- Email: [email protected]
Colistin-resistant Enterobacteriaceae bacteraemia: real-life challenges and options
Accepted Manuscript Colistin-resistant Enterobacteriaceae bacteremia: real life challenges and options Felipe F. Tuon, Thiago Alberto Santos, Raphael Almeida, Jaime L. Rocha, Juliette Cieslinsk, Guilherme Nardi Becker, Lavinia N. Arend PII:
S1198-743X(15)00904-0
DOI:
10.1016/j.cmi.2015.10.005
Reference:
CMI 405
To appear in:
Clinical Microbiology and Infection
Received Date: 28 September 2015 Accepted Date: 5 October 2015
Please cite this article as: Tuon FF, Santos TA, Almeida R, Rocha JL, Cieslinsk J, Becker GN, Arend LN, Colistin-resistant Enterobacteriaceae bacteremia: real life challenges and options, Clinical Microbiology and Infection (2015), doi: 10.1016/j.cmi.2015.10.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Colistin-resistant Enterobacteriaceae bacteremia: real life challenges and options
1 2 3
1
School of Medicine, Pontifícia Universidade Católica do Paraná 2
Division of Infectious and Parasitic Diseases, Hospital Universitário Evangélico de Curitiba, Curitiba, PR, Brazil; 3 Division of Microbiology, Frischmann Aisengart/DASA Medicina Diagnóstica, Curitiba, PR, Brazil; 4 Laboratory of Microbiology, Hospital Universitário Evangélico de Curitiba, Curitiba, PR, Brazil; 5 Laboratório Central do Estado LACEN-PR;
11 12 Running title: Combination therapy and KPC
M AN U
13 14 15
*Corresponding author:
17
Felipe F. Tuon
18
Division of Infectious and Parasitic Diseases,
19
Hospital Universitário Evangélico de Curitiba,
20
Alameda Augusto Stellfeld 1908, 3º. andar – SCIH - Bigorrilho,
21
CEP number 80730-150, Curitiba, Brazil.
22
Email: [email protected]
23
Telephone: 55-41-32405055
27
EP
AC C
25 26
TE D
16
24
SC
6 7 8 9 10
RI PT
Felipe F. Tuon, 1,2 * Thiago Alberto Santos, 1 Raphael Almeida, 1 Jaime L. Rocha, 2 Juliette Cieslinsk,3 Guilherme Nardi Becker,3 Lavinia N. Arend, 4
4 5
Fax: 55-41-32405274
Keywords: Klebsiella pneumoniae; sepsis; Klebsiella pneumoniae carbapenemases; carbapenems; tigecycline; polymyxin; meropenem
ACCEPTED MANUSCRIPT
28
Sir,
29
In the last decade, the use of polymyxin or colistin increased due to outbreaks and high
31
prevalence of several carbapenem-resistant bacteria. Colistin resistance came up fast in such
32
scenario and it became an important issue mainly in intensive care units of therapy. Evidence
33
based therapeutic options are scarce and combined therapies may be more costly for payers and
34
harmful to patients. Colistin-resistant Enterobacteriaceae in the era of carbapenemase
35
producing-bacteria is a hot topic and there is a gap of information in bacteremia. This is a
36
descriptive study of 14 patients with colistin-resistant Klebsiella pneumoniae bacteremia
37
between May 2013 and July 2014 in a general tertiary hospital with 660 beds, which is the major
38
reference center for trauma, burn unit and renal transplant.
M AN U
SC
RI PT
30
39
Klebsiella pneumoniae identification and susceptibility tests were performed with Vitek 2
41
(Biomérieux, Marcy-LÉtoile, France) according to the CLSI (Clinical Laboratory Standard
42
Institute) guidelines. Isolates showing reduced susceptibility to ertapenem/meropenem were
43
submitted to PCR for blaKPC using EasyQ KPC (Biomérieux, Marcy-LÉtoile, France) as
44
previously described [1]. Gender, age, Charlson comorbidity index score, length of
45
hospitalization before bacteremia, clinical outcome and therapy were evaluated. CDC (Center of
46
Diseases Control) criteria for bloodstream infection were used in the revision. All strains were
47
compatible with KPC-2 type. Nine strains were pan-resistant and the other five strains were
48
susceptible to aminoglycosides. Colistin MIC was high (≥16mg/L) for all strains of Klebsiella
49
sp. One single strain remained susceptible to both ciprofloxacin (≤0.25mg/dL) and meropenem
50
(≤0.25mg/dL) (table 1).
