|Year : 2022 | Volume
| Issue : 2 | Page : 187-191
Role of aminoglycosides in management of ventilator-associated pneumonia caused by Klebsiella pneumoniae: A report from a tertiary care hospital in Jaipur
Shaveta Kataria1, Ekadashi Rajni1, Priyanka Thandi2, Mohit Kumar3, Garima Kulhari1
1 Department of Microbiology, Mahatma Gandhi University of Medical Science and Technology, Jaipur, Rajasthan, India
2 Department of Medicine, Subdivisional Hospital Balachaur, Siana, Punjab, India
3 Department of Anesthesia, Rajasthan University of Health Sciences – College of Medical Sciences (RUHS-CMS), Jaipur, Rajasthan, India
|Date of Submission||03-Sep-2022|
|Date of Acceptance||15-Nov-2022|
|Date of Web Publication||23-Dec-2022|
Dr. Mohit Kumar
305, UDB Emarald Nandpuri, Janakpura, Malviya Nagar, Jaipur - 302 017, Rajasthan
Source of Support: None, Conflict of Interest: None
Background and Aim: Ventilator-associated pneumonia (VAP) is considered as a sub-category of healthcare-associated infections and is associated with high morbidity and mortality. Acinetobacter baumannii complex and Klebsiella pneumoniae (K. pneumoniae) are known to be the most important causes. During the last few decades, polymyxins have represented the most commonly used antimicrobial options against multidrug resistant K. pneumoniae. However, in some cases, aminoglycosides were also found to be effective. Materials and Methods: This retrospective observational study was conducted in a tertiary care hospital in Jaipur from June' 2020 to June' 2021. All endotracheal (ET) aspirate samples from the clinically suspected cases of VAP received in microbiology laboratory were processed using the standard procedures and relevant medical records were reviewed. VITEK 2 automated system was used for the bacterial identification and antimicrobial susceptibility testing. Results: Out of 705 ET aspirate samples received during the study period, 467 were found culture positive. Majority 304 (98.1%) were Gram-negative isolates, while only 6 (1.9%) were Gram-positive. 156;51.3% isolates belonged to A. baumannii complex, followed by K. pneumoniae (73;24.0%). Antimicrobial susceptibility profile of 73 K. pneumoniae isolates to aminoglycosides was noted. Out of 73 isolates, 42 were found to be resistant to both gentamicin and amikacin, 12 isolates were sensitive to both, while 19 isolates showed variable susceptibility. Conclusion: K. pneumoniae is an important causative agent of VAP. While polymyxins have an important role in the management of such cases, aminoglycosides need to be given a careful consideration. They can constitute an effective polymyxin sparing regimen, especially for carbapenem-resistant isolates.
Keywords: Aminoglycosides, Klebsiella pneumoniae, ventilator-associated pneumonia
|How to cite this article:|
Kataria S, Rajni E, Thandi P, Kumar M, Kulhari G. Role of aminoglycosides in management of ventilator-associated pneumonia caused by Klebsiella pneumoniae: A report from a tertiary care hospital in Jaipur. Arch Med Health Sci 2022;10:187-91
|How to cite this URL:|
Kataria S, Rajni E, Thandi P, Kumar M, Kulhari G. Role of aminoglycosides in management of ventilator-associated pneumonia caused by Klebsiella pneumoniae: A report from a tertiary care hospital in Jaipur. Arch Med Health Sci [serial online] 2022 [cited 2023 Jan 31];10:187-91. Available from: https://www.amhsjournal.org/text.asp?2022/10/2/187/364959
| Introduction|| |
In a point prevalence study conducted by the CDC in US acute care hospitals in 2015, pneumonia was found to be the most prevalent health care-associated infection, 32% of them being associated with ventilator. Another survey conducted for a period of 4 years from 2010 to 2014, highlighted that the prevalence of ventilator-associated pneumonia (VAP) was 1.6%, associated with a disproportionately high mortality rate of 21.6%.
The lower respiratory tract infection occurring after atleast 48 h of tracheal intubation is known as VAP and has been conventionally classified into early and late onset. Early-onset VAP is more commonly caused by antibiotic sensitive bacteria and presents within 96 h of intensive care unit (ICU) admission, while late-onset VAP is largely caused by multidrug-resistant (MDR) pathogens, presenting usually after 96 h of ICU admission.
