Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data

doi:10.21203/rs.3.rs-3956365/v1

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Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data

https://doi.org/10.21203/rs.3.rs-3956365/v1

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published 28 Oct, 2024

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Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections continue to be an important cause of morbidity and mortality. In this study, the effect of carbapenem or colistin resistance on mortality in Klebsiella pneumoniae bacteremia and combined meropenem + colistin administration in CRKp bacteremia was retrospectively evaluated. A total of 139 adult patients diagnosed with K. pneumoniae bacteremia(73 carbapenem sensitive and 66 carbapenem resistant) were included in the study. The 30-day mortality in entire cohort were 19.4%. 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group. Meropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n=39) and 25 (93%) of carbapenem resistant–colistin resistant patients(n=27). Notably, mortality was not significantly affected regardless of whether CRKp was colistin sensitive and whether a high dose and prolonged infusion of meropenem was administered. Mortality is higher in carbapenem resistant Klebsiella pneumoniae bacteremia compared to carbapenem susceptible group. In cases of combined meropenem and colistin administration, high dose and prolonged infusion of meropenem is not superior to standard dose and infusion in both carbapenem resistant–colistin sensitive and carbapenem resistant–colistin resistant K. pneumoniae bacteremia.

Biological sciences/Microbiology

Health sciences/Medical research

Klebsiella

bacteremia

carbapenem resistance

colistin

meropenem

Carbapenem-resistant Klebsiella pneumoniae (CRKp) infections are an important cause of morbidity and mortality. In a meta-analysis evaluating mortality, clinical and microbiological response for CRKp infections, mortality rate was 37.2%, clinical response was 69%, and microbiological response was 63.7% (1).

Paniagua-Garcia et al reported that the difference in 30-day mortality rates between patients with carbapenem–resistant Enterobacterales(88.5% Klebsiella spp.) infection compared with patients with carbapenem-susceptible(31.4% Klebsiella spp.) infection was 13.2%(2).

There are conflicting results in the carbapenem-resistant group on the effects of the bacteria also being resistant to colistin on mortality (3–7).

Treatment with new antibiotics such as ceftazidime-avibactam was reported to significantly reduce mortality in CRKp infections compared with older antibiotics such as meropenem, polymyxin (polymyxin-B and colistin), tigecycline, fosfomycin, and aminoglycosides (8–11).

However, access to new antibiotics is not always possible owing to economic factors, development of resistance, or intolerance. Therefore, older antibiotics may still be needed from time to time. One of the most commonly used combinations in CRKp infections is meropenem plus colistin (12, 13).

Tumbarello et al. showed that even if K. pneumoniae is carbapenem resistant, in combinations including meropenem (high dose, prolonged infusion) in the treatment, mortality was significantly lower in the MIC ≤ 8 mg/L group than infections caused by strains with MIC values > 8 mg/L (8). Similarly, Daikos et al. reported that mortality increased from 19.4–35.5% in drug combinations containing meropenem when the meropenem MIC value was > 8 mg/L (9).

In a study by Gomez-Simmonds et al. (meropenem MIC ≥ 16 mg/L in 90% of the isolates), combination therapy (a single effective antibiotic + meropenem or broad-spectrum cephalosporin) was not superior to monotherapy (a single effective antibiotic) (10).

Gianella et al. compared carbapenem-containing combinations with carbapenem-free combinations in bloodstream infections caused by CRKp and reported that meropenem-containing combinations were more effective than meropenem-free combinations in terms of 14-day mortality even if meropenem MIC was ≥ 16 mg/L (11).

In the present study, the primary objective was the effect of carbapenem resistance or carbapenem and colistin resistance on mortality in Klebsiella pneumonia bacteremia. In addition to that combined meropenem + colistin administration in CRKp bacteremia was retrospectively evaluated using minimal inhibitory concentration (MIC) and synergy data as a secondary objective.

A total of 139 patients (age, > 18 years) with K. pneumoniae bacteremia who were hospitalized in the Anesthesia and Reanimation Intensive Care Unit of our hospital between 01/01/2000 and 31/07/2019 were included in the study. The study was performed in accordance with relevant guidelines and regulation and approved by the Clinical Research Ethics Committee of Uludağ University Faculty of Medicine (2021-9/3). After informed consent was obtained, all patient information was retrieved from the electronic file system of our hospital. A case follow-up form was filled by all patients.

Bloodstream infection(BSI) was classified as primary, i.e., a laboratory confirmed BSI that is not secondary to another site infection, or secondary that is thought to be seeded from a site-specific infection at another body site (12).

In the presence of a focus of infection, the source of bacteremia was defined according to whether K. pneumoniae was isolated in the culture obtained from the focus of infection the day before or the same day after the positive blood culture. Catheter-associated bacteremia was defined as K. pneumoniae growth in blood culture from a catheter or in quantitative culture of catheter tip and peripheral blood culture, provided that there was no other active focus of infection (13–16).

