Ceftolozane-Tazobactam for the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Infections: Clinical Effectiveness and Evolution of Resistance.

TLDR: In this small study, ceftolozane-tazobactam was successful in treating 71% of patients with MDR-P.

Abstract: Background Data on the use of ceftolozane-tazobactam and emergence of ceftolozane-tazobactam resistance during multidrug resistant (MDR)-Pseudomonas aeruginosa infections are limited. Methods We performed a retrospective study of 21 patients treated with ceftolozane-tazobactam for MDR-P. aeruginosa infections. Whole genome sequencing and quantitative real-time polymerase chain reaction were performed on longitudinal isolates. Results Median age was 58 years; 9 patients (43%) were transplant recipients. Median simplified acute physiology score-II (SAPS-II) was 26. Eighteen (86%) patients were treated for respiratory tract infections; others were treated for bloodstream, complicated intraabdominal infections, or complicated urinary tract infections. Ceftolozane-tazobactam was discontinued in 1 patient (rash). Thirty-day all-cause and attributable mortality rates were 10% (2/21) and 5% (1/21), respectively; corresponding 90-day mortality rates were 48% (10/21) and 19% (4/21). The ceftolozane-tazobactam failure rate was 29% (6/21). SAPS-II score was the sole predictor of failure. Ceftolozane-tazobactam resistance emerged in 3 (14%) patients. Resistance was associated with de novo mutations, rather than acquisition of resistant nosocomial isolates. ampC overexpression and mutations were identified as potential resistance determinants. Conclusions In this small study, ceftolozane-tazobactam was successful in treating 71% of patients with MDR-P. aeruginosa infections, most of whom had pneumonia. The emergence of ceftolozane-tazobactam resistance in 3 patients is worrisome and may be mediated in part by AmpC-related mechanisms. More research on treatment responses and resistance during various types of MDR-P. aeruginosa infections is needed to define ceftolozane-tazobactam's place in the armamentarium.

Full text

Clinical Infectious Diseases
110 • CID 2017:65 (1 July) • Haidar etal
Ceolozane-Tazobactam for the Treatment of Multidrug-
Resistant Pseudomonas aeruginosa Infections: Clinical
Eectiveness and Evolution of Resistance
GhadyHaidar,
1
Nathan J.Philips,
2
Ryan K.Shields,
1,3,4
DanielSnyder,
2
ShaojiCheng,
4
Brian A.Potoski,
1,3,5
YoheiDoi,
1
BinghuaHao,
4
Ellen G.Press,
1
Vaughn S. Cooper,
2
Cornelius J.Clancy,
1,4,6a
and M. HongNguyen
1,3,4a
1
Department of Medicine, University of Pittsburgh,
2
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine,
3
Antibiotic Management Program, and
4
XDR Pathogen Laboratory, University of Pittsburgh Medical Center,
5
Department of Pharmacy and Therapeutics, University of Pittsburgh, and
6
VA Pittsburgh Healthcare System, Pennsylvania
Background. Data on the use of ceolozane-tazobactam and emergence of ceolozane-tazobactam resistance during multidrug
resistant (MDR)-Pseudomonas aeruginosa infections are limited.
Methods. We performed a retrospective study of 21 patients treated with ceolozane-tazobactam for MDR-P.aeruginosa infec-
tions. Whole genome sequencing and quantitative real-time polymerase chain reaction were performed on longitudinal isolates.
Results. Median age was 58 years; 9 patients (43%) were transplant recipients. Median simplied acute physiology score-II
(SAPS-II) was 26. Eighteen (86%) patients were treated for respiratory tract infections; others were treated for bloodstream, com-
plicated intraabdominal infections, or complicated urinary tract infections. Ceolozane-tazobactam was discontinued in 1 patient
(rash). irty-day all-cause and attributable mortality rates were 10% (2/21) and 5% (1/21), respectively; corresponding 90-day
mortality rates were 48% (10/21) and 19% (4/21). e ceolozane-tazobactam failure rate was 29% (6/21). SAPS-II score was the
sole predictor of failure. Ceolozane-tazobactam resistance emerged in 3 (14%) patients. Resistance was associated with de novo
mutations, rather than acquisition of resistant nosocomial isolates. ampC overexpression and mutations were identied as potential
resistance determinants.
