An infection in the lung parenchyma preceded by invasive mechanical ventilation for at least a duration of 48 to 72 h at intensive care unit (ICU) setup is known as ventilator-associated pneumonia (VAP). VAP is one of the most common mechanical ventilator-associated infections in intubated critically ill patients and a difficult-to-treat infection among the nosocomial infections with high rate of mortality worldwide. VAP accounts for up to 29.1% of nosocomial pneumonia [1]. VAP causes hospitalization time longer, amplified treatment cost, and wastage of medical resources [2]. Despite advancements of microbiological techniques, standard diagnosis criteria and treatment of VAP is still a dueling issue which impedes the overall treatment process and abates clinical outcome in critically ill patients [1,2].
According to the clinical guideline of the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) in 2016, up to 13% of patients die from VAP in each year [3], while another multi-center study showed that the 30-day mortality due to VAP, early VAP and late VAP was 29.9%, 19.2% and 31.4%, respectively in Europe [4]. A meta-analysis of 195 studies found that from 2006 to 2014 in China’s mainland, the cumulative VAP incidence rate was 23.8% with 22.83 patients per 1000 ventilator days [5]. A recent single-center study in Bangladesh found that 36.5% of mechanically ventilated patients in ICU developed VAP of which 78.9% and 21.2% was early and late VAP, respectively [6].
The gram-negative
The objective of this study is to compare the ability of eradication of PDR
This was a single-centre retrospective cohort study conducted on 222 (N) mechanically ventilated adult patients (≥ 18 years) admitted from May 11, 2019 to October 19, 2020 in the ICU of a tertiary care hospital in Dhaka, Bangladesh. All the patients of the study with PDR
The PDR
Susceptibility of Klebsiella pneumoniae to all available antibiotics according to the CLSIa and EUCASTb guideline.
Antibiotics | Clinical breakpoints (μg/mL) | MIC (μg/mL) | Interpretation | Comment: Type of resistance |
---|---|---|---|---|
Amikacin | ≤ 16, 32, ≥ 64 | > 16 | Resistant | Pandrug-resistant |
Cefepime | ≤ 2, 4-8, ≥ 16 | > 16 | Resistant | |
Cefixime | ≤ 1, 2, ≥ 4 | > 2 | Resistant | |
Ceftazidime/Avibactam | ≤ 8/4, ≥ 16/4 | > 8/4 | Resistant | |
Ceftriaxone | ≤ 1, 2, ≥ 4 | > 4 | Resistant | |
Cefuroxime | ≤ 4, 8-16, ≥ 32 | > 8 | Resistant | |
Ciprofloxacin | ≤ 1, 2, ≥ 4 | > 1 | Resistant | |
Colistin | ≤ 2, ≥ 4 | > 2 | Resistant | |
Gentamicin | ≤ 4, 8, ≥ 16 | > 4 | Resistant | |
Imipenem | ≤ 1, 2, ≥ 4 | > 4 | Resistant | |
Levofloxacin | ≤ 2, 4, ≥ 8 | > 2 | Resistant | |
Meropenem | ≤ 1, 2, ≥ 4 | > 8 | Resistant | |
Piperacillin/Tazobactam | ≤ 16/4, ≥ 28/4 | > 64/4 | Resistant | |
Polymyxin B | ≤ 2, ≥ 4 | > 2 | Resistant | |
Tigecycline | ≤ 1, 2, ≥ 2 | > 2 | Resistant |
Clinical and Laboratory Standards Institute;
European Committee for Antimicrobial Susceptibility Testing; μg: microgram; mL: milliliter; MIC: minimum inhibitory concentration
All the retrospective data of this study were collected from the electronic database and medical records of the hospital. The research related to human use has been complied with all the relevant national regulations, institutional policies, and under the tenets of the Declaration of Helsinki. This study was approved by the Research Ethics Committee, Square Hospitals Ltd, Dhaka, Bangladesh (no. 2101SH-OR02) on January 8, 2021. Written consent was taken from all participants in this study.
