and frequency of prescription of individual antimicrobial class under each rank categories are depicted in [Table 4]. Overall Rank 2 antimicrobials were most commonly used; the most common being antipseudomonal penicillins ± BLI (Beta lactam inhibitors) (21.4% of total DOTs and 20.5% of total prescriptions) followed by aminoglycoside higher generation (19.0% of total DOTs and 18.0% of total prescriptions). Amongst the Rank 3 antimicrobials, carbapenems were the most commonly used, (15.8% of total DOTs and 14.3% of total prescriptions) while it was 3rd most common amongst all the antimicrobials used. Polymyxins (e.g., colistin) was the most frequent antimicrobials used of Rank 4 category antimicrobials (5.8% of total DOTs and 6.4% of total prescriptions). Rank 1 antimicrobials were used least common. The most common among them are lower generation quinolones (2.4% of total DOTs and 2.4% of total prescriptions). Among the Gram-positive antimicrobials, glycopeptides were the most common to use (9.1% of total DOTs and 9.8% of total prescriptions).
|Table 4: Usage of individual antimicrobial class under each categories (expressed as n [%])|
Click here to view
The relative frequency of appearance of antimicrobials in prescriptions either as monotherapy or as part of combination therapy has been described for the 4 antimicrobial categories (Rank 1–4) in [Table 4]. Rank 2 (62.9%) antimicrobials were the most common category used followed by Rank 3 (17.3%). Overall combination of antipseudomonal penicillins ± BLI with other Gram-negative antimicrobials of various class accounted for the most frequent combination.
At day four (following the availability of culture report), we have evaluated the strategy of treatment followed by the physicians to modify the empirical antimicrobials. We have compared the treatment strategy indicated based on culture report with the treatment strategy followed [Table 5].
Among 200 study patients, we observed that de-escalation was indicated the most (57.5% (115)), followed by escalation (31.5% (63)) and continuation of antimicrobials (11% (22)). However, the appropriate de-escalation, escalation and continuation of antimicrobials as defined in the protocol were followed only in 20% (23/115), 17.4% (11/63) and 86.3% (19/22) of cases, respectively. The overall appropriate treatment was given in 26.5% (53/200) of cases, and inappropriate treatment was given in 73.5% (147/200) of cases.
[Table 6] and [Table 7] depict the various types of errors done during inappropriate treatment. Inappropriate continuation accounted for the most common type of inappropriate treatment 47% (69) followed by inappropriate escalation 29.2% (43) and inappropriate de-escalation 35% (23.8). The most frequent error done in inappropriate de-escalation was 'Narrowing down the spectrum not according to culture report' 74.2% (26/35) and in inappropriate escalation was 'Bringing up the class not according to culture report with/without removal of existing narrow-spectrum antimicrobials' 65.2% (26/35).
|Table 6: Comparison between strategy indicated and strategy followed at day four|
Click here to view
[Figure 2] depicts the association between treatment approach followed and 30th-day clinical outcome. Overall, the treatment failure was observed among 38.7% (74/191) patients. Nine patients were lost to follow-up (one in appropriate treatment group and eight in inappropriate treatment group). Among the patients received appropriate treatment, treatment failure was observed in 34% (18/52) whereas among inappropriately treated cases, treatment failure was noticed 40% (56/139). Among the cases with treatment failure, 71.6% (53/74) died and 6.8% (5) discharged with complications and 21.6% (16) were still in hospital with complications at 30th-day follow-up.
|Figure 2: Association between treatment approach followed and clinical outcome|
Click here to view
| Discussion|| |
BSIs remains an important therapeutic challenge and is considered as one among the leading cause of morbidity and mortality, particularly in developing countries. Early institution of empirical therapy is key to the successful clinical outcome. However, empirical therapy may not be always appropriate and has to be tailored at fourth day of infection following availability of culture report. Inappropriate definitive, i.e., pathogen-directed therapy may lead to therapeutic failure. This study was undertaken to find the association with appropriateness of pathogen-directed treatment (i.e., tailoring of empirical treatment according to culture report) with that of clinical outcome.
In the present study, the overall prevalence of microbiologically documented BSI was 17.1% which was in concordance to several studies published elsewhere (8%–43%).,, Before the start of antimicrobials, blood culture was sent only in 36% of cases. In a study conducted by Braykov et al., appropriate cultures were collected in only 59% of patient population. This explains for the lower rate of positivity of blood cultures. In the present study, the mean age was 44.1 years while other studies showed mean age of around 60 years. In our study, male predominance was there which was in concordance with other studies.,
In the current study, majority of patients were clinically diagnosed to have the source of infection from central line (22%), followed by urinary tract (21%), respiratory tract (18.5%) and gastrointestinal tract (13%) which was in concordance with studies done by Annamallaei and Bhat and Mehta et al. However, study done by Lueangarun and Leelarasamee showed predominance of respiratory tract infection (32.8%) followed by GI infection (23.6%) and UTI (20.5%).