AC C
EP
TE D
40
ACCEPTED MANUSCRIPT
51
Clinical data are detailed in the table 1. Young patients (mean age 45.21 years-old) with few
53
comorbidities may justify the observed low mortality rate (Thirty day and global mortality was
54
28.6%). Only two out of four patients who died had high Charlson index and one another patient
55
who died was not using antibiotic. Adequate therapy was prescribed in only 1 patient (7.1%)
56
within 24 hours of bacteremia. Within 48 hours, 3 patients at all were using at least one active
57
drug (21.4%). The active drugs were amikacin in two patients and ciprofloxacin in another.
58
Despite of high MICs for colistin and independent of meropenem MIC, seven patients continued
59
to use polymyxin B in combination with carbapenem, Drugs dosing used were: 25,000UI/kg of
60
polymyxin B every 12 hours (No renal adjustment); 2,000 mg of meropenem every 8h; 15mg/kg
61
of amikacin daily; 100mg of tigecycline twice in the first day followed by 50mg twice a day.
M AN U
SC
RI PT
52
62
In the literature, inactivation of the mgrB gene is the most important modification responsible for
64
acquired colistin-resistant in KPC-producing Klebsiella pneumonia in clinical samples, which
65
can be induced by low doses of polymyxin B [2]. In our hospital, 13% of KPC-KP from clinical
66
samples from different clones are colistin-resistant, a similar scenario with other surveillance
67
studies in Europe [3]. In a prospective cohort, colistin-resistance was an independent risk factor
68
for mortality. [3].
EP
AC C
69
TE D
63
70
Treatment of colistin-resistant bacteria is a major challenge. Treatment suggestions have been
71
based on case reports and in vitro results. Although several retrospective studies suggested
72
combined therapy against KPC-producing Enterobacteriaceae, there are no consistent findings
73
and data from current prospective studies are still missing. A synergic effect has been described
ACCEPTED MANUSCRIPT
when colistin is used in association with rifampin or carbapenem against colistin-resistant
75
bacteria, including Klebsiella, Pseudomonas and Acinetobacter [4]. Another reported option is
76
the combined therapy with two carbapenems. However, the number of patients treated with such
77
therapy is too small to come up with any conclusion. In vitro studies, it has also been showed
78
that combination of colistin with carbapenem decrease bacterial populations with low inoculum.
79
In the absence of strong evidence, some authors currently consider colistin plus carbapenem as a
80
frontline therapy for colistin resistant Enterobacteriaceae. The polymyxin and tigecycline
81
combination has not been successful in vitro and in animal models using our strain of KPC-
82
producing Klebsiella pneumoniae [4]. Gonzalez-Padilla et al. evaluated 50 cases of sepsis caused
83
by colistin-resistant K. pneumoniae and decreased mortality when gentamycin was used [5].
84
Amikacin, as well as fosfomycin and colistin, have been called “old drugs for new bugs”.
85
Unfortunately, these drugs have been extensively used and resistance is increasing each year in
86
our hospital.
TE D
M AN U
SC
RI PT
74
87
Despite of many doubts about the ideal treatment, infection control measures are fundamental in
89
current contest to avoid spread of these bacteria in the hospital. Stewardship program are
90
effective and must invest time to reduce the abuse of polymyxin and evaluate the ideal dosage.
91
Excessive combined therapy with drugs without in vitro activity should be discouraged. At
92
moment, colistin resistance seems not to have aggregate mortality. Despite inadequate treatment
93
and high rate resistance profile, mortality in the current sample was lower than it could be
94
expected.