Sample inclusion criteria were as follows:
patients with confirmed ventilator-associated pneumonia caused by pandrug-resistant no history of hospital admission, surgery, or development of pneumonia within the last four-weeks of hospital admission no history of sepsis or septic shock no other bacterial or fungal coinfection at the time of diagnosis of VAP
history of COVID-19 infection within last 6 months or positive COVID-19 RT-PCR test during hospital admission
patients shifted to the ICU from any other healthcare facility
patients discharged from the ICU against medical advice or upon intubation
evidence of concomitant bacterial or fungal respiratory tract infection during VAP treatment
patients on hemodialysis or peritoneal dialysis, or therapeutic plasma exchange
history of malignancy, obesity (pregnancy, and autoimmune diseases
The pneumonia developed within forty-eight hours of endotracheal intubation was considered as ventilator-associated pneumonia. The International Classification of Diseases (ICD)-10 code of the diagnosed VAP infection was J95. 851.VAP was confirmed by chest computed tomography (CT) scan or X-ray having the presence of progressive pulmonary infiltrates with any two of the following symptoms: (1) persistent fever ≥100.4° F; (2) white blood cell count ≥11,000\mm3 of blood; (3) Purulent tracheobronchial secretions [17].
Pandrug-resistant isolate of bacteria is usually resistant to all commonly available antibiotics or even to reserve antibiotics, and identified through MIC test [7]. In this study, the PDR
Patients in PMB group received polymyxin B (solution for injection) intravenously and in aerosolized form concomitantly. Intravenous dose and regimen: 20,000 units/Kg of body weight once at day one, and then 20,000 units/Kg of body weight/day divided into 2 equal doses (maximum 1.5 million units/day) from day two to fourteen.Aerosolized dose and regimen: 1 million unit/day divided into 2 equal doses.
Patients in CLN group received colistin (in the form of colistimethate Sodium solution for injection) intravenously and in aerosolized form concomitantly. Intravenous dose and regimen: 5 mg of colistin/Kg of body weight in a single dose at day one, and then 5 mg of colistin/Kg of body weight/day divided into 3 equal doses (maximum 300 mg colistin/day) from day 2 to 14. Each 33 mg of colistin (as base) is equivalent to 1 million units or 80 mg of colistimethate Sodium (CMS) [18]. Aerosolized dose and regimen: 99 mg of colistin/day divided into 3 equal doses. Along with polymyxin B or colistin therapy, usual dose of intravenous meropenem (adjusted in renal impairment) was given to all patients of both groups of the study.
Each intravenous and aerosolized dose of polymyxin B and colistin was administered in patients with 100 mL and 5 mL of 0.9% Sodium chloride solution over 1 h and 30 min, respectively. All the patients of both the groups (PMB/CLN) received aerosolized levosalbutamol over 30 min before receiving aerosolized dose of antibiotic (polymyxin B/colistin). The total duration of polymyxin B (PMB group) and colistin (CLN group) therapy was 14 days. All the patients in both groups received other medications according to the ICU’s treatment protocol. While creatinine clearance declined below 30 mL/min in patients of both groups, following intravenous doses of polymyxin B and colistin reduced to 50% of the total daily dose with same dosing frequency and aerosolized doses were remain unchanged. In case of bronchospasm, no antibiotic dose adjustment was done.