All patients were classified as “sepsis,” “severe sepsis,” or “septic shock” based on consensus conference sepsis-1 criteria (17).

For the diagnosis of nosocomial pneumonia, in addition to the development of pneumonia within at least 48 hours after the hospital admission and the presence of new or progressing infiltration on the chest radiography, at least two of the following criteria should be present (18):

Presence of high fever (body temperature > 38°C).

Presence of leukocytosis > 10,000/mm³ or leukopenia < 4,000/mm³.

Purulent bronchial secretion indicated by the presence of > 25 leukocytes and ≤ 10 epithelial cells in the gram staining examination of the Deep Endotracheal Aspiration (DTA) (10×).

Decreased oxygenation.

Diagnostic criteria of the international sepsis group were used for other infection diagnoses (19).

Use of prednisone or an equivalent steroid by the patient at a dose of 20 mg/day for 2 weeks or 30 mg/day for 1 week within the last one month was considered as a risk factor for steroid use (20).

Patients with a neutrophil count < 500/mm³ at the time of diagnosis were considered neutropenic.

Acute Physiology and Chronic Health Evaluation-II score was calculated within 24 hours of admission to the ICU (21). Pitt Bacteremia scores were calculated at the diagnosis of infection (22).

The 14-day and 30-day mortality values were calculated according to the first 14 days and 30 days from the date of diagnosis. Antibiotics used by the patients before the diagnosis—i.e., used for at least 48 hours in the last 30 days—were evaluated(23).

Colistin was administered as a maintenance dose after the standard loading dose in all patients (24). Meropenem was administered either as standard dose(3 g/d) and infusion or as high dose(6 g/d) and prolonged infusion(4 hours) (25).

Identification and antibiotic susceptibility testing of K. pneumoniae isolates were performed using a Phoenix 100 (Beckton Dickinson, USA) automated system. In order to confirm ESBL negativity and positivity of K. pneumoniae isolates, a combined disk confirmation test was performed as recommended by Clinical Laboratory Standarts Institute(CLSI). Carbapenem resistance was defined as a minimum inhibitory concentration (MIC) to meropenem of greater than 8 mg/L. The MIC of colistin was determined by broth microdilution method, and a strain with MIC ≤ 2 mg/L was considered to be susceptible to colistin(26).

For combinations containing colistin, meropenem, tigecycline, or fosfomycin, synergy testing was performed by gradient diffusion method and evaluated according to European Committee on Antimicrobial Susceptibility Testing(EUCAST) criteria. For Colistin, Meropenem, Tigecycline, and Fosfomycin, 0.5 McFarland turbidity bacterial suspensions were spread on 4 MHA plates. If the MIC values of antibiotics A and B, the combination of which was to be tested, were not known beforehand, gradient diffusion method strips containing the antibiotics were placed separately in a petri dish to determine their MICs individually. Strip B was placed in the third petri dish first and incubated for 1 hour. Strip B was removed with sterile forceps and strip A was placed on the same place. Strip A was placed in the fourth petri dish and stored for 1 hour. Strip A was removed and strip B was placed on the same place. After 24 hours of incubation at 35°C–37°C, the MIC of A in the presence of B in the third petri dish and the MIC of B in the presence of A in the fourth petri dish were measured and evaluated according to EUCAST recommendations. Interaction in combination tests was determined using fractional inhibition concentration (FIC) index and evaluated as synergistic for FIC ≤ 0.5, additive for 0.5 < FIC ≤ 1, indifferent for 1 < FIC < 4, and antagonistic for FIC ≥ 4 (26–28).

A total of 139 adult patients diagnosed with K. pneumoniae bacteremia between 01/01/2000 and 31/07/2019 were included in the study. The median age was 61 (33–98) years. Antibiotics were used in 58 (41.7%) of the patients in the last 30 days and 36 (25.9%) of these patients used carbapenems, 11 (7.9%) used 3rd generation cephalosporins, 6 (4.3%) used 4th generation cephalosporins, and 3 (2.2%) used tigecyclines.

The median length of stay in the intensive care unit until the diagnosis of K. pneumoniae bacteremia was 17 (1–42) days. Some demographic characteristics of the patients are shown in Table 1.