AC C
EP
88
95 96
Acknowledgement
ACCEPTED MANUSCRIPT
97
None
AC C
EP
TE D
M AN U
SC
RI PT
98
ACCEPTED MANUSCRIPT
Legends
101
Table 1. Clinical data of 14 patients with colistin-resistant Klebsiella pneumoniae.
102 103 104 105 106 107 108 109
Transparency declarations
SC M AN U
Funding: None
EP
TE D
Felipe F. Tuon received grants from MSD, Pfizer, Novartis, TEVA and AstraZeneca Jaime L. Rocha received grants from MSD, Pfizer, Novartis, Sanofi-Aventis and AstraZeneca
AC C
110 111 112 113 114
RI PT
99 100
ACCEPTED MANUSCRIPT
115 116 117
References 1
Tuon FF, Rocha JL, Toledo P, et al. Risk factors for kpc-producing klebsiella pneumoniae bacteremia. The Brazilian journal of infectious diseases : an official
119
publication of the Brazilian Society of Infectious Diseases. 2012; 16: 416-419.
120
2
RI PT
118
Jayol A, Poirel L, Brink A, Villegas MV, Yilmaz M, Nordmann P. Resistance to colistin associated with a single amino acid change in protein pmrb among klebsiella pneumoniae
122
isolates of worldwide origin. Antimicrobial agents and chemotherapy. 2014; 58: 4762-
123
4766. 3
M AN U
124
SC
121
Capone A, Giannella M, Fortini D, et al. High rate of colistin resistance among patients with carbapenem-resistant klebsiella pneumoniae infection accounts for an excess of
126
mortality. Clinical microbiology and infection : the official publication of the European
127
Society of Clinical Microbiology and Infectious Diseases. 2013; 19: E23-30.
128
4
TE D
125
Toledo PV, Aranha Junior AA, Arend LN, Ribeiro V, Zavascki AP, Tuon FF. Activity of antimicrobial combinations against kpc-2-producing klebsiella pneumoniae in a rat model
130
and time-kill assay. Antimicrob Agents Chemother. 2015.
132 133
134
5
Gonzalez-Padilla M, Torre-Cisneros J, Rivera-Espinar F, et al. Gentamicin therapy for
AC C
131
EP
129
sepsis due to carbapenem-resistant and colistin-resistant klebsiella pneumoniae. The Journal of antimicrobial chemotherapy. 2015; 70: 905-913.
ACCEPTED MANUSCRIPT
male male male male male female male female male female male female female female
active drug (<24h) no yes no no no no no no no no no no no no
POL+VAN+TZP POL+AK* MEM+POL MEM+TGC+POL+AK MEM+VAN CAZ+VAN None LNZ+MEM+POL MEM MEM+POL+TGC TGC CRO+MTZ POL+TGC+MEM+AK MEM+VAN
active drug (<48h) no yes no no no yes no no no no no yes no no
POL+MEM+CAZ+LNZ POL+AK* MEM+POL MEM+TGC+POL+AK MEM+VAN CIP* None MEM+POL MEM+POL+TGC MEM+POL+TGC+ERT TGC AK* POL+TGC+MEM+AK POL+VAN
COL MIC ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16
AK MIC
CIP MIC
EP
TE D
*Active drugs BSI = bloodstream infection; AK = amikacin; CAZ = ceftazidima; LNZ = linezolid; MEM = meropenem; POL = polymyxin; TGC = tigecycline; VAN = vancomycin; CRO = ciprofloxacin; MTZ = metronidazole
AC C
MEM MIC
≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≤2(S) ≤0.25(S) ≤0.25(S) ≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16
RI PT
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days age Charlson before index (y) BSI 63 0 40 65 0 41 28 0 11 66 5 24 40 0 17 36 3 2 37 0 43 36 6 1 45 0 13 42 0 10 46 0 13 49 0 0 50 0 15 30 0 11
SC
gender
M AN U
n
outcome survival death survival death survival survival death survival survival death survival survival survival survival
S1198-743X(15)00904-0
DOI:
10.1016/j.cmi.2015.10.005
Reference:
CMI 405
To appear in:
Clinical Microbiology and Infection
Received Date: 28 September 2015 Accepted Date: 5 October 2015
