Prevalence of meropenem susceptibility among Gram-negative ...

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THE INTERNATIONAL ARABIC JOURNAL OF ANTIMICROBIAL AGENTS

2011 Vol. 1 No. 1:3 doi: 10:3823/702

Original research

Prevalence of meropenem susceptibility among Gram-negative pathogens isolated from intensive care units in Jordan Jamal Wadi1*, Naheel Haloub2, Mais Al Ahmad1, Amani Samara2 and Amani Romman1

1 Al Khalidi Medical Center , Amman, Jordan 2 The Specialty Hospital, Amman, Jordan * Corresponding author: [email protected]

Abstract Background. Meropenem is a relatively new carbapenem in some Middle East countries; our aim is to evaluate its susceptibility in gram-negative pathogens isolated from ICU patients and to identify the prevalence of ICU bacterial isolates identified as pathogens based on CDC-NHSN definition for pathogens in the affected organs. Methods. Pathogens as identified by CDC-NHNS were studied for prevalence and antibiotic susceptibility. Patients and charts were prospectively reviewed; attending physician diagnosis was considered after being reviewed by two qualified infection control nurses and infectious diseases physician. Results. One-hundred and seventy-three gram-negative pathogen were reviewed for susceptibilities and ESBL production. E. coli was a dominant pathogen followed by Klebsiella, and Pseudomonas. ESBL-production was in E. coli (62.7%) and Klebsiella (58.6%), considering all gram-negative bacilli studied; ESBL rates were 30.7%. Both Carbapenems showed superior activity against gram-negative pathogens. Meropenem did better than imipenem against pseudomonas species, but PIP/TAZ did better than both carbapenems (p = 0.02). The difference in susceptibility patterns among ESBL-producing pathogens compared with same non-ESBL producers species showed that carbapenems were superior to other classes of antibacterials tested in this regard, and rates of resistant ESBL to both carbapenems were 5.6%; trustworthy in the initial empiric therapy in ICUs and hospitals that suffer from high rates of ESBL-producers. While PIP/TAZ showed highly significant difference (p < 0.0001) in activity against ESBL and non-ESBL producers. Conclusion. Meropenem and imipenem are trustworthy in the initial empiric therapy. Gram-negative pathogens are highly susceptibility to both carbapenems, and benefit extends to ICUs with high rates of ESBL-producers. Keywords: Meropenem, Imipenem, “Gram-negative pathogens ‘susceptibility”, ESBL-producer, ICU-Jordan

Introduction Intensive care units’ beds occupy about 10% of hospital beds meanwhile representing the hospital epidemiology in as much as 80%, where most of infections take place in ICU. (1, 2) Furthermore, the amount of antibacterial drugs used is enormous in this part of the hospital, especially wide-spectrum antibacterials as mono-therapy or in combination. Among antibacterials, carbapenems are widely used, and meropenem is a relatively new antimicrobial agent in our part of the world. Some © Under License of Creative Commons Attribution 3.0 License

studies state that it is different from imipenem in its potency and target attainment, especially against Pseudomonas species.(3) The major concern of infectious disease has been in the last decades the problem of combating resistance. Many antimicrobial agents became less useful as resistance evolve. (4) Resistance trends among bacteria are on the rise in hospitals, especially in ICUs where highly morbid patients are residing, with multiple interventions, and the use of wide-spectrum antimicrobials, among other risk factors.(5, 6) Gram-negative bacteria contribute to a large fraction of ICU nosocomial infec-

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tions, mostly contributing to a big part of ventilator-associated pneumonia (VAP), catheter-associated urinary tract infections (CAUTI) and central line associated infections (CLABSI) as identified by CDC-NHNS.(4, 7) Vigilance is highly needed in this regard and adjusting antimicrobials use in ICUs has to cope with the evolving changes in prevalence and susceptibility. The invaluable continued ICU surveillance for prevalence of pathogens and their antimicrobial susceptibility shed light on empiric treatment; here, using meropenem as a model to compare with.(7) The ultimate goal is that antimicrobial prescription would be more educated, based on proper suspicion of the likely pathogen (not simply isolate) and their antimicrobial susceptibility results.

