spiral.imperial.ac.uk · web viewa systematic search and review of the pubmed database was...

ANTIMICROBIAL SUSCEPTIBILITY TEST RESULTS AND ASSOCIATED CLINICAL

OUTCOMES IN INDIVIDUALS WITH CYSTIC FIBROSIS: A SYSTEMATIC REVIEW

Ranjani Somayaji1, Michael D. Parkins2, Anand Shah3,8 , Stacey L. Martiniano4, Michael M.

Tunney5, Jennifer Kahle6, Valerie J. Waters7, J. Stuart Elborn8, Scott C. Bell9, Patrick A. Flume10,

Donald R. VanDevanter11, on behalf of the Antimicrobial Resistance in Cystic Fibrosis

International Working Group

1- University of Washington, Seattle, WA, USA

2- University of Calgary, Calgary, AB, Canada

[3-] Imperial College and Royal Brompton and Harefield NHS Foundation Trust Hospital,

London, United Kingdom

3-[4-] University of Colorado School of Medicine, Aurora, CO, USA

4-[5-] Queens’ University, Belfast, United Kingdom

5-[6-] University of San Diego, San Diego, CA, USA.

6-[7-] Hospital for Sick Children, Toronto, ON, Canada

[8-] Imperial College, London, United Kingdom

7-[9-] The Prince Charles Hospital and QIMR Berghofer Medical Research Institute, Brisbane

QLD, Australia

8-[10-] Medical University of South Carolina, Charleston, SC, USA

9-[11-] Case Western Reserve University School of Medicine, Cleveland OH, USA

Correspondence to D.R. VanDevanter, [email protected] 33rd Street Ct EEdgewood WA 98372 USA+01-253-370-5859

TEXT (4551 words)ABSTRACT (289 words)

mailto:[email protected]

ABSTRACT

BACKGROUND. Antimicrobial susceptibility testing (AST) is a cornerstone of infectionm

management. AST has been recommended in Ccystic fibrosis (CF) treatment guidelines for

recommend the use of AST to selection of antimicrobial treatments forof CF airway infection but

its utility in this setting has never been objectively demonstrated.

METHODS. We conducted a systematic review of primary published articles designed to address

two PICO (patient, intervention, comparator, outcome) questions: 1) “For individuals with CF, is

clinical response to antimicrobial treatment of bacterial airways infection predictable from AST

results available at treatment initiation?” and 2) “For individuals with CF, is clinical response to

antimicrobial treatment of bacterial airways infection affected by the method used to guide

antimicrobial selection?” Relationships between AST results and clinical responses (changes in

pulmonary function, weight, signs and symptoms of respiratory tract infection, and time to next

event) were assessed for each article and results were compared across articles when possible.

RESULTS. Twenty-five articles describing the results of 20 separate studies were identified by a

predefined systematic review process. Of these 20 studies, 13 described antimicrobial treatment of

CF pulmonary exacerbations (PEx) and 7 described antimicrobial ‘maintenance’ of chronic

bacterial airways infections. Sixteen studies addressed PICO question #1 (11 with respect to PEx

treatment and five with respect to chronic airways infection treatment); the remaining four

addressed PICO question #2.

In only 3 of 16 studies addressing PICO question #1 was there a suggestion that baseline

bacterial isolate antimicrobial susceptibility was associated with clinical response to treatment;

there were no instances where different antimicrobial selection methods yielded different clinical

outcomes (addressing PICO question #2).

CONCLUSIONS. There is little evidence that AST reliably predicts the clinical outcomes of CF

antimicrobial treatment, suggesting a need for careful consideration of current use of AST by the

CF community.

INTRODUCTION

An important component of the management of bacterial infection is the use of in vitro

antimicrobial susceptibility testing (AST) to guide the selection of antimicrobial therapies.