Conclusions. In this small study, ceolozane-tazobactam was successful in treating 71% of patients with MDR-P.aeruginosa
infections, most of whom had pneumonia. e emergence of ceolozane-tazobactam resistance in 3 patients is worrisome and may
be mediated in part by AmpC-related mechanisms. More research on treatment responses and resistance during various types of
MDR-P.aeruginosa infections is needed to dene ceolozane-tazobactam’s place in the armamentarium.
Keywords. ceolozane-tazobactam; MDR Pseudomonas; resistance mechanisms; AmpC beta-lactamase; omega loop.
Infections due to multidrug-resistant (MDR)–Pseudomonas
aeruginosa are associated with poor outcomes [1–7]. β-lactams
are therapeutic mainstays, but development of resistance limits
their eectiveness [8, 9]. A signature resistance mechanism
in P. aeruginosa is production of AmpC β-lactamase, which
hydrolyzes penicillins, monobactams, and oxyimino-
cephalosporins (except cefepime) but not carbapenems [10,
11]. Other important β-lactam resistance mechanisms include
multidrug eux pumps and loss of outer membrane porin OprD
[12–19]. Acquisition of plasmid-borne extended-spectrum
β-lactamases (ESBLs) and carbapenemases is uncommon among
P.aeruginosa in the United States [13, 19, 20].
Ceftolozane–tazobactam was recently approved by the
US Food and Drug Administration (FDA) for the treat-
ment of complicated intraabdominal and urinary tract
infections (cIAIs, cUTIs) [21, 22]. Ceftolozane is an oxy-
imino-cephalosporin that structurally resembles ceftazi-
dime but has increased activity against P.aeruginosa and
decreased susceptibility to AmpC hydrolysis [23, 24].
We previously showed that 92% of 38 meropenem-resist-
ant P. aeruginosa isolates at our center were susceptible
to ceftolozane-tazobactam in vitro [25]. Clinical experi-
ence with ceftolozane-tazobactam for the treatment of
MDR-P.aeruginosa infections is limited. Furthermore, the
extent to which ceftolozane-tazobactam resistance may
emerge in MDR-P.aeruginosa isolates during treatment is
unknown. Our objectives in this study were to describe our
experience in treating MDR-P.aeruginosa infections with
ceftolozane-tazobactam, assess emergence of resistance,
and identify possible resistance mechanisms.
MAJOR ARTICLE
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/cix182
Received 28 December 2016; editorial decision 7 February 2017; accepted 24 February 2017;
published online February 25, 2017.
a
C.J.C. and M.H.N. contributed equally.
Correspondence: C.J. Clancy, University of Pittsburgh, 3550 Terrace Street, S867 Scaife Hall,
Pittsburgh, PA 15261 (cjc76@pitt.edu).