Please cite this article as: Tuon FF, Santos TA, Almeida R, Rocha JL, Cieslinsk J, Becker GN, Arend LN, Colistin-resistant Enterobacteriaceae bacteremia: real life challenges and options, Clinical Microbiology and Infection (2015), doi: 10.1016/j.cmi.2015.10.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Colistin-resistant Enterobacteriaceae bacteremia: real life challenges and options
1 2 3
1
School of Medicine, Pontifícia Universidade Católica do Paraná 2
Division of Infectious and Parasitic Diseases, Hospital Universitário Evangélico de Curitiba, Curitiba, PR, Brazil; 3 Division of Microbiology, Frischmann Aisengart/DASA Medicina Diagnóstica, Curitiba, PR, Brazil; 4 Laboratory of Microbiology, Hospital Universitário Evangélico de Curitiba, Curitiba, PR, Brazil; 5 Laboratório Central do Estado LACEN-PR;
11 12 Running title: Combination therapy and KPC
M AN U
13 14 15
*Corresponding author:
17
Felipe F. Tuon
18
Division of Infectious and Parasitic Diseases,
19
Hospital Universitário Evangélico de Curitiba,
20
Alameda Augusto Stellfeld 1908, 3º. andar – SCIH - Bigorrilho,
21
CEP number 80730-150, Curitiba, Brazil.
22
Email: [email protected]
23
Telephone: 55-41-32405055
27
EP
AC C
25 26
TE D
16
24
SC
6 7 8 9 10
RI PT
Felipe F. Tuon, 1,2 * Thiago Alberto Santos, 1 Raphael Almeida, 1 Jaime L. Rocha, 2 Juliette Cieslinsk,3 Guilherme Nardi Becker,3 Lavinia N. Arend, 4
4 5
Fax: 55-41-32405274
Keywords: Klebsiella pneumoniae; sepsis; Klebsiella pneumoniae carbapenemases; carbapenems; tigecycline; polymyxin; meropenem
ACCEPTED MANUSCRIPT
28
Sir,
29
In the last decade, the use of polymyxin or colistin increased due to outbreaks and high
31
prevalence of several carbapenem-resistant bacteria. Colistin resistance came up fast in such
32
scenario and it became an important issue mainly in intensive care units of therapy. Evidence
33
based therapeutic options are scarce and combined therapies may be more costly for payers and
34
harmful to patients. Colistin-resistant Enterobacteriaceae in the era of carbapenemase
35
producing-bacteria is a hot topic and there is a gap of information in bacteremia. This is a
36
descriptive study of 14 patients with colistin-resistant Klebsiella pneumoniae bacteremia
37
between May 2013 and July 2014 in a general tertiary hospital with 660 beds, which is the major
38
reference center for trauma, burn unit and renal transplant.
M AN U
SC
RI PT
30
39
Klebsiella pneumoniae identification and susceptibility tests were performed with Vitek 2
41
(Biomérieux, Marcy-LÉtoile, France) according to the CLSI (Clinical Laboratory Standard
42
Institute) guidelines. Isolates showing reduced susceptibility to ertapenem/meropenem were
43
submitted to PCR for blaKPC using EasyQ KPC (Biomérieux, Marcy-LÉtoile, France) as
44
previously described [1]. Gender, age, Charlson comorbidity index score, length of
45
hospitalization before bacteremia, clinical outcome and therapy were evaluated. CDC (Center of
46
Diseases Control) criteria for bloodstream infection were used in the revision. All strains were
47
compatible with KPC-2 type. Nine strains were pan-resistant and the other five strains were
48
susceptible to aminoglycosides. Colistin MIC was high (≥16mg/L) for all strains of Klebsiella
49
sp. One single strain remained susceptible to both ciprofloxacin (≤0.25mg/dL) and meropenem
50
(≤0.25mg/dL) (table 1).