Although AST is labour-, resource-, and time-intensive, it can be cost-effective when predictive

of clinical response to antimicrobial treatment. AST for bacterial infection is most predictive of

clinical response among “immunocompetent patients with monomicrobic bacterial infections who

are treated with a single antimicrobial agent which is administered parenterally in circumstances

in which the penetration of drug to the site of infection is predictable.”[1] In these situations,

infections associated with bacterial isolates identified as “susceptible” by AST have been reported

to respond to antimicrobial treatment ~90% of the time versus an ~60% response rate for

infections with “resistant” bacterial isolates.[2]

Antimicrobial treatment for bacterial infection is a cornerstone of cystic fibrosis (CF)

management, whether it be antibacterial prophylaxis,[3] ‘eradication’ (conversion to culture

negativity) of early Pseudomonas aeruginosa (Pa) respiratory tract infections,[4] treatment of

acute pulmonary exacerbations (PEx),[5] or ‘maintenance treatment’ of chronic bacterial

respiratory tract infections.[6] CF treatment guidelines support the use of AST to guide

antimicrobial treatment of respiratory tract infections,[7,8] although it has been suggested that

AST results may not be predictive of clinical response in patients with CF.[9]

If AST is not predictive of antimicrobialbacterial treatment response in CF, it may be in the

CF community’s interest to consider more selective use of this resource-intensive test. As part of

the aims of the Antimicrobial Resistance in Cystic Fibrosis International Working Group, we

have conducted a systematic review of the published primary literature to address the following

PICO (patient, intervention, comparator, outcome) research questions:

#1. For individuals with CF, is clinical response to antimicrobial treatment of bacterial

airways infection predictable from AST results available at treatment?

#2. For individuals with CF, is clinical response to antimicrobial treatment of bacterial

airways infection affected by the method used to guide antimicrobial selection?

METHODS

A systematic search and review of the PubMed database was performed according to

Cochrane guidelines.[10] Peer-reviewed, primary research articles published in English

describing clinical outcomes after antimicrobial treatment of individuals with CF were identified

using the search strategy: (cystic fibrosis terms) AND (susceptibility, resistance, sensitivity terms)

AND (antimicrobial, antibiotic, anti-bacterial terms). The actual search string is provided in an

on-line supplement. In a primary screen, a single researcher (JK) excluded articles from search

results that were non-English language, did not report CF treatment outcomes, lacked an abstract,

or were reviews, meta-analyses, or case studies. In a secondary screen, article abstracts with or

without entire manuscripts were reviewed by four researchers independently (teams of 4 drawn

from DV, RS, MP, MT, AS, SM, JK). Unanimous agreement by all four researchers in each team

was required for article inclusion. Uncertainties and discrepancies were reconciled in a tertiary

screen based on reading of the full text of the articles and open discussion among the four

researchers.

Included articles were those reporting results of studies in which 1) antimicrobial

treatments were administered and clinical outcomes were compared among groups based on AST

results available at treatment initiation for bacterial isolates and/or 2) differing methodologies

were used to guide antimicrobial selection for treatment of study groups and clinical outcomes

were compared between treated groups. Where applicable, data from multiple articles describing

outcomes from the same study were merged for analysis.

Analyses of results were divided by antimicrobial treatment modalities: a) treatment of

first/early airways infection, b) treatment of CF PEx and c) maintenance treatment of chronic

airways infection in ‘stable’ individuals with CF. Differences in clinical outcomes among

subject groups identified by either AST test results (PICO question #1) or methods used to guide

antimicrobial treatments (PICO question #2) were assessed using the authors’ statistical tests

(when available) and their associated conclusions.

Outcome analyses were limited to reported differences in clinical responses to

antimicrobial treatments such as spirometry, signs and symptoms of respiratory tract infection,

days in hospital, and/or survival and did not include microbiological responses to treatment such

as culture negativity or changes in sputum bacterial density. Response data were descriptively

summarized and compared across studies where possible.