Clinical Infectious Diseases
®
2017;65(1):110–20
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• CID 2017:65 (1 July) • 111
Ceftolozane-Tazobactam vs Pseudomonas
METHODS
Study Design and Definitions
We conducted a retrospective study of patients with MDR-
P.aeruginosa infections treated with ceftolozane-tazobactam
at the University of Pittsburgh Medical Center from June
2015 to March 2016. MDR was defined by nonsusceptibil-
ity to ≥1 agent in ≥3 classes that are typically active against
P.aeruginosa [26]. Types of infection were classified accord-
ing to National Healthcare Safety Network criteria [27]. FDA-
approved dosing was defined as compliance with the FDA label
dosage for ≥5days during the first week of therapy, regard-
less of the site of infection (1.5g intravenously [IV] every 8
hours with adjustments for renal dysfunction and intermittent
hemodialysis [iHD]) [28]. Recent pharmacokinetic (PK) data
suggest that 3g IV every 8 hours may improve target attain-
ment within pulmonary epithelial lining fluid (ELF) [29]. This
dosage is being used in a phase 3 trial of ventilator-associated
pneumonia (VAP) but it is not currently FDA approved for
any indication [30]. PK-derived dosing was defined as com-
pliance with the higher dosing regimen for respiratory tract
infections (with renal adjustment) for ≥5days during the first
week of therapy. By these definitions, a patient with a creati-
nine clearance >50mL/min treated for pneumonia with a dose
of 1.5g every 8 hours would be labelled as receiving FDA-
approved dosing, whereas a patient treated with 3g every 8
hours would be labelled as receiving PK-derived dosing. Since
the phase 3 VAP trial excludes patients receiving any form of
renal replacement therapy, we considered dosing for patients
who had pneumonia but were on renal replacement therapy as
“not defined” [30].
Primary outcome was 30-day all-cause mortality.
Secondary outcomes were 90-day all-cause mortality,
30- and 90-day attributable mortality, 90-day clinical fail-
ure, recurrent colonization, and emergence of resistance.
Mortality was attributed to P. aeruginosa if the patient died
with signs and symptoms of infection, microbiologic or his-
tological evidence of an active P. aeruginosa infection, and
if other potential causes of death were reasonably excluded.
Although attributable mortality is often difficult to ascertain
and definitions are controversial, we included it in the out-
come analysis in order to compare our data with attributable
mortality rates reported in previous studies of pseudomonal
infection. Clinical failure was defined as attributable mor-
tality due to P. aeruginosa, persistent signs or symptoms
of infection or positive culture despite ≥7 days of ceftolo-
zane-tazobactam, or recurrent P. aeruginosa infection
(recurrent signs and symptoms and recurrent culture posi-
tivity within 90 days). Combination therapy was defined as
receipt of ceftolozane-tazobactam plus ≥1 anti-pseudomonal
drug for ≥72 hours. Acute kidney injury (AKI) was defined
as ≥1.5-fold increase in serum creatinine from baseline.
Ceftolozane-tazobactam resistance was defined as minimum
inhibitory concentration (MIC) ≥16 µg/mL (E-test), in
accordance with Clinical Laboratory and Standards Institute
recommendations [31]. MICs for other agents were deter-
mined by MicroScan or disc diffusion.
Whole Genome Sequencing and Analysis
Full details of whole genome sequencing (WGS) and
analysis are provided in the Supplementary Methods [32].
Susceptible isolates from 5 patients prior to ceftolozane-
tazobactam therapy were selected as ancestral strains for
phylogenetic analyses. A P. aeruginosa genome most closely
related to the consensus of the isolates (PA_BWHPSA022, as
revealed by Mash [33]) was used to determine phylogenetic
relationships among isolates. Longitudinal isolates with
preexisting (rather than emergent) ceftolozane-tazobactam
resistance from a sixth patient were sequenced as controls
(this patient is referred to as patient 22). The genome of
the founding isolate for each patient was the reference for
identifying putative evolved mutations (single nucleotide
polymorphisms [SNPs], insertions–deletions [indels], and
structural variants) in subsequent isolates by breseq [34].
Raw predicted mutations and filtered lists of mutations
are reported in Supplementary Tables 1 and 2. The filtered
list, per patient, was curated to highlight genes that were
categorically linked to β-lactam resistance in previous
studies, including β-lactamases, efflux pumps, porins, and
cell wall synthesis machinery [35–37].
