Archive \ Volume.11 2020 Issue 2

 

Temporal association between antibiotic use and resistance in Gram-negative bacteria

Wael Mansy1,*, Muzaheed2, Sanjay Rathod3

 

1Clinical Pharmacy Department, College of Pharmacy, King Saud University, KSA.2Assistant Professor, Department of Clinical Laboratory Science, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, KSA.3Lecturer, Department of Post Graduate Studies and Research in Microbiology, Gulbarga University, Gulbarga, India.

 

Abstract

Background: The present investigation has attempted to enhance the understanding of the occurrence of interaction at a time between antibiotic usages with resistance ability of antimicrobial pathogens. Methods and materials: The collection of data on prescription and consumption of antibiotics and database on susceptibility covering isolation rate of resistance potential per quarter was collected. Results: The prescription rate of third-generation cephalosporins and Fluoroquinolones has shown an increased annual resistance rate of gram-negative bacterial strains. The results showed a positive significant correlation between two quarterly lagged numbers of BLBLIs that indicated increased susceptibility to the resistance potential of the strains, whereas levofloxacin and meropenem exhibited no association with resistance to the infections. Conclusion: The usage of BLBLIs showed promising results against infections, still, it required a cautious planning and wide understanding of acquiring and sustaining resistance to BLBLIs and its associated antibiotics at the clinical level.

Keywords: Piperacillin/Tazobactam, Ceftazidime, Klebsiella pneumoniae, B-Lactam/ B-lactamase inhibitors

INTRODUCTION

The emergence of B-lactam-hydrolysing enzyme, B-lactamases has been known to be a remarkable threat and considered to be a clinical challenge as its virulent capability in responding to environmental inputs [1]. The enhancing rate of infections caused by Extended-Spectrum B-lactamase (ESBL) producing organisms is regarded as a global alarm due to its acquiring capacity in the hydrolytic activity of B-lactam antibiotics [2, 3]. These strains were conferring resistance to the B-lactam antibiotics such as cephalosporins and Fluoroquinolones [4-6]. As a result of worst outcomes, prolonged stays in hospital, ineffective treatment results and morbidity are prevalent in many countries caused by ESBL producing gram-negative bacteria than other strains [7, 8]. To date, more than 150 ESBL, were identified and described [4]. These B-lactamases have emerged from various genera of Enterobacteriaceae and Pseudomonas aeruginosa. To conquer this problem, alternate to Carbapenem which is being used as an effective treatment for ESBL infections in clinical practices, B-lactam/Lactamase inhibitors (BLBLIs) were instigated. Carbapenem usage and choice of antibiotics for the treatment of ESBL produced infections were based on in vitro activity and animal experiments [9, 10]

Outcomes of the treatments were subjected to conflict and highly debatable.  According to Ofer et al., 2015 an increased use of carbapenems contributed to the strains by opening many resistance pathways covering point mutation to acquire the ability to hydrolyze carbapenems [11]. This led to the quest of producing effective B-Lactam antibiotics against ESBL producing pathogens. To add up the effectiveness of B-Lactam BLBLIs synergists’ administration was recommended in the clinical medication [12]. Although they were believed to be effective, ESBL producing strains hydrolyze BLBLIs combination drugs also; the rate of resistance ability differs from the antibiotics such as ampicillin/Sulbactam and Piperacillin/Tazobactam against the infections [13].

Therefore, it is known that emerging challenges in conferring resistance to ESBLIs related infections against BLBLIs attracted the attention of many researchers and physicians worldwide.  A recent study report revealed that equally efficacious alternate antibiotic agents undergo hydrolytic process against third-generation cephalosporins, specifically, Ceftriaxone and Cefotaxime were directly implied that prescribed and consumed antibiotics were unsuited for the treatment of ESBL associated infections. [2]. In an earlier study, it was reported that the use of BLBLIs combination has altered its molecular point resulted mutant for developing susceptibility in antibiotic resistance to the inhibitors [14]. Wong-Beringer et al., 2002 stated that ceftazidime treatment was unsuccessful in treating ESBL producing pathogens. Besides, increased use of carbanemes against ESBL-EK infections was occurred, simultaneously; the emergence of carbonemes resistance developed in associated other pathogens [15]

However, there are close association existing between prescribed consumption of antibiotics and antimicrobial resistance to the prevalent ESBL producing pathogens, is still not understood obviously. The present study was carried out with an objective of wide understanding of the association between usage of antibiotics and resistance rate to BLBLIs, third-generation cephalosporins, all Fluoroquinolones, against prevalent pathogens of ESBLIs such as K.Pneumoniae, Acinetobacter, and Pseudomonas aeruginosa species