Study quality was assessed using the GRADE criteria with eight domains: (a) risk of bias,

(b) directness of results, (c) precision of results (d) consistency of results, (e) risk of publication

bias, (f) magnitude of effect, (g) presence of residual plausible confounding and (h) dose-response

gradient.[11,12] GRADE criteria were assessed separately for each PICO question by outcome

and study design (prospective vs observational) and were assessed by two reviewers (RS and DV)

with discrepancies resolved through consensus.

RESULTS

Search Results

An initial PubMed search yielded 1214 citations, of which 441 were excluded by primary

screen. Of 773 remaining articles, 25 articles [13-37] comprising the results of 20 separate

studies were selected by group consensus for inclusion (Figure 1). Of these, 21 articles

addressed PICO question #1 and four addressed PICO question #2. In three instances, two

articles described different aspects of the same study and in one instance three articles

described results from a single study (Tables 1 and 2). No studies were found that

examined relationships between AST and treatment of first bacterial infection. Thirteen

studies examined antimicrobial treatment of PEx (Table 1) and 7 studies examined

maintenance antimicrobial treatment of chronic airway infection (Table 2).

Methods for determination of clinical benefits of antimicrobial treatment varied

across studies. Several studies identified a categorical variable of response to treatment,

including some variant of treatment-associated change in percent predicted forced

expiratory volume in 1 second (ppFEV1), either as absolute or relative change from

treatment initiation or as a follow-up value relative to a pre-treatment value. Similarly,

microbiologic reporting varied widely across studies, ranging from simple reporting of

antimicrobial susceptibilities of single patient isolates (R=resistant, S=susceptible) to

reporting of minimum inhibitory concentrations (MICs) for multiple isolates per patient.

Included studies were found to be of low to moderate quality for addressing PICO

questions #1 and #2 when assessed by GRADE criteria, with downgrading primarily a

result of either indirectness of the study design to address the question or imprecision in

assessing outcomes. Because most randomized trials were double-blinded with adequate

accounting for subjects and observational studies included specific eligibility criteria with

no serious identified flaws in measurement, there was no downgrading due to risk of bias

(tabular details of GRADE assessments are provided in an on-line supplement).

Treatment of PEx

Fourteen articles described 13 studies of antimicrobial treatment of PEx, seven of

which were prospective and six of which were retrospective; 11 of 13 studies addressed

PICO question #1 and two addressed PICO question #2 (Figure 1; Table 1).

PICO Question #1: Is clinical response to antimicrobial treatment of bacterial airways

infection predictable from AST results available at treatment?

Three prospective studies of IV antimicrobial treatment of PEx lacked systematic

reporting of clinical responses stratified by subject isolate antimicrobial susceptibilities.

[13-16] However, all three noted as detailed below that clinical responses were not related

to antimicrobial susceptibility: “Patients with sputum bacteria that were resistant to one or

both of the antibiotics they were receiving fared no worse in terms of pulmonary function

than patients with antibiotic-susceptible sputum bacteria”;[14] “There was no significant

correlation between severity of CF, antibiotic susceptibility of the initial Pseudomonas

isolates, or measured netilmicin concentrations and any of these improvements”;[15] and

“The presence of antibiotic-resistance… was not inversely related to response” and

“Patients with antibiotic-resistant P. aeruginosa or P. cepacia… responded as well to

treatment as those with only susceptible isolates.”[16] A prospective study of IV once-

daily high-dose tobramycin and thrice daily IV tobramycin/ceftazidime assessed 98

treatments among 44 enrolled subjects.[18] Although study investigators did not explicitly

comment on a possible discordance between Pa tobramycin susceptibilities and treatment

responses, 83 of 98 treatments (84.7%) resulted in pulmonary function improvements

despite 43 of 52 Pa isolates (82.7%) being tobramycin-resistant (MIC ≥8 mcg/mL) at

study entry.[18]