AC C
EP
TE D
40
ACCEPTED MANUSCRIPT
51
Clinical data are detailed in the table 1. Young patients (mean age 45.21 years-old) with few
53
comorbidities may justify the observed low mortality rate (Thirty day and global mortality was
54
28.6%). Only two out of four patients who died had high Charlson index and one another patient
55
who died was not using antibiotic. Adequate therapy was prescribed in only 1 patient (7.1%)
56
within 24 hours of bacteremia. Within 48 hours, 3 patients at all were using at least one active
57
drug (21.4%). The active drugs were amikacin in two patients and ciprofloxacin in another.
58
Despite of high MICs for colistin and independent of meropenem MIC, seven patients continued
59
to use polymyxin B in combination with carbapenem, Drugs dosing used were: 25,000UI/kg of
60
polymyxin B every 12 hours (No renal adjustment); 2,000 mg of meropenem every 8h; 15mg/kg
61
of amikacin daily; 100mg of tigecycline twice in the first day followed by 50mg twice a day.
M AN U
SC
RI PT
52
62
In the literature, inactivation of the mgrB gene is the most important modification responsible for
64
acquired colistin-resistant in KPC-producing Klebsiella pneumonia in clinical samples, which
65
can be induced by low doses of polymyxin B [2]. In our hospital, 13% of KPC-KP from clinical
66
samples from different clones are colistin-resistant, a similar scenario with other surveillance
67
studies in Europe [3]. In a prospective cohort, colistin-resistance was an independent risk factor
68
for mortality. [3].
EP
AC C
69
TE D
63
70
Treatment of colistin-resistant bacteria is a major challenge. Treatment suggestions have been
71
based on case reports and in vitro results. Although several retrospective studies suggested
72
combined therapy against KPC-producing Enterobacteriaceae, there are no consistent findings
73
and data from current prospective studies are still missing. A synergic effect has been described
ACCEPTED MANUSCRIPT
when colistin is used in association with rifampin or carbapenem against colistin-resistant
75
bacteria, including Klebsiella, Pseudomonas and Acinetobacter [4]. Another reported option is
76
the combined therapy with two carbapenems. However, the number of patients treated with such
77
therapy is too small to come up with any conclusion. In vitro studies, it has also been showed
78
that combination of colistin with carbapenem decrease bacterial populations with low inoculum.
79
In the absence of strong evidence, some authors currently consider colistin plus carbapenem as a
80
frontline therapy for colistin resistant Enterobacteriaceae. The polymyxin and tigecycline
81
combination has not been successful in vitro and in animal models using our strain of KPC-
82
producing Klebsiella pneumoniae [4]. Gonzalez-Padilla et al. evaluated 50 cases of sepsis caused
83
by colistin-resistant K. pneumoniae and decreased mortality when gentamycin was used [5].
84
Amikacin, as well as fosfomycin and colistin, have been called “old drugs for new bugs”.
85
Unfortunately, these drugs have been extensively used and resistance is increasing each year in
86
our hospital.
TE D
M AN U
SC
RI PT
74
87
Despite of many doubts about the ideal treatment, infection control measures are fundamental in
89
current contest to avoid spread of these bacteria in the hospital. Stewardship program are
90
effective and must invest time to reduce the abuse of polymyxin and evaluate the ideal dosage.
91
Excessive combined therapy with drugs without in vitro activity should be discouraged. At
92
moment, colistin resistance seems not to have aggregate mortality. Despite inadequate treatment
93
and high rate resistance profile, mortality in the current sample was lower than it could be
94
expected.
AC C
EP
88
95 96
Acknowledgement
ACCEPTED MANUSCRIPT
97
None
AC C
EP
TE D
M AN U
SC
RI PT
98
ACCEPTED MANUSCRIPT
Legends
101
Table 1. Clinical data of 14 patients with colistin-resistant Klebsiella pneumoniae.