The statistical analyses were performed by Statistical Product and Service Software (SPSS ver. 22.0, Chicago, IL, USA).All the tests were two-tailed. The categorical variables were analyzed between the treatment groups using Pearson’s chi-squared test. Continuous variables were compared Student’s t-test. Data were presented as numbers with percentage or medians with interquartile ranges (IQR), as appropriate. The hazard ratio (HR) with 95% confidence intervals (CI) was analyzed using the Cox proportional-hazard model. The multivariate model was adjusted for age, PaO2/FiO2 ratio, Acute Physiology and Chronic Health Evaluation (APACHE II), microbial eradication, intubation length, and length of ICU stay. The 60-day survival rate was assessed by Kaplan Meier (KM) plot using treatment groups (polymyxin B vs colistin) as factors; death as event and time to death as time variable. A
Of 222 patients, 106 patients (N) and 116 patients (N) were included in PMB and CLN group, respectively. The Number of male patients was higher than that of female patients in both groups (74%/26%: PMB group and 53%/47%: CLN group), and the median age of patients in PMB and CLN group was 56 years (IQR: 44.5-68) and 55 years (IQR: 46-65), respectively. The body mass index value of all patients of the study was from 20 to 24. Comorbidities in all patients were recorded at the time of hospital admission and mentioned in Table 1. Before starting PMB and CLN therapy, the median peripheral capillary oxygen saturation in blood (SpO2), the median fraction of inspired oxygen (FiO2), and the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 96% (IQR: 93-98)/96% (IQR: 94-98), 50 (IQR: 40-65)/45 (IQR: 40-65), and 240 mmHg (IQR: 193-255)/243 mmHg (IQR: 206.72-256) in patients of PMB and CLN group, respectively (
Patients treated with intravenous plus aerosolized polymyxin B in PMB group showed better microbial eradication (83%, N=106) than the patients treated with intravenous plus aerosolized colistin in CLN group (68.1%, N=116) (
Baseline demographic information, comorbidity and laboratory findings in patients.
Variable | PMB group (N=106) | CLN group (N=116) | P value |
---|---|---|---|
Male/female, n (%) | 78/28 (74/26) | 62/54 (53/47) | |
Age (year), median (IQR) | 56 (44.5-68) | 55 (46-65) | 0.091 |
Fever (°F), median (IQR) | 100.5 (100-101) | 101 (100-101) | 0.559 |
Diabetes, n (%) | 89 (83.95) | 97 (83.62) | 0.022 |
Hypertension, n (%) | 72 (67.93) | 80 (68.96) | 0.421 |
CVD, n (%) | 61 (57.52) | 53 (45.68) | 0.542 |
Bronchial asthma, n (%) | 27 (25.51) | 30 (25.86) | 0.031 |
CKD, n (%) | 25 (23.63) | 31 (26.72) | 0.011 |
COPD, n (%) | 25 (23.6) | 27 (23.27) | 0.058 |
Obesity, n (%) | 22 (20.82) | 18 (15.51) | 0.316 |
PUD, n (%) | 19 (17.94) | 8 (6.89) | 0.644 |
CLD, n (%) | 9 (8.55) | 12 (10.34) | 0.021 |
PD, n (%) | 4 (3.86) | 9 (7.75) | 0.465 |
SpO2 (%), median (IQR) | 96 (93-98) | 96 (94-98) | 0.249 |
FiO2, median (IQR) | 50 (40-65) | 45 (40-65) | 0.939 |
Respiratory rate, (breaths/min), median (IQR) | 19 (16-24) | 21 (18.29-24.7) | 0.487 |
Heart rate (beat/min), median (IQR) | 87 (83-97.37) | 85 (78-90) | 0.487 |
PaO2/FiO2 (mmHg) , median (IQR) | 240 (193-255) | 243 (206.72-256) | 0.517 |
CRP (mg/L), median (IQR) | 158 (136-268.3) | 152.5 (125-243.81) | 0.282 |
Procalcitonin (ng/mL), median (IQR) | 5 (3.35-8) | 6 (4.81-9) | 0.114 |
WBC (K/μL), median (IQR) | 18 (16.52-21) | 16.46 (13.2-24) | 0.001 |
Neutrophils (%), median (IQR) | 65 (55.77-75) | 75 (65-85) | 0.454 |
Platelet (K/μL), median (IQR) | 186 (151-263) | 162 (125-242.5) | 0.132 |
D-dimer (mg /L FEU), median (IQR) | 0.96 (0.36-1.74) | 0.57 (0.35-1.4) | 0.005 |
LDH ((U/L), median (IQR) | 419 (314-522) | 425 (356.5-500.25) | 0.117 |
Serum creatinine (mg/dL), median (IQR) | 0.9 (0.7-1.2) | 1 (0.8-1.6) | 0.097 |
ALT (U/L), median (IQR) | 56 (45-76) | 57 (45-75) | 0.597 |
AST (U/L), median (IQR) | 48 (39-58) | 46 (34-59) | 0.813 |
Bilirubin (mg/dL), median (IQR) | 0.8 (0.47-0.9) | 0.8 (0.6-0.92) | 0.737 |
MEWS, median (IQR) | 4 (3-4) | 4 (3-4) | 0.032 |
APACHE II (score range: 0-71) , median (IQR) | 20 (20-24) | 20 (18-24) | 0.171 |
IQR = interquartile range; n = number; % = percentage; °F = grade Fahrenheit; CVD = cardiovascular disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; PUD = peptic ulcer disease; CLD = chronic liver disease; PD = parkinson’s disease; SpO2 = oxygen saturation in blood; ; FiO2 = fraction of inspired oxygen; min = minute; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; CRP = C-reactive protein; mg = milligram; L = liter; FEU = fibrinogen equivalent units; ng = nanogram; WBC = white blood cells; K/μL = thousand cells per micro liter; IL = interleukin; pg/mL = picograms per milliliter; LDH = lactate dehydrogenase; U/L = units per liter; dL = deciliter; ALT = alanine aminotransferase; AST = aspartate aminotransferase; MEWS = Modified Early Warning Score; APACHE II = Acute Physiology and Chronic Health Evaluation.