Table-1

Demographic characteristics of patients

Demographic Characteristics	Number of Patients (n)	Percentage (%)
Sex Male Female	82 57	59 41
Age (years) ≥ 65 < 65	56 83	40.2 59.8
CVC +	87	62.6
APACHE II ≥ 20	57	41
APACHE II < 20	82	59
PBS ≥ 4	116	83.4
PBS < 4	23	16.6
Neutropenia	27	19.4
Mechanical Ventilation Support	100	71.9
Antibiotic use in the last 30 days	58	41.7
Carbapenem use in the last 30 days	36	25.9
APACHE-II: Acute Physiology and Chronic Health Evaluation-II; CVC: Central Venous Catheter; PBS: Pittsburg bacteremia score,

A total of 97 (69.7%) patients had various underlying diseases. Among these, 29 (20.8%) had more than one underlying disease (Table 2).

Table-2

Underlying diseases of the patients

Underlying disease	Number of patients (n)	Percentage (%)
COPD	10	7.1
CRF	29	20.8
DM	43	30.9
SOT	3	2.1
CHF	27	19.4
Other	8	5.7
Total illness	120
Total patients	97	69.7
CHF: Congestive Heart Failure, COPD: Chronic Obstructive Pulmonary Disease, CRF: Chronic Renal Failure, SOT: Solid Organ Transplantation, DM: Diabetes Mellitus

The 14-day mortality was 8.6% (n = 12) and 30-day mortality was 19.4% (n = 27). No significant difference was noted between the 14- and 30-day mortality rates in terms of the source (Table-3).

Table-3

Mortality rates by source of bacteremia

	14-day mortality			30-day mortality
Source	Deceased n (%)	Survivor n (%)	P	Deceased n (%)	Survivor n (%)	P	Total n
Primary bacteremia	6 (11.3)	47 (88.6)		12 (22.6)	41 (77.3)		53
Catheter-associated bacteremia	4 (6.4)	58 (93.5)	1.000	12 (19.3)	50 (80.6)	0.982	62
Ventilator-associated pneumonia	2 (8.3)	22 (91.6)		3 (12.5)	21 (87.5)		24
Total	12 (8.6)	127 (91.3)		27 (19.4)	112 (80.5)		139

14-day mortality was significantly higher in the carbapenem resistant-colistin resistant group compared to the carbapenem sensitive (extended spectrum beta-lactamase-ESBL positive) group and the carbapenem resistant-colistin sensitive group.

30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group compared to the carbapenem susceptible (ESBL positive) group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group (Table-4).

Table-4

Mortality rates according to resistance profile

	14-day mortality			30-day mortality
	Number of patients (n)	Percentage (%)	P value	Number of patients (n)	Percentage (%)	P value
Carbapenem sensitive-ESBL positive (n = 73)*	1	1.3		1	1.3
Carbapenem resistant-colistin sensitive (n = 39)	0	0	1.000	15	38.4	< 0.001
Carbapenem sensitive-ESBL positive (n = 73)*	1	1.3		1	1.3
Carbapenem and colistin resistant (n = 27)	11	40.7	< 0.001	11	40.7	< 0.001
Carbapenem resistant-colistin sensitive (n = 39)	0	0		15	38.4
Carbapenem and colistin resistant (n = 27)	11	40.7	< 0.001	11	40.7	0.852

*All carbapenem-susceptible-ESBL postive patients were treated with carbapenem monotherapy.

Meropenem + colistin combination was administered to 37 (95%) of carbapenem resistant–colistin sensitive (n = 39) patients. The 30-day mortality rate was 37.8% in 37 patients receiving meropenem + colistin. A high dose and prolonged infusion of meropenem was administered in 19 of 39 patients and as standard dose and infusion in 20 patients; furthermore, no intergroup differences in mortality were noted in terms of mortality (36% vs. 40%, p = 0.839). Synergy testing was performed in 14 of 37 patients receiving meropenem + colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was ≥ 32 mg/L in all strains.

Of the 27 carbapenem resistant–colistin resistant patients, 25 (93%) received meropenem + colistin combination. In these 25 patients, the 30-day mortality rate was 40%. In 13 patients, a high dose and prolonged infusion of meropenem was administered, whereas 14 patients received a standard dose and infusion. No significant intergroup difference was noted in terms of mortality (38% vs. 42%, p = 0.816). In this group, synergy testing was performed in 16 of 25 patients receiving meropenem + colistin. No synergy or antagonism was detected between meropenem and colistin and was considered as indifferent. Meropenem MIC level was ≥ 32 mg/dl in all strains.

Many studies have demonstrated that carbapenem resistance significantly increases mortality compared with carbapenem susceptible groups. In a multicenter study, 30-day mortality rate in bloodstream infections caused by CRKp was 44% (29). In a meta-analysis evaluating CRKp bacteremia, mortality was 42.14% in the carbapenem-resistant group and 21.16% in the carbapenem-sensitive group. Mortality was reported to be 54.30% in bloodstream infections and 13.52% in urinary tract infections (30). The very low mortality rates in the carbapenem susceptible group in the present study may be explained by the fact that carbapenem was used in all of these cases.