A prospective 69-subject crossover study of continuous versus intermittent IV

ceftazidime infusion (coupled with thrice-daily IV tobramycin) identified ceftazidime

susceptibility-based differences in ppFEV1 responses between ceftazidime infusion

methods.[22] Subjects with ceftazidime-susceptible Pa isolates receiving continuous

infusion ceftazidime (N=26) experienced a mean 7.9 ppFEV1 improvement (SD=9.7)

while those with ceftazidime-resistant isolates (N=18) had a mean 6.2 (6.6) ppFEV1

improvement. In contrast, when subjects who had ceftazidime-susceptible isolates (N=28)

received ceftazidime by intermittent infusion, they had a mean 8.1% (8.4) ppFEV1

improvement versus only a mean 1.7 (5.6) improvement among those subjects with

ceftazidime-resistant isolates (N=15; Figure 2, left panel).[22] The difference in mean

ppFEV1 responses to treatment among subjects with ceftazidime-resistant isolates (6.2%

predicted for continuous infusion versus 1.7% predicted for intermittent infusion) was

statistically significant (P<0.05).

Six retrospective studies analyzed relationships between Pa isolate antimicrobial

susceptibilities and clinical response to PEx treatments. In an analysis of 31 combination

IV antimicrobial PEx treatments among 17 patients that included AST of 177 Pa isolates,

there was no apparent correlation between isolate susceptibilities and categorical treatment

response (as any FEV1 improvement from admission).[17] Mean FEV1 changes by

susceptibility patterns, however, suggest a more nuanced result: 12 events in which all Pa

isolates were susceptible had a mean 8.3 ppFEV1 change (SD=7.7) compared with a mean

3.3 (4.6) ppFEV1 change for 3 events where patients had isolates resistant to both

antimicrobials used (Figure 2, middle panel). Among 28 events in which at least one Pa

isolate was susceptible, mean ppFEV1 change was 6.3 (6.8). A sub-analysis of 24 PEx

events treated with IV tobramycin/ceftazidime showed that mean FEV1 responses were

numerically smaller among patients with isolates resistant to either antimicrobial than

when susceptible to both, although this difference did not reach statistical significance

(Figure 2, middle panel).[17]

In a retrospective analysis of 77 PEx occurring among subjects receiving inhaled

placebo during inhaled tobramycin studies, no correlations were observed between Pa

ceftazidime or tobramycin susceptibilities and the proportion of patients observed to have

a ≥5 ppFEV1 response to IV tobramycin/ceftazidime treatment.[19] An exhaustive

analysis of the antimicrobial susceptibility patterns (including use of several synergy test

methods) of 128 Pa isolates from 9 patients receiving combination IV antimicrobial

treatment for PEx concluded that “synergy testing methods appeared to be poor at

predicting the clinical… response” of treated patients.[21] An analysis of treatment-

associated responses as a function of Pa isolate susceptibilities to IV antimicrobial

treatments of 103 PEx in 52 patients reported “no association between change in FEV1

(P=0.54), change in BMI (P=0.12) or time to next exacerbation (P=0.66) and concordance

between antibiotic susceptibility and the antibiotics administered” (Figure 2, right panel).

[23]

An analysis of PEx treatment failures (a composite outcome defined as recorded

antibiotic regimen change, prolongation of therapy beyond 20 days, a recurrent event

within <45 days, or failure to recover lung function to >90% of baseline FEV1) associated

with 452 PEx among treatments 101 patients reported a significant (P=0.018) inverse

association between treatment failure rates and the number of antimicrobials used in PEx

treatments to which patient isolates were susceptible.[24] Among 65 events in which Pa

isolates were susceptible to none of the up to three IV antimicrobials used, 28 (43%) were

treatment failures, while 38 failures were observed among 140 events (27%) where

isolates were susceptible to one of the IV antimicrobials used and 59 failures were

observed among 245 events (24%) where isolates were susceptible to two IV

antimicrobials used. Among 3 events where isolates were susceptible to three IV

antimicrobials used, there were no treatment failures.[24] Multivariate logistic regression

modeling of event-specific risk factors for PEx failure rates, however, found that PEx

“severity” at initial presentation (measured by the relative FEV1 decline observed at

treatment initiation: odds ratio 1.02 [95% CI 1.10-1.04], P=0.05) and systemic

inflammatory levels (measured by C-reactive protein [CRP] concentration at admission:

1.01 [1.00-1.02], P=0.01; white blood cell count at discharge: 1.20 [1.08-1.35], P=0.001;

CRP concentration at discharge: 1.02 [1.00-1.04], P=0.09) were “the most important

factors influencing PEx outcomes.”[24] The presence of multi-drug resistant or pan-

resistant Pa isolates were not identified as significant factors for failure of antimicrobial

treatment of PEx once these other factors were accounted for. A similar retrospective

analysis of PEx treatment failures (defined as failure to recover at least 90% of baseline

FEV1) among 144 PEx treatments in 46 patients also reported that the number of

antibiotics used with ‘predicted activity’ (i.e., the number of antibiotics used for which Pa

isolates were susceptible by AST) did not affect PEx outcomes.[25]


infection affected by the method used to guide antimicrobial selection?

Two prospective randomized, blinded, multicenter studies analyzed the effects of

different antimicrobial selection methods for PEx treatment with clinical outcomes.[20]

[26] Aaron and colleagues conducted a Canadian/Australian (multi-site) study of 251

subjects comparing mean lung function responses and median times to next PEx among

subjects treated with antimicrobials selected by their treating physicians with those of

subjects whose antimicrobials were selected centrally based on multiple combination

bactericidal antibiotic testing (MCBT) results.[20] Unlike traditional AST that measures

growth inhibition as a function of drug concentration, MCBT tests 2-4 agents

simultaneously at pharmacologically relevant, but fixed concentrations, to identify

antibiotic combinations that kill a given bacterial isolate. In the Aaron study, time to next

PEx requiring new oral or IV antibiotics, changes in FEV1, forced vital capacity (FVC),

and dyspnea scores did not differ between subjects treated with antimicrobials chosen by

their physicians (who presumably had access to traditional AST results from previous

bacterial cultures) versus those treated with antimicrobials chosen based on MCBT

conducted by a central laboratory. A retrospective analysis of mean FEV1 changes,

however, found that 81 subjects who were treated with regimens that were subsequently

shown to be bactericidal (regardless of which study arm they had been on) had

significantly greater mean FEV1 changes than 48 subjects who were treated with

combinations that were not shown to be bactericidal (0.32 liters vs 0.18 liters, P=0.046).

[20] Yau et al. conducted a study of differences in PEx treatment outcomes when

antipseudomonal antimicrobials were selected based on results of conventional

(planktonic) or biofilm growth in vitro susceptibility tests. Evaluating the responses of 74

PEx treatments occurring among 39 subjects, the investigators reported that lung function

improvements were similar in the two treatment groups, and biofilm testing “did not lead

to improved microbiological or clinical outcomes.”[26]

Maintenance Treatment of Chronic Bacterial Infection.

Eleven articles described seven studies of antimicrobial treatments in stable patients with

chronic respiratory tract infections; five studies addressed PICO question #1 and two

addressed PICO question #2 (Figure 1; Table 2).


infection predictable from AST results available at treatment?

An analysis of data pooled from two 24-week blinded, placebo-controlled studies of

inhaled tobramycin [27] showed a trend towards greater mean relative FEV1 improvement

at week 20 for 171 tobramycin-treated subjects who had tobramycin-susceptible Pa isolates

(+11% [95% CI –35%, +57%]) compared with 58 subjects with tobramycin-resistant

isolates (+8% [–34%, +50%]).[26] Among tobramycin-treated subjects who rolled over

into a subsequent 18-month open label, single-arm inhaled tobramycin follow-on study,

mean ppFEV1 change or the proportions of subjects showing net ppFEV1 after 92 weeks

was not predicted by Pa isolate tobramycin MIC category (<16 mcg/ml, 16-64 mcg/mL,

>64 mcg/mL).[31,32] Similar lack of correlation between susceptibility and response was

observed in two prospective 28-day randomized studies of inhaled antibiotics, an open-label

study comparing inhaled tobramycin and inhaled colistimethate among 115 subjects [29,30]

and a blinded, placebo-controlled study of inhaled levofloxacin among 151 subjects,[36]

where baseline Pa isolate susceptibilities did not predict FEV1 change from baseline at day

28 of treatment.