Quantitative Reverse Transcription-Polymerase Chain Reaction
DNase-treated RNA was obtained from late-exponential
phase cultures in Luria broth at 37°C (RiboPure-Bacteria kit,
ThermoFisher Scientific, Waltham, Massachusetts). cDNA
was made using qScript cDNAMix (Quanta Biosciences,
Gaithersburg, Maryland). Quantitative reverse transcrip-
tion-polymerase chain reaction (qRT–PCR) of P. aeruginosa
genes encoding common β-lactam resistance mechanisms,
such as ampC, efflux genes mexB, mexD, mexY, and porin
gene oprD, was performed using the Applied Biosystems
7900 system, with established primers (Supplementary Table
2 [38–40]), and the SYBR Green kit (Quanta Biosciences,
Maryland). Gene expression was normalized using rspL.
Relative expression was calibrated against corresponding
baseline ceftolozane-tazobactam susceptible isolates. qRT-
PCR for all isolates was performed in at least triplicate on 3
separate days.
Statistical Analyses
Statistical analysis was performed using Stata 13.0 (College
Station, Texas) and GraphPad Instat 3 (San Diego, California).
Univariate analysis of contingency data was performed by
2-tailed χ
2
or 2-tailed Fisher exact tests. P<.05 was considered
significant.
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112 • CID 2017:65 (1 July) •
Haidar etal
RESULTS
Patient Characteristics, Microbiology, and Treatment Regimens
Twenty-one patients were included (Table 1). Nine patients
(43%) were transplant recipients (7 lung, 1 lung–kidney, 1 stem
cell). Twenty patients (95%) received an anti-pseudomonal anti-
biotic within 14days prior to the index culture. Types of infec-
tion and susceptibility profiles are shown in Table1. Eighteen
patients (86%) were treated for respiratory tract infections;
the remaining 3 patients were treated for bacteremia, cIAI, or
cUTI. Initial isolates were MDR but susceptible to ceftolozane-
tazobactam (median MIC, 1.5µg/mL, range, 0.75–4µg/mL). Fif teen
(71%) of the initial isolates were resistant to all anti-pseudomonal
β-lactams tested except ceftolozane-tazobactam. Six patients
(29%) had coinfections with other pathogens (Table2).
Median duration of therapy was 14 days (range, 3–52 days).
Of 18 patients with respiratory tract infections, 5 (28%) received
PK-derived dosages and 9 (50%) received FDA-approved dos-
ages. Patients with nonrespiratory tract infections were treated
with FDA-approved dosages. Four (22%) of 18 patients with
respiratory tract infections were receiving renal replacement
therapy, and a patient with primary bacteremia was receiving
iHD (Table 2); these are settings in which dosing is not dened.
Sixteen (76%) patients received combination anti-pseudomonal
therapy for ≥72 hours, including 2, 9, and 5 who received con-
comitant systemic, inhaled, and both systemic and inhaled
agents, respectively (Table 2).
Outcomes
The 30-day mortality rate was 10% (2/21) and the attributable
mortality rate was 5% (1/21) (Table2). Corresponding 90-day
rates were 48% (10/21) and 19% (4/21). Attributable 90-day
mortality was due to persistent or recurrent MDR-P.aeruginosa
pneumonia (patients 1, 6, 10, 11). In patient 11, ceftolozane-
tazobactam was discontinued after 3days due to arash.
e clinical failure rate of ceolozane-tazobactam treat-
ment was 29% (6/21). Clinical failures included the 4 patients
with attributable deaths at 90days, and 2 patients with MDR-
P. aeruginosa pneumonia who survived to 90days but devel-
oped recurrent pneumonia or suppurative tracheobronchitis
(patients 4 and 8). Four patients who were successfully treated
for pneumonia (patients 14 and 15), cIAI (patient 7), and cUTI
(patient 18) were colonized by MDR-P. aeruginosa within
90days of the index infection.