Materials and Methods Settings and Microbiology The study was conducted in Amman-Jordan in two private hospitals with a total bed occupancy of 370 and total ICU beds of 45 (The Specialty Hospital and Al Khalidi Hospital). The study period was from September 2009 – February 2011. Isolates were processed for susceptibility by Viteck II ( BioMérieux SA. F-69280 Marcy l’Etoile, France) few isolates were processed by E-test (AB BIODISK Dalvägen 10, S - 169 56 Solna, Sweden). Antimicrobials used for susceptibilities including meropenem, imipenem, ertapenem, PIP/TAZ, tigecycline, cefepime, ceftazidime, ceftriaxone,, ciprofloxacin, levofloxacin and aztreonam. Gram-negative pathogens tested were those isolated from all sources (table 1); Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Pseudomonas species, Acinetobacter complex, Enterobacter spp. Serratia marscesenece and others bacteria spp. like (Proteus mirabilis, Morganella morgani, Providentia stuarti, Chrysomonas luteola, Flavimonoas arrhyzohabitans).

2011 Vol. 1 No. 1:3 doi: 10:3823/702

Definitions and Methodology F our major indicators are utilized in both hospitals (quality performance indicators) were considered for obtaining isolates (VAP, CLABSI, CAUTI and SSI), an isolate is considered a pathogen and included in the study when causing infection in the organ as it followed the definition for hospital-acquired infections described by CDC-NHSN. (7) Qualified infection control nurses (M.A and A.S) collect cultures results from the microbiology laboratory. The methodologies of pathogens’ sampling were monitored, especially in VAP, whether samples were taken from tracheal aspiration or BAL or other methods, abiding by CDC-NHSN definition. Daily collected cultures were discussed on case-by-case basis, with patients’ chart review, radiological review, urine analysis and blood cultures with an infectious diseases physician, before enrolling the suspect pathogen in the study. In the other hospital, a qualified experienced infection control nurse did the review and strictly applied same CDCNHNS definitions, keeping in contact with the same infectious diseases physician (J.W). Microbiological Methodology Microbiological procedures to identify the target microorganisms: specimens from the target sources are cultured on bloodagar, chocolate-agar, MacConkey’s agar & SAB agar plates Pus was cultured on two plates of blood agar (aerobic and anaerobic incubation) and on chocolate agar, MacConkey’s agar & SAB agar plates. Pus is also incubated in thioglycolate for growth augmentation, subsequently cultured on plates as above in twenty-four, forty-eight hours and at the end of incubation i.e. five days. Chocolate agar plates were incubated in CO2 environment for twenty-four hours. Microorganisms were identified from growth plate by colony morphology (shape, color, size) and gram stain; Gram-negative bacteria grew on selective Mac-

TABLE 1. Gram-negative Pathogens isolated in ICU Setting, and their Distribution according to Source. Pathogens

CLABSI

CAUTI

VAP

SSI

Total No. of Pathogens

E.coli

17

32

0

7

56

K. pneumonia

9

14

4

2

29

P. aeruginosa

7

10

4

5

26

Acinetobacter spp.

9

7

8

4

28

Enterobacter spp.

2

2

0

2

6

Pseudomonas spp.

6

0

0

0

6

Other GNB

7

6

0

9

22

Total

57

71

16

29

173

CLA-BSI: Central line associated blood stream infection. CA-UTI: Catheter associated urinary tract infection. VAP: ventilator associated pneumonia. SSI: Surgical site infection. Others GNB: Serratia marscesence, Flavimonas arryzohabitanz, Hemophilus influenzae, Proteus mirabilis, Morganella spp., Providentia spp., Chrysomonas luteola, Achromobacter sppecies.