There are various risk factors for the acquisition of VAP in critically ill patients. They are mainly related to the intubation techniques, intolerance to enteral feed, long stay in the ICU, and multiple antibiotic intake, etc., In spite of various studies conducted on VAP and its prevention, this lower respiratory infection is still a serious complication in critically ill patients requiring intensive care. VAP can cause patients to have difficulty in weaning off the ventilator, necessitating longer hospital stay, causing a huge financial burden to patients and healthcare infrastructure. It is thus essential to understand the etiopathogenesis of this clinical entity, especially with regard to the risk factors.
The pathogenesis of VAP includes endogenous as well as exogenous causes. The key role is played by the microaspiration of bacteria from the secretions in the space surrounding the endotracheal (ET) tube cuff or the oropharynx. Hence, the early identification of microorganisms responsible for VAP, can be facilitated by the introduction of routine investigation of the bacterial flora in both the upper and lower respiratory tract infections.
The predominant causative organisms of VAP are Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii complex (A. baumannii), Klebsiella pneumoniae (K. pneumoniae) and methicillin-resistant Staphylococcus aureus. Considerably high mortality rates among VAP patients can be attributed to their high rates of antibiotic resistance observed in these bugs., K. pneumoniae was first described by Carl Friedlander in 1882 as a bacterium isolated from the lungs of patients who had died from pneumonia. It is the causative agent of several types of infections in humans, including respiratory tract infections, urinary tract infections, and bloodstream infections.
There are no foolproof tools to determine whether the patient has a VAP. It includes a thorough assessment of clinical profile of the patients, along with biochemical and microbiological parameters. There is the rise in mortality and morbidity due to inadequate treatment of these patients so, when there is higher clinical suspicion of VAP, the empirical antimicrobial therapy must be initiated immediately. However, only 33.3% of the patients fulfils the clinical criteria of sepsis. While in patients having no clinical signs of severe sepsis or septic shock with no microorganisms present on preliminary microbiological testing (gram's staining), the treatment can be withheld for more 18–24 h of collection of specimens till culture reports are collected.
In 2015, antimicrobial resistance was designated as one of the major problems affecting human health and economy by various official reports including those of the UK Government, the Infectious Diseases Society of America, and the World Health Organization. According to the current guidelines, third or fourth generation cephalosporins, piperacillin-tazobactam or a carbapenem in combination with a fluoroquinolone or an aminoglycosides are recommended as an empirical therapy for GNB associated VAP. These infections were treated with “second-line” antibiotics, prior to the sensitisation of usage of newer drugs active against K. pneumoniae carbapenemase producers, such as ceftazidime-avibactam and meropenem-vaborbactam. Further high-level meropenem resistance and resistance to colistin complicated the treatment and their usage was lowered due to renal and nephrotoxicity. Hence, lesser toxic drugs such as aminoglycosides can be considered as a important option in combination with other antibiotics against MDR K. pneumoniae.
K. pneumoniae even showed variable resistance to different types of aminoglycosides. To our knowledge, there is less literature on the comparison on patients who develop VAPs regarding the usage of different aminoglycosides in drug-resistant K. pneumoniae cases. Hence, this study was done to study the prevalence of K. pneumoniae in clinically suspected VAP cases in our set up and to compare the effectiveness of gentamicin and amikacin in these isolates.
| Materials and Methods|| |
This retrospective observational study was conducted in 1400 bedded tertiary care teaching hospital with an approximate annual admission of 5560 ICU inpatients and with 10 ICU wards; from June 1, 2020 to June 30, 2021. The study was conducted after taking due approval from the Institutional Ethical Committee.
The ET aspirate was collected in clinically suspected VAP patients and were inoculated on blood agar and Macconkey agar and incubated at 37°C for 24–48 h. Gram staining was also done. Cultures were then identified by the standard laboratory methods and VITEK 2 automated system (BioMerieux, France). The microbiological interpretive criteria used were quantitative ET aspirate culture with ≥105 CFU/ml and positive gram stain (>10 polymorpho nuclear cells/low-power field and ≥1 bacteria/oil immersion field with or without intracellular bacteria). Only one isolate per patient was included for study purposes. Polymicrobial infections (>3 isolates) were excluded from the analysis.