Ceolozane-tazobactam resistance was identied in 3
patients (14%), emerging during recurrent pneumonia that
led to death at 90days (patient 1), airway colonization follow-
ing intraabdominal infection (patient 7), and suppurative tra-
cheobronchitis following pneumonia (patient 8). Resistance
emerged 2 weeks aer completion of a 30-day treatment course
and on days 8 and 19 of treatment, respectively.
e only variable that was signicantly associated with clinical
failure was simplied acute physiology score-II (SAPS-II) score
(median, 35 for failure and 23 for success; P=.04); there was
a trend toward an association between clinical failure and age
(median, 72.5 vs 58years; P=.07). Site of infection, renal failure,
combination vs monotherapy, use of inhaled therapy, time to
initiation of ceolozane-tazobactam, presence of coinfections,
and FDA-approved or PK-derived dosing were not signicantly
associated with clinical failure or 90-day mortality. None of
these factors were associated with emergence of ceolozane-
tazobactam resistance. rombocytopenia occurred in 2 patients
Table1. Demographics, clinical descriptions, and resistance patterns
Factor Percent (n) Age or Score
Age, median (range) 58 y (23–91)
Male sex % (n) 48 (10)
Underlying diseases
Immunosuppressed 43 (9)
Organ transplant 38 (8)
Stem cell transplant 5 (1)
Ventilator-dependent respiratory failure 38 (8)
Surgery within 30days prior to index
culture
33 (7)
Cystic fibrosis 29 (6)
a
Renal failure requiring renal replacement
therapy at the time of initiation of
ceftolozane-tazobactam
24 (5)
Cardiovascular disease 10 (2)
Malignancy 10 (2)
Chronic obstructive pulmonary disease 10 (2)
Severity of illness scores
Simplified acute physiology score-II
score, median (range)
26 (8–49)
Sequential organ failure assessment
score, median (range)
6 (0–17)
Charlson comorbidity index, median
(range)
5 (1–12)
Type of infection
Respiratory tract 86 (18)
Pneumonia
b
76 (16)
Purulent tracheobronchitis 10 (2)
Recurrent bacteremia 5 (1)
Complicated intraabdominal infection 5 (1)
Complicated urinary tract infection 5 (1)
Coinfection with other pathogens
c
29 (6)
Antibiotic resistance
≥1 anti-pseudomonal fluoroquinolone
d
95 (20)
Aztreonam 95 (20)
Cefepime 90 (19)
≥1 anti-pseudomonal carbapenem
e
90 (19)
Piperacillin-tazobactam 81 (17)
Ceftazidime 76 (16)
≥1 aminoglycoside 67 (14)
Colistin 20 (2/10)
f
a
Four of 6 cystic fibrosis patients were lung transplant recipients
b
Two had empyema, which was surgically drained.
c
Details in Table2.
d
Ciprofloxacin and/or levofloxacin.
e
Meropenem, imipenem, and/or doripenem.
f
Colistin susceptibility testing is performed upon clinician request (10 isolates).