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2011 Vol. 1 No. 1:3 doi: 10:3823/702

Conkey’s agar plate, and then identified as lactose fermenter (LF) or non-fermenter (NLF) and processed by the automated Viteck II. Microorganism susceptibility is processed by isolating colonies in one of sterile solutions (saline solution for use in Viteck II); suspension density is checked by the digital density check (0.5-0.63) densitocheck(add the name of company and country). The results are reported as minimum inhibitory concentration (MIC) according to the published document by clinical and laboratory standards institute (CLSI) break points( 8). E. coli ATCC 25922 and P. aeruginosa ATCC 25423 were used as Controls.

Results

Statistical analysis

One-hundred seventy-three gram-negative pathogens (table 1) were isolated from CLABSI, CAUTI, VAP and SSI. E. coli was dominant (N = 56) pathogen, mostly was isolated from urinary source (n = 32) followed by CLABSI (n = 17). K. pneumonia (N = 29) was isolated from CATUI (n = 14), followed by CLABSI (n = 9) and VAP (n = 4). P. aeruginosa (N = 26) from CAUTI (n= 10), from CLABSI (n = 7), and from VAP (n = 4) and SSI (n = 5) pathogens. Acinetobacter species were more-or-less uniformly isolated from all sources (N = 28). Enterobacter species and Pseudomonas species were minor in numbers; the “other gramnegatives” were heterogenous and came from SSI, CLABSI and CAUTI.

All results were uploaded into statistical software (SPSS version 15). Data generation for tables, numbers, ratios as well as raters were measured. Where appropriate, the differences in susceptibility among gram-negative pathogens were calculated using 95% confidence intervals and P-value (p-value to be < 0.05). The hypothesis was that meropenem is different from other antimicrobials especially imipenem, in its activity against major ICU gram-negative pathogens. Susceptibility of pseudomonas to meropenem and imipenem were specifically measured for the claim that meropenem is more of anti-pseudomonal than imipenem. Furthermore, p-value was calculated based on meropenem as a reference for other selected antipseudomonal antimicrobials, representing different antimicrobials classes (Figure 1).

100 80 60

66.6

58.6

78.7 51.5

42.4

40

58.3

Two-hundred twenty pathogen were isolated; 39 gram-positive, 173 gram-negative (54 ESBL; 30.7%), and 8 Candida species. Eight were duplicate isolates considered all as pathogens; it was not certain which one was the pathogen in the absence of lung biopsy for gram staining, to correlate with culture (however, 6 Candida were isolated with gram-negative bacilli, and 2 S. fecalis with gram negative-bacilli), gram-negative bacilli were considered the pathogens for they were treated by the attending physician.

Carbapenems (meropenem, imipenem and ertapenem) showed superior activity over other tested antimicrobial classes against E. coli, K. pneumonia and Enterobacter spp. (Table 2),

66.6 48.1

FIGURE 1. Susceptibility of Pseudomonas aeruginosa including Pseudomonas species to selected antimicrobial agents expressed in percentages.

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26/33 17/33 14/24 22/33 P = 0.02 P = 0.43 P = 0.97 P = 0.35 Z = 2.34 Z = -0.77 Z = -0.03 Z = 0.99

Aztreonam

Cefepime

Levofloxacin

22/33 P = 0.35 Z = 0.99

Ciprofloxacin

14/33 P = 0.07 Z = -1.88

PIP/TAZ

Amikacin

17/29

Imipenem

Meropenem

0

13/27 P = 0.25 Z = -1.15

Numbers below antimicrobials denote the total pathogens susceptible over total tested for that antimicrobial. P-values are for comparing meropenem with the respected antimicrobial. Z: the standard normal variant for same comparison.