The etiological agents causing sepsis & AST pattern is constantly changing. This plays an important role in effective management of the BSI. We found that Gram-negative bloodstream infections outnumbered the Gram-positive bacteremia (73.7% vs. 26.3%). This was concordant to various studies (60%–80% Gram-negative bacilli [GNB]).,, Rate of MRSA (Methicillin resistant Staphylococcus aureus), VRE (Vancomycin resistant Enterococci) and VRSA (vancomycin Resistant Staphylococcus aureus)/VISA (vancomycin intermediate Staphylococcus aureus) were found as 30%, 17% and 0%, respectively. These data were concordant to previous study done in the same centre. Forty per cent of MDR-GNB were MDR, similar to as reported by other studies.,
Monotherapy and combined therapy (≥2 antimicrobials) were used in 40.2% and 59.8% of prescriptions, respectively, accounting for 27.5% and 72.5% of DOTs, respectively. Rank 2 antimicrobials were the most common to use either as monotherapy or in combination. A study conducted by Paul et al. and Braykov et al. also showed increased use of Rank 2 and Rank 3 class antimicrobial agents., In the present study overall, the most commonly used antimicrobial agent was antipseudomonal penicillins with or without BL-BLI. However, in contrast to our finding, Braykov et al. reported Rank 2 quinolones as the most frequent class used. This discordance is due to the increased rates of prevalence of MDR Gram-negative organisms such as Pseudomonas and Acinetobacter species.
Antimicrobial de-escalation is a strategy proposed to allow for the rational use of broad-spectrum antimicrobial therapy as the empiric treatment for infections and minimise the exposure to these agents. The need for prompt, effective antimicrobial therapy for patients with known or suspected infections is a mandate to reduce misuse of antimicrobial agents and to limit the emergence of resistance to antimicrobial therapy. We evaluated the appropriateness of the treatment strategy followed by the physicians to modify the empirical antimicrobials at day four (following the availability of culture report) and found that de-escalation was done only in 20% of cases where it was indicated. Shime et al. documented a de-escalation carried on 57% of indicated cases and Paskovaty et al. reported de-escalation rate of 58%. In our study, we also encountered that the appropriate escalation and continuation of empirical treatment were carried out only on 17.4% and 86.3% of indicated.
The appropriate and inappropriate treatment was given in 26.5% and 73.5% of cases, respectively. Based on this, we further studied the association between treatment & 30th day mortality. We observed that the treatment inappropriate group was associated with higher (40%) treatment failure as compared to treatment appropriate group (34%). Although this is not a very big difference, still, it is statistically significant (P < 0.05). Various studies published elsewhere showed higher association of treatment failure in inappropriate treatment group.,,
| Conclusion|| |
In our study, we found that, amongst the various types of antimicrobials used in BSI, the rank 2 & 3 antimicrobials used were higher. This can be due to the fact that there are more MDR GNB isolated in the Blood culture.
We also found that in most of the patients, the empirical treatment was inappropriately modified at day four after availability of culture reports, i.e., inappropriately escalated or de-escalated or continued while there was no indication to do so. Treatment inappropriate group was associated with higher treatment failure as compared to treatment appropriate group. Studies of the other factors associated with inappropriate treatment such as changes in resistance patterns, antimicrobial-related adverse effect and the long-term clinical outcomes are warranted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S, et al.
The global threat of antimicrobial resistance: Science for intervention. New Microbes New Infect 2015;6:22-9.
Walia K, Ohri VC, Mathai D; Antimicrobial Stewardship Programme of ICMR. Antimicrobial stewardship programme (AMSP) practices in India. Indian J Med Res 2015;142:130-8.
] [Full text]
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al.
Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45:486-552.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al.
The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10.
Annamallaei S, Bhat KS. Correlation of empiric antibiotic use with susceptibility pattern of blood isolates in septicemic patients in an Intensive Care Unit. J Curr Res Sci Med 2017;3:29-35. [Full text]
Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, Corcia-Palomo Y, Fernández-Delgado E, Herrera-Melero I, et al.
De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2014;40:32-40.
Yamana H, Matsui H, Tagami T, Hirashima J, Fushimi K, Yasunaga H. De-escalation versus continuation of empirical antimicrobial therapy in community-acquired pneumonia. J Infect 2016;73:314-25.
Paul M, Dickstein Y, Raz-Pasteur A. Antibiotic de-escalation for bloodstream infections and pneumonia: Systematic review and meta-analysis. Clin Microbiol Infect 2016;22:960-7.
Braykov NP, Morgan DJ, Schweizer ML, Uslan DZ, Kelesidis T, Weisenberg SA, et al.
Assessment of empirical antibiotic therapy optimisation in six hospitals: An observational cohort study. Lancet Infect Dis 2014;14:1220-7.
Pandey S, Raza S, Bhatta CP. The aetiology of the bloodstream infections in the patients who presented to a tertiary care teaching hospital in Kathmandu, Nepal. J Clin Diagn Res 2013;7:638-41.
Parajuli NP, Parajuli H, Pandit R, Shakya J, Khanal PR. Evaluating the trends of bloodstream infections among pediatric and adult patients at a teaching hospital of Kathmandu, Nepal: Role of drug resistant pathogens. Can J Infect Dis Med Microbiol 2017;2017:8763135.
Lueangarun S, Leelarasamee A. Impact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: A retrospective study. Interdiscip Perspect Infect Dis 2012;2012:765205.
Mehta M, Dutta P, Gupta V. Antimicrobial susceptibility pattern of blood isolates from a teaching hospital in North India. Jpn J Infect Dis 2005;58:174-6.
Moolchandani K, Sastry AS, Deepashree R, Sistla S, Harish BN, Mandal J. Antimicrobial resistance surveillance among intensive care units of a tertiary care hospital in Southern India. J Clin Diagn Res 2017;11:DC01-7.
Shime N, Kosaka T, Fujita N. De-escalation of antimicrobial therapy for bacteraemia due to difficult-to-treat gram-negative bacilli. Infection 2013;41:203-10.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]