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• CID 2017:65 (1 July) • 113
Ceftolozane-Tazobactam vs Pseudomonas
Table2. Clinical Characteristics, Antibiotic Regimens, and Outcome of Patients Treated With Ceftolozane-tazobactam for Multidrug Resistant-Pseudomonas aeruginosa Infections
Patient
Age in
Years
(Sex)
Underlying
Diseases Type of Infection
SAPS
II,
SOFA
Scores
Dosing (g every 8 hours)
Duration
of Therapy
With
Ceftolozane-
Tazobactam
(days)
Anti-Pseudomonal
Agents Given With
Ceftolozane-
Tazobactam for ≥72
Hours
c
Coinfection With Other
Pathogens (treatment)
Outcome
Ceftolozane-Tazobactam
Minimum Inhibitory
Concentration (µg/mL)
CrCl
(mL/
min)
FDA-
Label
dose
Actual
Dose
FDA or
PK-Derived
Dosing
Outcome at
30 and 90
Days
Clinical
Outcome
(success
or failure)
Recurrent
Infections or
Colonization
at 90 Days
Initial
Isolate
Subsequent
Isolate(s)
1 58 (M) COPD, VDRF Pneumonia,
empyema
35, 11 iHD Not
defined
0.15 Not
defined
a
29 Inhaled tobramycin None Died within
90days
(attribut-
able)
Failure Recurrent
infections
due to
resistant
isolates
4 32 (14days after
therapy)
2 23 (F) Cystic fibrosis,
lung trans-
plant, VDRF
Pneumonia 23, 6 >50 1. 5 1. 5 FDA dosing 14 Inhaled tobramycin MRSA pneumonia
(linezolid)
Alive Success 2
3 84 (F) Dementia Pneumonia 25, 7 >50 1. 5 1. 5 FDA dosing 17 Inhaled colistin MRSA pneumonia
(linezolid)
Alive Success 4
4 70 (M) Lung
transplant
Pneumonia,
empyema
35, 8 CRRT Not
defined
1. 5 Not
defined
a
14 Ciprofloxacin,
inhaled colis-
tin, inhaled
tobramycin
None Alive Failure Recurrent
infection
2 2 (6days after
therapy)
5 48 (F) Cystic fibrosis,
lung trans-
plant, VDRF
Pneumonia 19, 3 >50 1. 5 3 PK-dosing 41 Ciprofloxacin,
inhaled colistin
None Alive Success 2
6 75 (M) Dementia,
VDRF
Purulent tracheo-
bronchitis
27, 4 >50 1. 5 1. 5 FDA dosing 31 Inhaled tobramycin None Died within
90days
(attribut-
able)
Failure Recurrent
infection
Isolate
N/A
Isolate N/A
7 58 (F) Pancreatitis,
VDRF
Complicated
intraabdomi-
nal infection
26, 8 15–29 0.75 0.75 FDA dosing 40 Inhaled colistin None Alive Success Colonization
with
resistant
isolates
4 128 (day 8 of
therapy); >256,
128, 256 (3, 20,
and 41days
after therapy,
respectively)
8 55 (F) Cystic
fibrosis
Pneumonia 19, 3 >50 1. 5 3 PK-dosing 42 Ciprofloxacin,
tobramycin
None Alive Failure Recurrent
infections
due to
resistant
isolates
2 32 (day 17 of ther-
apy), 64 (19days
after therapy)
9 25 (F) Cystic fibro-
sis, lung
and kidney
transplant
Pneumonia 26, 4 30–50 0.75 1.5 PK-dosing 52 Inhaled ceftazidime,
inhaled colistin,
ciprofloxacin,
meropenem
None Died within
90days
(not
attributable)
Success 2
10 89 (F) Dementia,
VDRF
Pneumonia 40, 10 30–50 0.75 0.75 FDA dosing 14 Inhaled tobramycin MRSA pneumonia
(vancomycin)
Died within
90days
(attribut-
able)
Failure Recurrent
infection
2 2 (24days after
therapy)
11 84 (F) Mesenteric
ischemia
Pneumonia 43, 15 15–29 0.375 0.375 FDA dosing 3 Inhaled tobramycin None Died within
30days
(attributable)
Failure 1
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114 • CID 2017:65 (1 July) •
Haidar etal
Patient
Age in
Years
(Sex)
Underlying
Diseases Type of Infection
SAPS
II,
SOFA
Scores
Dosing (g every 8 hours)
Duration
of Therapy
With
Ceftolozane-
Tazobactam
(days)
Anti-Pseudomonal
Agents Given With
Ceftolozane-
Tazobactam for ≥72
Hours
c
Coinfection With Other
Pathogens (treatment)
Outcome
Ceftolozane-Tazobactam
Minimum Inhibitory