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TABLE 2. Antimicrobial Susceptibility of all Gram-negative pathogen isolates in ICUs. Antibiotic

Meropenem Imipenem S/R S/R

Amikacin S/R

PIP/TAZ S/R

Tigecycline Ciprofloxacin Levofloxacin Ertapenem Ceftraixone Cefepime Aztreonam S/R S/R S/R S/R S/R S/R S/R

E. col n=56

49 / 1

54 / 1

54 / 1

29 / 24

11 / 4

18 / 38

17 / 33

50 / 1

19 / 13

18 /12

13 / 13

K.pneumoniae n= 29

27 / 2

27 / 2

28 / 1

17 / 11

8/3

12 / 15

12 / 13

24 / 1

13 / 4

11 / 6

10 / 3

P. aeruginosa n = 26

13 / 10

14 / 12

21 / 5

18 / 7

0/3

15 / 11

12 / 9

0/1

0/6

18 / 8

10 / 11

Acinetobacter n = 28

2 / 26

2 / 26

10 / 17

2 / 26

14 / 8

1 / 24

1 / 21

0 / 11

1 / 19

2 / 23

1 / 20

Enterobacter n=6

6/0

6/0

4/1

4/1

1/0

3/2

3/4

2/1

3/2

3/1

2/1

Pseudomonas spp. n = 7

4/2

0/7

1/6

7/0

0/1

2/5

2/1

--------

0/4

4/3

3/3

PIP/TAZ: pipracillin-tazobactam. S; Susceptible, R: resistant, n: total number of pathogens tested to various antimicrobials.

TABLE 3. Antimicrobial susceptibility of all Gram-negative bacilli isolated from all sources

Antibiotics

Susceptible

Intermediate

Resistant

% Susceptible

The Percent difference of each antimicrobial vs. Meropenem and (95% C.I.)

Meropenem

125

5

54

67.4

---

Imipenem

134

5

68

64.7

-2.7 (-6 to 12)

PIP/TAZ

106

4

85

54.4

-13 (-3 to -23)

Ertapenem

86

1

15

84.3

16.9 (7- 27)

Levofloxacin

69

5

99

39.9

-27.5 (-17 to -37)

Ciprofloxacin

71

3

127

35.3

-32.1 (-22 to -41)

Ceftriaxone

45

1

64

40.9

-26.5 (-15 to - 38)

Amikacin

135

2

35

78.5

11.1 (2 - 20)

Tigecycline

70

6

18

74.5

7.1 (-4 to 18)

Cefepime

66

5

52

53.6

-13.8 (-3 to -25)

but within the same class; meropenem did better than imipenem against pseudomonas species, However both carbapenems have 5.6% resistance rates among the fifty-four tested ESBL producing gram-negative bacilli. PIP/TAZ did better than both carbapenems (p = 0.02) against Pseudomonas aeruginosa and species (Figure 1). Lumping gram-negative pathogens susceptibility together, as what actually occur in “clinical initial empiric therapy”; carbapenems, tigecycline, and amikacin were better in activity than other tested antimicrobials (Table 3 and Figure 2).

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ESBL was detected by Viteck II employing Ceftazidime, ceftriaxone and aztreonam plus clavulonic acid (in combination with amoxicillin), subtypes were CTX-M 31%, SHV 10.3%, AmpC 19%, others 5.2% and untypable 34.5%. ESBL’s distribution among each gram-negative were; E. coli (62.7%), K. pneumonia (58.6%) and Enterobacter (100%). ESBL rates were 30.7% of all gram-negatives, and 44.5% of ESBL-producing gram-negative pathogens.




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PIP/TAZ: pipracillin-tazobactam FIGURE 2. Forest representation of the 95% confidence interval comparing meropenem activity against Gram-negative pathogens with other antimicrobials (data from table 3).