102 103 104 105 106 107 108 109
Transparency declarations
SC M AN U
Funding: None
EP
TE D
Felipe F. Tuon received grants from MSD, Pfizer, Novartis, TEVA and AstraZeneca Jaime L. Rocha received grants from MSD, Pfizer, Novartis, Sanofi-Aventis and AstraZeneca
AC C
110 111 112 113 114
RI PT
99 100
ACCEPTED MANUSCRIPT
115 116 117
References 1
Tuon FF, Rocha JL, Toledo P, et al. Risk factors for kpc-producing klebsiella pneumoniae bacteremia. The Brazilian journal of infectious diseases : an official
119
publication of the Brazilian Society of Infectious Diseases. 2012; 16: 416-419.
120
2
RI PT
118
Jayol A, Poirel L, Brink A, Villegas MV, Yilmaz M, Nordmann P. Resistance to colistin associated with a single amino acid change in protein pmrb among klebsiella pneumoniae
122
isolates of worldwide origin. Antimicrobial agents and chemotherapy. 2014; 58: 4762-
123
4766. 3
M AN U
124
SC
121
Capone A, Giannella M, Fortini D, et al. High rate of colistin resistance among patients with carbapenem-resistant klebsiella pneumoniae infection accounts for an excess of
126
mortality. Clinical microbiology and infection : the official publication of the European
127
Society of Clinical Microbiology and Infectious Diseases. 2013; 19: E23-30.
128
4
TE D
125
Toledo PV, Aranha Junior AA, Arend LN, Ribeiro V, Zavascki AP, Tuon FF. Activity of antimicrobial combinations against kpc-2-producing klebsiella pneumoniae in a rat model
130
and time-kill assay. Antimicrob Agents Chemother. 2015.
132 133
134
5
Gonzalez-Padilla M, Torre-Cisneros J, Rivera-Espinar F, et al. Gentamicin therapy for
AC C
131
EP
129
sepsis due to carbapenem-resistant and colistin-resistant klebsiella pneumoniae. The Journal of antimicrobial chemotherapy. 2015; 70: 905-913.
ACCEPTED MANUSCRIPT
male male male male male female male female male female male female female female
active drug (<24h) no yes no no no no no no no no no no no no
POL+VAN+TZP POL+AK* MEM+POL MEM+TGC+POL+AK MEM+VAN CAZ+VAN None LNZ+MEM+POL MEM MEM+POL+TGC TGC CRO+MTZ POL+TGC+MEM+AK MEM+VAN
active drug (<48h) no yes no no no yes no no no no no yes no no
POL+MEM+CAZ+LNZ POL+AK* MEM+POL MEM+TGC+POL+AK MEM+VAN CIP* None MEM+POL MEM+POL+TGC MEM+POL+TGC+ERT TGC AK* POL+TGC+MEM+AK POL+VAN
COL MIC ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16 ≥16
AK MIC
CIP MIC
EP
TE D
*Active drugs BSI = bloodstream infection; AK = amikacin; CAZ = ceftazidima; LNZ = linezolid; MEM = meropenem; POL = polymyxin; TGC = tigecycline; VAN = vancomycin; CRO = ciprofloxacin; MTZ = metronidazole
AC C
MEM MIC
≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≤2(S) ≤0.25(S) ≤0.25(S) ≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16 ≤2(S) ≥4 ≥16 ≤2(S) ≥4 ≥16 ≥64 ≥4 ≥16 ≥64 ≥4 ≥16
RI PT
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days age Charlson before index (y) BSI 63 0 40 65 0 41 28 0 11 66 5 24 40 0 17 36 3 2 37 0 43 36 6 1 45 0 13 42 0 10 46 0 13 49 0 0 50 0 15 30 0 11
SC
gender
M AN U
n
outcome survival death survival death survival survival death survival survival death survival survival survival survival