In contrast, a prospective, randomized, open-label 8-week comparison of two

inhaled tobramycin formulations suggested that Pa isolates of differing tobramycin

susceptibilities were associated with significantly different FEV1 responses after 4 weeks

of treatment.[37] Among 135 subjects with Pa isolates with higher tobramycin MICs (still

below the parenteral breakpoint of ≤4 mcg/mL), mean FEV1 change from baseline after 4

weeks was >8% predicted, while the mean change for 24 subjects with Pa isolates with

higher tobramycin MICs (among those with MICs ≥16 mcg/mL) was approximately 3.5%

predicted (P=0.014).[37] Interestingly, after 4 weeks off inhaled tobramycin, the mean

FEV1 change from baseline decreased about 3% predicted in subjects with tobramycin-

susceptible isolates and stayed about the same for subjects with resistant isolates.[37] In

the open-label portion of this study, there was one visit where changes from baseline

differed significantly between subjects with tobramycin-susceptible and -resistant isolates:

at week 32 (the end of the 4th off-drug period) subjects with resistant isolates had a mean

FEV1 reduction from baseline of >2% predicted while those with susceptible isolates had a

mean FEV1 improvement of >4% predicted (P=0.003). At all other study time points

through 56 weeks, mean ppFEV1 improvements from baseline were not statistically

different between subjects with and without resistant isolates.[37] In the same study,

investigators reported differences in mean FEV1 responses for subjects with Pa isolates

with tobramycin MICs ≤64 mcg/mL and ≥128 mcg/mL. Although numbers of subjects

with isolates with tobramycin MICs ≥128 mcg/mL were small (ranging from 6 to 18

subjects), mean FEV1 declined from baseline at 5 of 11 visits. At visits at weeks 28, 32 and

52, lung mean function changes were significantly lower in those with isolates with higher

tobramycin MICs compared with subjects with isolates with lower tobramycin MICs, but

not at other visits.[37]


infection affected by the method used to guide antimicrobial selection?

Two studies addressed PICO question #2 in persons with CF not experiencing PEx

but receiving antimicrobial treatment for chronic infection. In a retrospective analysis,

Etherington et al. described clinical outcomes of quarterly IV antimicrobial treatments at a

care center following changes in practice that reduced the frequency of routine AST by

>50%.[34] Clinical outcomes (changes in FEV1, FVC, and weight) for 119 patients treated

from June to November of the year prior to the change were compared to outcomes for the

same patients between June and November of the following year, after change in practice.

Investigators reported that there were no significant differences in median FEV1, FVC, or

weight responses between the two periods, suggesting that changing the frequency of

routine AST may not alter clinical outcomes in CF patients.[34]

In a pilot study intended to provide information for treatment of PEx, Moskowitz et

al. compared clinical responses in stable CF patients following IV antimicrobial treatments

selected based on two different susceptibility test methods: conventional (planktonic) broth

microdilution and biofilm-based testing.[35] This was a randomized, prospective,

multicenter study in 39 stable CF subjects with chronic Pa infections. Among 34 subjects

with complete lung function data, there was a difference of 70 mL in the mean FEV1

response (P=0.34) favoring subjects randomized to antibiotics chosen according to biofilm

antimicrobial susceptibility testing compared with those treated with antibiotics based on

conventional AST.

DISCUSSION

We have conducted a systematic literature review to describe relationships between in vitro

AST results and clinical response to antimicrobial treatments among individuals with CF and

bacterial respiratory tract infections. There is little evidence in these articles that AST results are

predictive of antimicrobial response in this treatment setting: investigators from only 3 of 20 unique

studies [22,24,37] suggested correlation between in vitro testing results and clinical response (2 of

13 studies of PEx management and 1 of 7 studies of chronic infection maintenance.) Hubert et al.