Discussion In our current study as well as in others, Enterobacteriaceae dominated the isolates, thus, being frequent candidate pathogens causing sepsis in ICUs. (8) E. coli was the prevalent pathogen 56 (32.4%), followed by K. pneumonia, Pseudomonas aeruginosa and Acinetobacter species. This is divergent from some prevalence studies of isolates where it showed dominance of Pseudomonas aeruginosa in a US study.(9) While in Europe Enterobacteriaceae lead by E. coli was dominant.(8) However both studies show that Acinetobacter and Serratia marscesence defined as pathogens are less than what physicians use to diagnose and treat in ICUs.(8, 9) Meropenem is a carbapenem belongs to the same family of antimicrobials with imipenem and ertapenem as well as others not yet available in our part of the world e.g. Doripenem, Faropenem, Panipenem, and the investigational agents; Tomopenem, Tebinepem, Razupenem.(10) Meropenem mechanism of action against pseudomonas is exerted through binding to © Under License of Creative Commons Attribution 3.0 License

PBP2 and PBP3, while in E. coli it binds to PBP2, much similar to the recently released doripenem, while imipenem binds to PBP1a and PBP1b in Pseudomonas.(11) This may reflect on meropenem in being a marginally better anti-pseudomonal and antigram-negative agent.(12) In our study meropenem showed tendency towards being better anti-pseudomonal than imipenem (p = 0.07), while it showed no significant difference against the other tested gram-negative pathogens (p > 0.05). PIP/TAZ showed a significant but marginal better anti-pseudomonal activity than meropenem, p = 0.02 (Fig 1). Both carbapenems harbor 5.6% resistance rates among the fifty-four tested ESBL producing gram-negative bacilli. However, considering all gram-negative pathogens together for susceptibility, as actually what happens in the clinical approach for initial empiric therapy, Imipenem is the only antimicrobial that is comparable with meropenem. While other antimicrobials like Amikacin (95% C.I, 0.02 - 0.27), ertapenem (95% C.I, 0.07-0.27) show tendency towards a better suscep-

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TABLE 4. Gram-negative bacilli showing ESBL production and ESBL-producers distribution according to their source. Source

Gram-negative pathogens

CLA-BSI

CA-UTI

VAP

SSI

Total (%)

Escherichia coli ESB

yes No Total

9 8 17

21 11 32

0 0 0

7 0 7

37 (62.7) 19 59

Klebsiella pneumonia ESB

yes No Total

3 6 9

10 4 14

2 2 4

2 0 2

17 (58.6) 12 29

Enterobacter spp. ESBL

yes No Total

2 0 2

2 0 2

0 0 0

2 0 2

6 (100) 0 6

14 (50%)

33 (68.7%)

2 (50%)

11 100%

Total ESBL-Producing bacteria and rates per source

Total ESBL rates from E.coli, K. pneumonia and Enterobacter spp. from all sources were = 44.5%. Total ESBL rates from all gram-negative pathogens isolated from all sources were 30.7%. CLA-BSI: Central line associated blood stream infection. CA-UTI: Catheter associated urinary tract infection. VAP: ventilator associated pneumonia. SSI: Surgical site infection. ESBL-GNB: Extended spectrum beta lactamase- producing gram-negative bacilli.

TABLE 6. Susceptibility of ESBL-producing and-nonproducing Gram-negative bacilli to meropenem and to other tested comparator antimicrobials Susceptible ESBL Yes No

Intermediate ESBL Yes No

Resistant ESBL Yes No

(%) Susceptible ESBL Yes No

Difference in percent Susceptibility and (95% C.I)

Meropenem

46

27

0

0

3

1

94

96

4

(-8 - 12)

Imipenem

50

28

0

0

3

3

94

90

4

(-8 - 16)

PIP/TAZ

18

25

2

0

30

3

36

89

Tigecycline

13

8

0

0

4

3

76

73

3

(-30 - 36)

Ertapenem

46

25

0

0

2

0

96

93

3

(-8 - 14)

Levofloxacin

7

20

2

0

37

7

15

74

-59 (-39 to -78)*

Ciprofloxacin

7

23

1

0

44

7

14

77

63 (-45 to -81) *

Ceftriaxone

3

26

0

0

16

2

16

93

77 (-58 to -96) *

Amikacin

51

28

1

0

1

0

98

100

Aztreonam

0

19

0

0

16

1

00

95

-53 ( -35 to- 70)*

-2

(-2 - 6)

-95 (-85 to -100)*

* Starred antimicrobials show significant difference in activity against ESBL and non-ESBL producing gram-negative bacilli. ESBL-GNB: Extended spectrum beta lactamase- producing gram-negative bacilli.