Balkan et al reported that colistin resistance increased 28-day mortality in bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae(5). Menekşe et al found that increasing MIC of colistin as a independent mortality factor in Klebsiella pneumoniae bloodstream infections(6).On the other hand, Aslan et al reported that colistin resistance in CRKp had no impact on 30-day mortality(3).

In the present study, we found that the presence of colistin resistance in addition to carbapenem resistance did not affect 30-day mortality. However, we found that significantly increased 14-day mortality. Different colistin susceptibility methods, whether colistin loading dose was given or not, whether meropenem dose and prolonged infusion were used or not, meropenem MIC values, combination or monotherapy and design of studies may have played a role in these different results.

In the present study, meropenem + colistin combination was indifferent (neither synergistic nor antagonistic) by gradient diffusion system.

In vitro synergy studies for carbapenem-resistant Enterobacteriaceae, the combination of polymyxin + carbapenem was generally found to be synergistic (36).

In their study with the time-kill method, Sharma et al. showed that the combination was bactericidal if the MIC of meropenem was ≤ 16 mg/L in colistin-susceptible and meropenem-resistant K. pneumoniae strains (37).

Kulegowski et al. also showed that if the MIC of meropenem is ≤ 32 mg/L, the combination of meropenem + polymyxin B generally has a synergistic effect on polymyxin B-susceptible strains (38).

However, in a study involving 19 patients with bloodstream infection caused by K. pneumoniae, Bono et al. did not reach the PK/PD targets in cases with MIC values ranging from 256 to 1024 mg/L, although the patients were given high dose and prolonged infusion. Furthermore, in vitro synergy with colistin was not detected. However, measured serum meropenem levels could reach the hypothetically determined T > 40% 1xMIC PK/PD targets of meropenem at a rate of 98% for the MIC value of 8 mg/L, 68% for 16 mg/L, and 32% for 32 mg/L (25). The lack of synergistic effect in our study may be attributable to meropenem MIC levels of ≥ 32 mg/L.

There was no therapeutic drug monitoring(TDM) for meropenem to evaluate PK/PD parameters in our study. We consider that TDM could be useful for infections caused by CRKp with MIC ≤ 64 mg/L(39, 40).

In the present study, no significant difference in mortality was noted between high dose - prolonged infusion of meropenem and normal dose - standard infusion of meropenem. In the carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant groups, no significant difference in mortality was observed between high dose and prolonged infusion of meropenem and normal dose infusion.

It was shown that meropenem MIC is very important in the success of meropenem plus colistin combination in CRKp infections. If meropenem MIC > 8 mg/L, we can expect higher mortality(8, 9).

The fact that the synergy test results were indifferent and that there was no mortality difference between high-dose and prolonged infusion of meropenem and standard dose infusion in both groups suggests that high-dose and prolonged infusion meropenem treatment does not provide any benefit compared to standard dose and infusion if the meropenem MIC is ≥ 32 mg/L.

There are certain limitations of this study. The study was conducted retrospectively. The number of cases was relatively small and the study was single centered. Not all carbapenem-resistant strains were tested for synergy. The results were not compared with a group given colistin monotherapy. Lastly, the strains were not epidemiologically analyzed at the molecular level and carbapenemase enzymes were not analyzed.

In conclusion, 30-day mortality was significantly higher in the carbapenem resistant-colistin sensitive group and in the carbapenem resistant-colistin resistant group compared to the carbapenem susceptible (ESBL positive) group. When combined with colistin, if meropenem MIC is ≥ 32 mg/L, meropenem administration with high dose and prolonged infusion is not superior to standard dose and infusion in both carbapenem resistant-colistin sensitive and carbapenem resistant-colistin resistant K. pneumoniae bacteremia.

We would like to thank Prof. Dr. Güven Özkaya for evaluating the statistical analysis of our study.

HA is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. CS contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. Rİ, NKG and FK are responsible for clinical follow-up, data collection and data interpretation. CS, KE and CÖ contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript.

Funding and Conflict of Interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.

Acknowledments

We would like to thank Prof. Dr. Güven Özkaya for evaluating the statistical analysis of our study.

Funding and Conflict of Interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There is no conflict of interest.

Author Contribution

H.A. is responsible for the content of the manuscript, data analysis and interpretation, study design, writing of the manuscript, and critical review. C.S. contributed to data collection, data analysis, interpretation of results and the writing of the manuscript. R.İ., N.K.G. and F.K. are responsible for clinical follow-up, data collection and data interpretation. C.S., K.E. and C.Ö. contributed substantially to the in vitro study design, data analysis and interpretation, and the writing of the manuscript.

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No competing interests reported.

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published 28 Oct, 2024

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Carbapenem or colistin resistant Klebsiella pneumoniae bacteremia in the intensive care unit: real life data

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