[22] reported that Pa-isolate ceftazidime susceptibilities were associated with differences in mean

ppFEV1 response to thrice daily ceftazidime/tobramycin treatment (but not to continuous infusion

ceftazidime treatment) (Figure 2, left panel). Presumably, response differences observed between

different ceftazidime treatment regimens can be accounted for by beta-lactam pharmacodynamics,

which are dependent upon the proportion of time organisms are exposed to inhibitory antimicrobial

concentrations. Among all PEx studies reporting FEV1 response (including Hubert et al.), however,

mean FEV1 improvements from treatment initiation were observed irrespective of AST results.

Wolter et al. [17] reported non-significant trends where patients with susceptible isolates appeared

to have greater mean ppFEV1 responses to antimicrobial treatments (Figure 2, middle panel), while

Hurley et al. [23] reported no such trends (Figure 2, right panel). A second instance of AST

apparently predicting PEx antimicrobial treatment response was reported by Parkins et al., where

proportions of patients meeting a composite treatment failure endpoint differed by the number of

antimicrobials used to which bacterial isolates were determined to be susceptible (by AST) at

treatment initiation.[24] When modeling included other factors such as inflammatory status,

however, AST results were no longer significant predictors of treatment failure. Finally, Mazurek et

al. reported significant differences in ppFEV1 response at some visits (and not others) to inhaled

tobramycin by baseline Pa tobramycin susceptibilities in an open-label, uncontrolled 56-week study

of chronic infection maintenance.[37]

Recognition that traditional AST has only poorly correlated with CF antimicrobial treatment

response has in part motivated the search for alternative measures of antimicrobial susceptibility,

including MBCBT [20] and biofilm [26,35] susceptibility test methods. Although retrospective

testing of samples collected at the time of PEx treatment initiation using either MBCBT [20] or

MBCBT/biofilm [38] methods has suggested that patients treated with antimicrobials for which

isolates were shown to be susceptible in vitro by either method had better average outcomes than

those patients with isolates shown to be resistant, no study to date has shown that selecting

antimicrobial treatments prospectively based on either MCBT or biofilm test results available at

treatment initiation has an effect on outcomes when compared with ‘usual’ antimicrobial selection

methods.

There are important qualifiers to this general observation that AST appears not to predict

response to antimicrobial treatment for chronic CF airway infections. First, almost all studies

reviewed focused on Pa treatment; thus, conclusions may not be generalizable to other important

CF opportunists (e.g., Stenotrophomonas maltophilia [39]). Second, in vitro antimicrobial

susceptibility results are based on interpretive criteria for systemic antimicrobial treatment that are

not applicable to inhalation antibiotic treatment, where drug concentrations achieved at the site of

infection may be considerably higher than achievable by systemic administration; 5 of 20 studies

reviewed inhaled antibiotics for treatment of chronic respiratory tract Pa infection. In these

instances, traditional systemic antimicrobial breakpoints are not expected to predict clinical

response. It is of interest to note, however, that Mazurek et al. did report occasionally significant, if

sporadic, differences in FEV1 response to inhaled tobramycin in their 56-week study based on Pa

isolate tobramycin susceptibilities.[37]

Our analyses of relationships between bacterial isolate antimicrobial susceptibilities and

clinical responses to antimicrobial treatment are only as robust as descriptions of bacterial isolate

susceptibilities and response endpoints employed in published studies. Indeed, the GRADE

evaluation of studies for certainty in addressing PICO questions ranged from “Low” to “Moderate”

(see on-line supplement). Few studies described bacterial isolate susceptibilities in detail; most

identified single isolates as being Susceptible, Intermediate or Resistant to a given agent. Studies

Michael Tunney, 11/06/18,

This sentence is very long and difficult to follow-would it be better split?

reviewed here focused heavily on pulmonary function as clinical response to PEx treatment,

although it has recently been suggested that reduction in elevated signs and symptoms of infection