The K. pneumoniae isolates were further processed and their antibiotic susceptibility testing was done using VITEK 2 compact automated system using the ID-GNB LF 363 cards. The susceptibility patterns of amikacin and gentamicin were further analyzed as in our hospital these aminoglycosides are predominantly used.
Electronic patient records were reviewed and data regarding patients' baseline characteristics, comorbidities, laboratory findings, and clinical outcome were tabulated in Excel worksheet and analyzed.
The data pertaining to demographic and clinical variables were entered in the form of data matrix in Microsoft® Excel® and analyzed using IBM® SPSS® 20.0. (IBM Corp. Release 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). The descriptive statistics for categorical variables were represented in the form of frequencies and percentages. The correlated proportions were compared using McNemar's test for dependent proportions. P < 0.05 was considered as statistically significant.
| Results|| |
The total of 705 ET aspirate samples were received during the study period, out of which 467 (66.2%) were found to be culture positive. 342 (48.5%) samples had a single microbial isolate and were included in the study. One hundred and twenty-five samples revealed the growth of more than three isolates (polymicrobial), hence excluded from the study.
32 Candida spp isolates were disregarded as colonizers as per the NHSN guidelines. Out of remaining 310 clinically significant isolates, majority were Gram-negative (304/310; 98.1%), while only 6 (1.9%) were Gram-positive. Among, Gram-positive isolates predominant were S. aureus (4;66.7%), followed by Enterococcus faecium (2;33.3%). Among Gram-negative organisms', maximum (156;51.3%) isolates were A. baumannii complex, followed by K. pneumoniae (73;24.0%) and P. aeruginosa (46;15.1%) [Table 1]. Further the antibiotic susceptibility pattern of 73 K. pneumoniae spp. isolates was studied. Fourty-two isolates were sensitive only to colistin and tigecycline. On analyzing the susceptibility pattern of aminoglycosides, variable results were observed and their minimum inhibitory concentrations are shown in [Table 2].
|Table 1: Distribution of various Gram-negative organisms isolated from endotracheal aspirate (n=304)|
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|Table 2: Minimum inhibitory concentrations of aminoglycosides observed in Klebsiella pneumoniae isolates (n=73)|
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Out of 73 isolates, 42 were found to be resistant to both gentamicin and amikacin and 12 isolates were sensitive to both. While rest of isolates (19) showed variable susceptibility to both the antibiotics. 5 were resistant to gentamicin and sensitive to amikacin and 11 were resistant to amikacin and sensitive to gentamicin. Two isolates were amikacin sensitive and intermediate susceptibility to gentamicin while single isolate showed vice versa. There was no statistically significant difference observed between the antibiotic susceptibility for these two drugs (amikacin and gentamicin), i.e., P = 0.17 [Table 3].
|Table 3: Aminoglycoside resistance profile of 73 Klebsiella pneumoniae isolates|
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| Discussion|| |
In the present study, the prevalence of microorganisms in clinically suspected VAP cases was 66.2%. Majority were Gram-negative isolates, i.e., 304 (98.1%), while only 6 (1.9%) were Gram-positive isolates. Salehi et al. have also reported 152 (72.4%) isolates as GNB amongst the 210 VAP patients studied.
Among the Gram-positive, predominant isolates were S. aureus (66.7%). While among Gram-negative maximum (51.3%) isolates were A. baumannii complex, followed by K. pneumoniae (24.0%) and P. aeruginosa (15.1%). In a study conducted in China, K. pneumonia was the predominant isolate in 70 mechanically ventilated patients and out of these isolates, 61.4% developed VAP during their ICU stay. Study conducted by Liu and Guo also revealed 73 K. pneumoniae patients at two different hospitals within a time period of 9 years. Recent studies have shown a steep rise in the incidence of K. pneumoniae and Acinetobacter species in such cases.
The antibiotic susceptibility pattern of K. pneumoniae isolates was studied. 42 isolates were XDR (extensively drug resistance), sensitive only to colistin and tigecycline. A study conducted by Salehi et al. revealed more than 3/4th isolates to be resistant to meropenem and amikacin, while piperacillin-tazobactam and colistin showed 12.0% and 8.0% resistance respectively.