Concentration (µg/mL)
CrCl
(mL/
min)
FDA-
Label
dose
Actual
Dose
FDA or
PK-Derived
Dosing
Outcome at
30 and 90
Days
Clinical
Outcome
(success
or failure)
Recurrent
Infections or
Colonization
at 90 Days
Initial
Isolate
Subsequent
Isolate(s)
12 91 (F) Dementia,
VDRF
Pneumonia 42, 8 30–50 0.75 0.75 FDA dosing 10 None Serratia marcescens
pneumonia (did not
require additional
antibiotics)
Died within
90days
(not
attributable)
Success 1
13 59 (F) Stem cell
transplant
Pneumonia 20, 4 >50 1. 5 3 PK-dosing 13 Gentamicin VRE bacteremia
(linezolid)
Died within
90days
(not
attributable)
Success 2
14 41 (F) Lung
transplant
Pneumonia 14, 1 >50 1. 5 3 PK-dosing 14 None None Alive Success Colonization 0.5, 1 0.5 (20days after
therapy)
15 58 (M) Lung
transplant
Pneumonia 34, 8 iHD Not
defined
0.15 Not
defined
a
15 Inhaled tobramycin None Alive Success Colonization 2, 4 2, 4 (28days after
therapy)
16 58 (M) Lung
transplant
Recurrent
bacteremia
18, 5 iHD Not
defined
0.375 Not
defined
b
48 Ciprofloxacin,
inhaled
tobramycin
None Died within
90days (not
attributable)
Success 1
17 23 (M) Cystic fibrosis Pneumonia 8, 0 >50 1. 5 1. 5 FDA dosing 10 Imipenem, inhaled
colistin, tobramycin
None Alive Success Isolate
N/A
18 67 (M) Diabetes
mellitus,
resection
of bladder
carcinoma
Complicated
urinary tract
infection
14, 4 >50 1. 5 1. 5 FDA dosing 10 None None Alive Success Colonization 1 0.5, 1 (41days after
therapy)
19 39 (M) Biliary sur-
gery with
abscesses,
VDRF
Pneumonia 29, 17 CRRT Not
defined
1. 5 Not
defined
a
13 None VRE bacteremia (dap-
tomycin); Citrobacter
fruendii abdominal
wound infection
(ceftolozane-tazo-
bactam); Candida
tropicalis fungemia
(caspofungin)
Died within
30days
(not
attributable)
Success 2
20 65 (M) Recent car-
diac arrest
Pneumonia 49, 15 30–50 0.75 0.75 FDA
dosing
13 Inhaled tobramycin None Died within
90days
(not
attributable)
Success 0.75
21 34 (M) Cystic fibro-
sis, lung
transplant
Purulent
tracheobron-
chitis
18, 2 >50 1. 5 1. 5 FDA
dosing
4 None None Alive Success NA
Creatinine clearance was calculated using the Cockroft-Gault formula; dosing encompasses the dose used for ≥5days during the first week of therapy.
Abbreviations: COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; CRRT, continuous renal replacement therapy; F, female; FDA, US Food and Drug Administration; iHD, intermittent hemodialysis; M, male; MRSA, methicillin-resistant
Staphylococcus aureus; N/A, not available; PK, pharmacokinetic; SAPS-II, simplified acute physiology score; SOFA, sequential organ failure assessment; VDRF, ventilator-dependent respiratory failure; VRE, vancomycin-resistant Enterococcus faecium.
a
These patients were on either intermittent hemodialysis or continuous renal replacement therapy, situations in which there are no PK-derived data for respiratory infections.
b
This patient had primary bacteremia and was receiving intermittent hemodialysis; dosing for this situation is not established.
c
Number of isolates susceptible to the antibiotics used in combination with ceftolozane-tazobactam were as follows: ciprofloxacin (2/5 susceptible), tobramycin (2/2 susceptible), gentamicin (1/1 susceptible), meropenem (1/1 susceptible), imipenem (1/1
resistant), inhaled tobramycin (9/9 susceptible), inhaled colistin (6/6 susceptible), inhaled ceftazidime (1/1 susceptible).
Table 2. Continued
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