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tibility patterns in vitro, and tigecycline show no significant difference (95% C.I, -0.04 to 0.18) in susceptibility patterns in comparison with meropenem. Nevertheless, the later three agents are not approved and should not be used in sever sepsis syndrome or bacteremia.(13, 14, 15, 16) Moreover, PIP/TAZ showed tendency towards less activity than meropenem when gram-negative pathogens were considered together (95%C.I, -0.023 to – 0.030). ESBL- producers were found among E. coli, K. pneumonia, and Enterobacter species. The prevalence of ESBL-producers was 30.7% of all gram-negative pathogens, and 44.5% among the aforementioned ESBL-producers. E. coli lead the three pathogens in ESBL production (Table 4) contrary to other previous studies that showed K. pneumonia was the leader.(17) The difference in susceptibility among ESBL-producing pathogens compared with same non-ESBL producers show that meropenem (difference = 4, 95% C.I -8 to 12) and imipenem (difference = 4, 95% C.I -8 to 16) are again trust worthy in the initial empiric therapy in ICUs and hospitals that suffer from high rates of ESBL-producers, and both were comparable. PIP/TAZ, an agent that is frequently used in ICU for sever sepsis of different sources, showed highly significant difference in activity


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against ESBL-producers and non-producers (difference = -53, 95% C.I, -35 to -70, p < 0.0001). The finding in these pathogens point that IDSA recommendations in using PIP/TAZ in ESBLproducers in complicated intra-abdominal infections is to be employed in community-acquired infections or health careassociate intra-abdominal infections if their total rates of ESBL are less than 20%, or ESBL-subtypes are known, e.g. SHV and Toho-2 were not prevalent. (17, 18) ESBL sub-typing is not available in a good number of laboratories. This study utilizing pathogens showed that meropenem and imipenem are trustworthy in the initial empiric therapy before the the documented pathogen is known, since the rates of gram-negative pathogens’ susceptibilities are the highest among tested agents potentially used in ICU sepsis. Looking for antimicrobials’ susceptibility among pathogens is not common in literature for being tedious, though this approach may be more accurate in clinical management of patients, especially bacteria of the same species may be different in genotypes or serotypes, which translate to pathogenesis potentials.(19, 20)

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16. Benjamin A Lipsky, David G Armstrong, Diane M Citron, Alan D Tice, David E Morgenstern, Murray A Abramson. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, doubleblinded, multicentre trial. Lancet 2005; 366: 1695–703. 17. S. V. Yakovlev & L. S. Stratchounski & G. L. Woods & B. Adeyi & K. A. McCarroll & J. A. Ginanni & I. R. Friedland & C. A. Wood & M. J. DiNubile. Ertapenem versus cefepime for initial empirical treatment of pneumonia acquired in skilled-care facilities or in hospitals outside the intensive care unit. Eur J Clin Microbiol Infect Dis: DOI 10.1007/s10096-006-0193-0. 18. Kenneth S. Thomson and Ellen Smith Moland. Cefepime, Piperacillin-Tazobactam, and the Inoculum Effect in Tests with Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae. Antimicrobial Agents and Chemotherapy. Dec. 2001, p. 3548–3554 19. Joseph S. Solomkin et al. Diagnosis and Management of Complicated Intra-abdominal Infection in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clinical Infectious Diseases 2010; 50:133–64. 20. Edouard Bingen. Combined Multilocus Sequence Typing and O Serogrouping Distinguishes Escherichia coli Subtypes Associated with Infant Urosepsis and/or Meningitis. The Journal of Infectious Diseases 2007; 196:297–303. 21. Yu-Chung Chuang. Influence of Genospecies of Acinetobacter baumannii Complex on Clinical Outcomes of Patients with Acinetobacter Bacteremia. Clinical Infectious Diseases 2011;52(3):352–360.

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