The aminoglycosides primarily bind to the aminoacyl site of 16S ribosomal RNA, misreading of the genetic code and further inhibits the process of translocation. The early steps required for the synthesis of proteins are not altered, but due to alteration in the mechanisms for ensuring translational accuracy, the elongation fails to occur. The developing antimicrobial activity is usually bactericidal against susceptible aerobic GNB. While the mechanism of resistance of aminoglycosides is drug inactivation by aminoglycoside-modifying enzyme, drug permeability through Gram-negative outer membrane and decrease influx of drug.,
The susceptibility pattern of aminoglycosides was studied and observed that out of 73 isolates, 42 were found to be resistant to both gentamicin and amikacin and 12 isolates were sensitive to both. While rest of isolates (19) showed variable susceptibility to both the antibiotics. 5 were resistant to gentamicin and sensitive to amikacin and 11 were resistant to amikacin and sensitive to gentamicin. Two isolates were amikacin sensitive and intermediate susceptibility to gentamicin while single isolate showed vice versa. The statistical analysis between gentamicin and amikacin was studied and it was observed that there is no statistical significance difference between these drugs i.e., P = 0.17. This means that both the antibiotics are equally effective in the treatment of K. pneumoniae induced VAP. Similar results were observed by Forgan-Smith and McSweeney, wherein both aminoglycosides had a similar spectrum of action and are highly active against most of aerobic GNB. Gentamicin was more effective than amikacin against most species of Enterobacterales and other organisms like Haemophilus influenzae and S. aureus while amikacin showed better activity against Klebsiella and Providencia isolates.
A variable resistance against aminoglycosides (n = 74) was observed in the study conducted by Liu and Guo. 18 (12 hyper virulent + 6 capsular) isolates were found to be resistant to amikacin, while 29 (8 hypervirulent +21 capsular) isolates were found to be gentamicin resistant. While a study conducted in China, showed similar results to that of our study. Out of 43 isolates, 32 were found to amikacin resistant while, only 31 were found to be gentamicin resistant.
Hence, the variable resistance pattern toward aminoglycosides was observed and molecular studies need to be done to find out the actual reason for such difference as mechanism of action and mechanism of resistance of both the antibiotics is found to be similar.
The authors strongly advocate that each hospital generate its own antibiogram, (location wise and sample wise if resources permit) to guide clinicians in making an informed and optimal choice of antibiotics. This would enable the empiric treatment regimens to be customized according to the local distribution of pathogens associated with VAP and their respective antimicrobial susceptibilities. It is very difficult to streamline a blanket treatment guideline for VAP caused by MDR-GNBs, but aminoglycosides may have an pivotal role to play, if the culture report shows the isolate to be susceptible and the patient's clinical milieu permits its usage.
So, the benefits of this study is that, aminoglycosides can be used as treatment option, especially in the set ups wherein VAP is predominantly caused by MDR and XDR organisms, polymyxins constitute an important part of empirical regimen. However, there are serious issues pertaining to its increasing usage, namely growing resistance and hence compromising its life saving role as antibiotic of last resort in future. In such situations, aminoglycosides may be used as an alternative therapy (if the laboratory report predicts susceptibility) and help preserve their efficacy. There are concerns regarding its usage like increased risk of ototoxicity and nephrotoxicity and poor lung penetration which need to be considered. Limitation of the present study is that we are not able to reach the root cause of difference between susceptibility patterns of these antibiotics.
| Conclusion|| |
K. pneumoniae is an emerging second most common causative agent for VAP. Due to increase in resistance against most of the antibiotics, the prevalence of MDR K. pneumoniae cases is rising, leading to colistin and polymyxin B as only source of treatment. While polymyxins have an important role in the management of such cases, aminoglycosides need to be given a careful consideration. They can constitute an effective polymyxin sparing regimen. Some of these MDR organisms shows variable resistance against aminoglycosides and molecular studies need to be done to find out the actual reason for such difference as mechanism of action and mechanism of resistance of both the antibiotics are found to be similar, and hence, they can be used as treatment option before going toward higher antibiotics.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Corrado RE, Lee D, Lucero DE, Varma JK, Vora NM. Burden of adult community-acquired, health-care-associated, hospital-acquired, and ventilator-associated pneumonia: New York City, 2010 to 2014. Chest 2017;152:930-42.
Gunalan A, Sistla S, Sastry AS, Venkateswaran R. Concordance between the National Healthcare Safety Network (NHSN) surveillance Criteria and Clinical Pulmonary Infection Score (CPIS) criteria for diagnosis of Ventilator-Associated Pneumonia (VAP). Indian J Crit Care Med 2021;25:296-8.