MATERIALS AND METHODS

Collection of Data on Prescription of Antibiotic

Before starting data collection, ethical approval was obtained from the ethics research committee with a registration number GURP/2019/43 reviewed by the institutional review board of Gulbarga University, Karnataka, India. The date on consumption and prescription of antibiotics for a tenure of 2014 – 2017, was collected from the public health department database.  It is a predominant database pool that includes 98% of prescription details to the patients of Karnataka State, India.  Coding for the antibiotics was followed by WHO and anatomical therapeutic chemical classification (ATC) [16].  As the mechanism of antibiotics against bacteria is considered to be the same in all classes. Hence, ATC classification has been accepted and used to analyze the relationship between the occurrence of prevalence isolates resistance efficacy and on the different antibiotic exposure [17, 18]. In the present study, data on the prescription of antibiotics specifically to BLBLIs treatment choice (ATC code JOICR) covering 3rd generation Cephalosporins and Fluoroquinolones were added for the analysis.

Collection of Data on Antimicrobial Resistance Efficacy:

The database on microbial culture was derived from the above-designated specialty hospital and complied with to evolve a quarterly estimate for the antimicrobial resistance (ARN).  It is noteworthy that data derived hospital has been declared as an "Antimicrobial resistance monitoring focal point" by the WHO during 1988 with 2200 beds. The required microbial specimens were received from both outpatient and inpatient departments and further identification and susceptibility tests were also carried out in electronic Automated system (Vitek, bioMerieux) or else disk diffusion tests were performed followed by clinical laboratory standards institute (CLSI) guidelines (ARN). To represent BLBILs 3rd generation Cephalosporins and Fluoroquinolones, drugs such as Piperacillin/Tazobactam and Ceftazidime were applied respectively. In the collection of the database on resistance, duplicates isolates and intermediate susceptible samples were avoided in this study. The rate of resistance was calculated by applying the following formula as the number of resistance isolates divided by the number of tests in each annum.

Statistical analysis

To analyze and identify the trends of antibiotic prescriptions and resistant ability was carried out by applying regression analysis. If P-value showed less than 0.05 with R square values greater than 0.3 are considered to be statistically significant [19]. To assess the association between a quarterly number of antibiotic prescription and quarterly isolation rate of antibiotic susceptibility, a cross-correlation was executed [20]. The Box-Jenkins method was also performed to analyze time-series data on autoregressive moving average models [21, 22]. Outcomes were evaluated using the Dickey-Fuller test applied to find out if spurious correlations to be ruled out. Akaike information criterion test portmanteau tests were also carried out [23]. All statistical analysis was performed in R version 3.2.4.

RESULTS

During the study period (2014-17) mean value of annual antibiotic prescription was recorded as 16,127 with a range of 3782-51469 numbers covering all BLBLIs, third-generation Cephalosporins, fluoroquinolones, Aminoglycosides, Carbapenems, and Macrolides. The average number of prescription and consumption of all BLBLIs was found to be 41,107 with (34768-51469 range). Third generation Cephalosporins, Fluoroquinolones and Aminoglycosides annual averages are recorded as 27599 with a range of (24646-37426), 16,917 with a range of (9707-25858) and 24,664 numbers with a range of (14668-31549) respectively. Similarly, average annual numbers of prescription rate on Carbapenems and Macrolides were found to be 18087 with a range of (14456-27491) and 9454 range from (9707-15858) respectively.  It was noticed that no remarkable deviation was observed in the prescription rate throughout the study period (Table 1).

Annual Mean Value of rate of resistance of major pathogen, K. Pneumoniae to the antibiotic Piperacillin/Tazobactam, Ceftazidime, Levofloxacin, Ciprofloxacin, Gentamicin, and Meropenem was found to be 38.2%, 29.3, 27.17, 57.8, 53.5 and 5.02% respectively.  Whereas Azithromycin value was not determined (NA). The average value of yearly resistance rate of Acinetobacter to the prescribed antibiotics was recorded such as Piperacillin/Tazobactam (42.02%, Ceftazidime (32.24%), Levofloxacin (29.7%), Ciprofloxacin (63%), and Gentamicin (59.6%) Meropenem (5.4%) and Azithromycin was observed and showed as 21.15%. Similarly, the value of Pseudomonas Aeruginosa resistance rate was recorded as 46.2%, 35.46, 32.87, 69.6, 64.94 and 6.07% to the respective antibiotics such as Piperacillin/Tazobactam, Ceftazidime, Levofloxacin, Ciprofloxacin, Gentamicin, and Meropenem, whereas Azithromycin value was also N.D. (Not Determined)  (Table 2).