Clinical outcomes in patients treated with intravenous and aerosolized polymyxin B or colistin
Parameters | PMB group (N=106) | CLN group (N=116) | P value |
---|---|---|---|
Microbial eradication, n (%) | 88 (83) | 79 (68.1) | 0.001 |
21-day secondary bacterial infection, n (%) | 24 (22.64) | 28 (27.58) | 0.013 |
Length-of-intubation (day), median (IQR) | 10 (9-12.25) | 14 (11-19) | 0.001 |
Length-of-ICU stay (day), median (IQR) | 12 (10-14) | 15 (9-18.5) | 0.072 |
Adverse drug event, n (%) | |||
Bronchospasm | 39 (36.79) | 8 (6.89) | 0.001 |
Nephrotoxicity | 12 (11.32) | 33 (28.44) | 0.002 |
PMB = polymyxin B; CLN = colistin; IQR = interquartile range; ICU = intensive care unit; n = number; % = percentage.
Sixteen deaths were observed in patients of PMB group (15%, N=106) while 25 deaths occurred in the CLN group (21.55%, N=116). The Cox proportional hazard model (adjusted for age, PaO2/FiO2 ratio, APACHE II, microbial non-eradication, length of intubation; and length of ICU stay) showed a significantly greater survival rate in PMB group as compared to CLN group (multivariate HR for death: 0.035; 95% CI=0.007-0.168,
Results from the Cox Proportional Hazard model. GROUP=main variable (polymyxin B versus colistin).
Variable | HR | 95% CI | P value | |
---|---|---|---|---|
Lower | Upper | |||
Group | 0.035 | 0.007 | 0.168 | <0.001 |
Age | 1.028 | 1.001 | 1.055 | 0.045 |
PaO2/FiO2 ratio | 1.005 | 0.994 | 1.015 | 0.379 |
APACHE II | 0.958 | 0.862 | 1.063 | 0.415 |
Microbial non-eradication | 1.148 | 0.484 | 2.721 | 0.038 |
Length of intubation | 0.965 | 0.882 | 1.057 | 0.044 |
Length of ICU stay | 1.043 | 0.99 | 1.099 | 0.117 |
HR=hazard ratio; CI =Confidence Intervals; CRP=C-reactive protein; PaO2/FiO2 = ratio of arterial oxygen partial pressure to fractional inspired oxygen; APACHE II = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit
In this study, compared to colistin, concomitant intravenous and aerosolized polymyxin B exhibited better eradication of PDR
The emergence of PDR gram-negative bacteria, such as
Colistin is the bioactive form of CMS (administration form) and following an intravenous single dose of CMS, only 20% to 25% of the total CMS is rapidly converted to colistin-base activity (CBA)
In contrast, polymyxin B is administered as pharmacologically active sulfate salt form [19]. The
To determine the actual pharmacokinetics and pharmacodynamics of polymyxin B and colistin in post intravenous plus aerosolized administration and the definite mechanism of high polymyxins concentration-mediated killing of pandrug-resistant
Pandrug-resistant