Kuroiwa R, Tateishi Y, Oshima T, Inagaki T, Furukawa S, Takemura R, et al
. Mechanical insufflation-exsufflation for the prevention of ventilator-associated pneumonia in intensive care units: A retrospective cohort study. Indian J Crit Care Med 2021;25:62-6.
Gupta A, Ampofo K, Rubenstein D, Saiman L. Extended spectrum beta lactamase-producing Klebsiella pneumoniae
infections: A review of the literature. J Perinatol 2003;23:439-43.
Papajk J, Mezerová K, Uvízl R, Štosová T, Kolář M. Clonal diversity of Klebsiella
spp. And Escherichia
spp. Strains isolated from patients with ventilator-associated pneumonia. Antibiotics (Basel) 2021;10:674.
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al.
International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9.
Perez F, Endimiani A, Ray AJ, Decker BK, Wallace CJ, Hujer KM, et al
. Carbapenem-resistant Acinetobacter baumannii
and Klebsiella pneumoniae
across a hospital system: Impact of post-acute care facilities on dissemination. J Antimicrob Chemother 2010;65:1807-18.
Friedlaender C. Ueber die schizomycetenbei der acuten fibrösen pneumonie. Arch Patholog Anat Physiol Klin Med 1882;87:319-24.
Sugden R, Kelly R, Davies S. Combatting antimicrobial resistance globally. Nat Microbiol 2016;1:16187.
Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002;165:867-903.
Koulenti D, Lisboa T, Brun-Buisson C, Krueger W, Macor A, Sole-Violan J, et al.
Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units. Crit Care Med 2009;37:2360-8.
Canadian Critical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated pneumonia. N Engl J Med 2006;355:2619-30.
World Health Organization (WHO). Antimicrobial Resistance: No Action Today, No Cure Tomorrow. Geneva, Switzerland: WHO Press; 2011. Available from: https://www.who.int/world-health-day/2011/en
. [Last updated on 2019 Feb 19].
Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases society of America and the American Thoracic Society. Clin Infect Dis 2016;63:e61-111.
Rivera-Espinar F, Machuca I, Tejero R, Rodríguez J, Mula A, Marfil E, et al.
Impact of KPC production and high-level meropenem resistance on all-cause mortality of ventilator-associated pneumonia in association with Klebsiella pneumoniae
. Antimicrob Agents Chemother 2020;64:e02164-19.
Petrosillo N, Taglietti F, Granata G. Treatment options for colistin resistant Klebsiella pneumoniae
: Present and future. J Clin Med 2019;8:934.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; 31st
Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute; 2021.
Porzecanski I, Bowton DL. Diagnosis and treatment of ventilator-associated pneumonia. Chest 2006;130:597-604.
Funke G, Monnet D, deBernardis C, von Graevenitz A, Freney J. Evaluation of the VITEK 2 system for rapid identification of medically relevant gram-negative rods. J Clin Microbiol 1998;36:1948-52.
Salehi M, Jafari S, Ghafouri L, Malekafzali Ardakani H, Abdollahi A, Beigmohammadi MT, et al.
Ventilator-associated pneumonia: Multidrug resistant acinetobacter versus. Extended spectrum beta lactamase-producing Klebsiella
. J Infect Dev Ctries 2020;14:660-3.
Guo S, Xu J, Wei Y, Xu J, Li Y, Xue R. Clinical and molecular characteristics of Klebsiella pneumoniae
ventilator-associated pneumonia in mainland China. BMC Infect Dis 2016;16:608.
Liu C, Guo J. Characteristics of ventilator-associated pneumonia due to hypervirulent Klebsiella pneumoniae
genotype in genetic background for the elderly in two tertiary hospitals in China. Antimicrob Resist Infect Control 2018;7:95.
Cavallo G, Martinetto P. The mechanism of action of aminoglycosides. G Batteriol Virol Immunol 1981;74:335-46.
Doi Y, Wachino JI, Arakawa Y. Aminoglycoside resistance: The emergence of acquired 16s ribosomal RNA methyltransferases. Infect Dis Clin North Am 2016;30:523-37.
Forgan-Smith WR, McSweeney RJ. Gentamicin and amikacin – An in vitro
comparison using 1000 clinical isolates. Aust N Z J Med 1978;8:383-6.
[Table 1], [Table 2], [Table 3]