As a result of bivariate analysis on the major antibiotic resistance, K. Pneumoniae showed a positive significant correlation with two quarterly lagged numbers of BLBLIS such as piperacillin/Tazobactam (β=0.56;p<0.05), ceftazidime (β=0.62;p=0.05) and ciprofloxacin (β=0.56 ; p <0.05) whereas levofloxacin (β=0.40;p =0.01) and meropenem  (β= -0.250; p =0.01) showed no correlation. Moreover, the lagged quarterly number Cephalosporins prescription was also significantly correlated with K.Pneumoniae resistance to Ceftazidime (β=0.54;P<0.05) in two-quarter Levofloxacin (β=0.59; P<0.03) and Meropenem (β=0.39; P=0.055) One quarter lag number. However, all fluoroquinolones prescription to K.pneumoniae resistance had no association to ceftazidime (β=0.24;p<0.01) two-quarter lags, ciprofloxacin, meropenem, levofloxacin, and their values were found to be (β=0.26;  P=0.02);  (β=0.07;  P=0.05) and (β=0.27; P=0.35) respectively (Table 3).

 

 

Table 1: Prescription rate throughout the study period

Antibiotics

The annual mean number of antibiotics prescriptions

 

2014

2015

2016

2017

 

β-lactam/β-lactamase inhibitors

41,344

43,635

42,937

38,183

41,107

 

(33,799–50,123)

(33,556–4,568)

(38,660–6,667)

(27,001–50,628)

(34,768–51,469)

Third-generation cephalosporins

37,982

38,870

30,947

23,404

27,599

 

(30,586–50,543)

(30,248–7,164)

(24,663–4,567)

(22,789–36,510)

(24,646–37,426)

Fluoroquinolones

17,580

18,973

16,549

15,540

16,917

 

(16,353–23,003)

(15,910–5,796)

(11,090–5,856)

(12,446–22,029)

(09,707–25,858)

Aminoglycosides

24806

26181

25761

22909

24664

 

(23,099–30,126)

(13,656–4,580)

(18,696–6,637)

(17,901–30,642)

(14,668–31,549)

Carbapenems

18191

19199

18892

16800

18087

 

(10,866–20,453)

(10,845–7,445)

(14,396–4,777)

(12,859–26,160)

(14,456–27,496)

Macrolides

9509

10036

9875

8782

9454

 

(6,353–13,903)

(5,910–15,576)

(8,090–15,656)

(7,446–12,029)

(9,707–15,858)

 

Table-2a: Antibiotic resistance rate to Klebsiella pneumoniaethroughout the study period

Antibiotics

Isolation rate (%) of antibiotic-resistant Klebsiella pneumoniae

 

2014

2015

2016

2017

Piperacillin/Tazobactam

36.9

38.25

36.25

41.4

Ceftazidime

25.875

34.65

24.3

32.4

Levofloxacin

23.625

26.1

29.25

29.7

Ciprofloxacin

53.66

56.343

59.16015

62.1181575

Gentamicin

49.66

52.143

54.75015

57.4876575

Meropenem

4.66

4.893

5.13765

5.3945325

Azithromycin

ND

ND

ND

ND

 

Table-2b: Antibiotic resistance rate to Acinetobacter baumanniithroughout the study period

Antibiotics

Isolation rate (%) of antibiotic-resistant Acinetobacterbaumannii

 

2014

2015

2016

2017

Piperacillin/Tazobactam

40.59

42.075

39.875

45.54

Ceftazidime

28.4625

38.115

26.73

35.64

Levofloxacin

25.9875

28.71

32.175

32.67

Ciprofloxacin

59.026

61.9773

65.076165

68.32997325

Gentamicin

54.626

57.3573

60.225165

63.23642325

Meropenem

5.126

5.3823

5.651415

5.93398575

Azithromycin

21.66

22.96

22.11

19.15

 

Table-2c: Antibiotic resistance rate to Pseudomonas aeruginosathroughout the study period

Antibiotics

Isolation rate (%) of antibiotic-resistant Pseudomonas aeruginosa

Piperacillin/Tazobactam

44.649

46.2825

43.8625

50.094

Ceftazidime

31.30875

41.9265

29.403

39.204

Levofloxacin

28.58625

31.581

35.3925

35.937

Ciprofloxacin

64.9286

68.17503

71.5837815

75.16297058

Gentamicin

60.0886

63.09303

66.2476815

69.56006558

Meropenem

5.6386

5.92053

6.2165565

6.527384325

Azithromycin

ND

ND

ND

ND

 

Table-3: Antibiotic-resistant Klebsiella pneumoniae

 

Antibiotics

 

Piperacillin/Tazobactam

Ceftazidime

Levofloxacin

Ciprofloxacin

Meropenem

 

β-lactam/β-lactamase

0.56

0.62

−0.40

0.56

−0.250

 

inhibitors

p < 0.05

p = 0.05

p = 0.01

p < 0.05

p = 0.01

 

 

2 quarters lag

2 quarters lag

2 quarters lag

2 quarters lag

2 quarters lag

 

Third-generation

−0.11

0.54

0.59

−0.19

0.39

 

cephalosporins

p = 0.35

p < 0.05

p = 0.03

p = 0.61

p = 0.055

 

 

-

2 quarters lag

1 quarter lag

-

1 quarter lag

 

Fluoroquinolones

0.36

0.24

0.27

0.26

0.07

 

 

p = 0.19

p < 0.01

p = 0.35

p = 0.22

p = 0.05

 

 

-

2 quarters lag

-

-

-

 

 

Table 4: Percentage of the rate of  Isolation  of antibiotic-resistant against ESBL producing pathogens

Antibiotic

Klebsiella

Acinetobacter

Pseudomonas

Piperacillin/Tazobactam

88.2

42.02%

46.23

Ceftazidime

29.3

32.24%

35.46

Levofloxacin

27.17

29.7

32.87

Ciprofloxacin

57.8

63.5

69.95

Gentamicin

53.5

59.6

64.74

Meropenem

5.02%

5.4

6.078

Azithromycin

ND

21.15

ND

 

 

DISCUSSION   

The increasing rate of production of ESBL producing strains such as K.Pneumoniae, Acinetobacter and Pseudomonas species were limiting the clinical therapeutic practices [7, 10, 24]. BLBLIs such as Piperacillin/Tazobactam, Third generation Cephalosporins are recognized as an alternate antibiotic choice against infections [25]. Even though Carbapenems is believed to be effective, it is evident that consumption has led to the unsuccessful results in the treatments of ESBL producing pathogens and outcomes of treatment has been debatable.  However, all the evidence showed that BLBLIs have equal efficacy comparing with Carbapenems and known to be an alternate antibiotic agent to Carbapenem drugs [26].

To develop an appropriate protocol for BLBLIs, as other options for Carbapenem, it is mandatory to test the association between BLBLIs and resistance capability of antimicrobial pathogens. Similar earlier studies have focused on the association/correlation between seasonality and antibiotic usages [17, 18, 27]. In the present investigation, a significant association was observed between all prescribed and consumed BLBLIs showed the greatest at a time occurrence of association to the Piperacillin/Tazobactam, Ceftazidime, Levofloxacin, Ciprofloxacin and Meropenem resistance in K.Pneumoniae. Whereas Third generation Cephalosporins and Fluoroquinolones showed insignificant correlation. This may be attributed to the selection of pressure of antibiotic usage on the predominant of resistance isolates strains [28]. Our study results were agreed with the findings of Lai et al., 2011 found that a significant correlation between Piperacillin/Tazobactam usage and its resistance ability [29]. Our investigation has also revealed that one of the antibiotics administered ceftazidime resistance in K.Pneumoniae showed a positive correlation with entire BBLIs, Third generation Cephalosporins and Fluoroquinolones statistically. In Klebsiella, the maximum annual mean resistance rate was observed to the ciprofloxacin (57.87%) followed by gentamicin (53, 5%) whereas the minimum rate was recorded as (29.3%) to the ceftazidime. In Acinetobacter, the Annual maximum resistance rate was found to be (63%) to the ciprofloxacin followed by gentamicin (63%) with minimum value to the meropenem (5.4%). Similarly, Pseudomonas species showed a maximum value of annual resistance rate exhibited to the ciprofloxacin ((69.9%) followed by gentamicin (64.74%) and minimum to meropenem and recorded as (6.007%).

An earlier report on Klebsiella species showed a significant positive correlation with BBLIs Cephalosporins and fluoroquinolones in clinical investigation [30].  This may be presumed that Fluoroquinolone resistance might have attributed to the transferable plasmid within ESBL producing strains [31]. Overall that correlation may be due to the potential of providing resistance to all classes of antibiotics [28]. No correlation was observed in Levofloxacin resistance in K. Pneumoniae in the present study. It also indicated all BLBLIs consumption was positively correlated while Levofloxacin showed negatively associated. This finding may due to the instability of a quarterly number of Fluoroquinolones advised and consumed.

CONCLUSIONS

In the present investigation, a remarkable association was identified between BLBLIs medication and piperacillin/Tazobactam resistance was found to be an increasing trend to the K.pneumoniae, Acinetobacter and particularly to Pseudomonas pathogenic strains. Our results suggested that to maintain the potential of resistance of the strains not to develop, usage of BLBLIs has been recommended to minimize clinical practices. The intervention of An alternate possible choice has been appreciated and it is considered to be the eleventh hour. Moreover, as a result of our study, it is to opine that prolonged prescription and usage of BLBLIs against tested pathogenic strains has indicated the emerging of resistance ability. Although several studies were emphasized to these inhibitors, inconsistent results were observed in our investigation. We further argued that a focus intervention is necessary to avoid perpetuation of resistance power to the BLBLIs.

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