(whether reported by physicians or patients) is an important motivation for PEx antimicrobial

treatment, and such reduction appears to be a more important clinical outcome for patients than

lung function recovery.[40] Most studies reviewed included ppFEV1 treatment responses, but it is

important to note that ppFEV1 has a relatively large variance, and these studies may have been

underpowered to prospectively test for significant differences in mean ppFEV1 change between

treatment groups.[41] Furthermore, interpretations of the continuous ppFEV1 variable and inclusion

of FEV1 change in categorical outcomes (PEx treatment success/failure) were inconsistent across

studies, complicating comparisons. One study defined any positive FEV1 change from admission as

PEx treatment success [17] while another used >5% predicted FEV1 improvement to define

treatment success.[19] Two similar studies defined treatment failure as achieving <90% of a prior

year’s best FEV1 measure.[24,25] Observational studies have shown, however, that approximately

18% of CF patients treated with antimicrobials for PEx have an FEV1 at treatment initiation that is

higher than any recorded in the past year.[41,42] It is difficult to merge the two definitions: If a

patient experiences no FEV1 improvement from antimicrobial treatment initiation but retains an

FEV1 that is greater than any recorded in their previous year, have they responded to treatment? In

addition, these analyses assume that PEx are relatively homogenous events within and between

patients and that all PEx should respond to antimicrobial treatments, which may not be the case.

Finally, PEx management involves more than simple antimicrobial administration;[7] airway

clearance, nutritional support, and psychosocial support available to admitted patients may also

contribute to FEV1 response.

There are important limitations to our analysis. Our search strategy relied heavily on citation

titles and abstracts: if important susceptibility-related differences in outcomes were not at least

alluded to in titles or abstracts, an article was unlikely to advance beyond secondary screening. As

methods of analysis and reporting were highly variable across studies, it was not possible to

combine these small studies into a larger dataset for meta-analyses, and so our analyses are non-

statistical syntheses of the data.

In addition to the interpretive challenges outlined above, a more fundamental question

remains: are treatment responses in individuals with CF and Pa strains that are susceptible versus

resistant to antimicrobials truly comparable in the manner reported here? Subjects in these studies

have not been ‘randomly assigned’ resistant versus susceptible organisms and an inference that

bacterial isolate susceptibility ‘causes’ differences in antimicrobial clinical response may be

confounded by an individual’s age and lung disease phenotype (Figure 3). A substantial majority of

new CF Pa acquisitions are wild-type, susceptible organisms.[44] In CF, selection for antimicrobial

resistance is generally achieved by successive antimicrobial treatments, presumably due to repeated

clinical presentation of signs and symptoms of respiratory tract infection. This is in contrast to the

situation outside of CF (and other) chronic airway infections, where horizontal transfer between

patients is the more common cause of isolation of antimicrobial-resistant Pa strains.[45] In this

context, antimicrobial resistance is a biomarker for CF populations with both more aggressive and

more advanced airway disease.[46] These patients may not respond to antimicrobial treatment in

the same manner as those with less aggressive and/or less advanced disease, regardless of isolate

susceptibility. The crossover design of Hubert and colleagues [22] was the only study included in

our review in which this type of confounding was not a possibility.

Definitive answers to the questions we have posed are unlikely to be addressed by future

prospective trials, but there is certainly opportunity for larger, more comprehensive retrospective

analyses of relationships between bacterial isolate susceptibilityties, antimicrobial treatments, and

treatment responses utilizing data residing in care center records or patient registries. Such analyses

may substantially improve understanding of CF antimicrobial treatment outcomes, particularly if

addressing possible confounders such as patient age, disease aggressiveness, and disease stage.

In light of our observations, the CF community may consider reducing the frequency of

routine susceptibility testing (as was studied by Etherington et al. [34]) and potentially eliminating

it altogether in instances where no practical value can be realized. Our findings highlight

knowledge gaps relating to a routine practice in CF and suggest a robust evaluation of existing AST

processes and outcomes in CF and a prioritization of innovative research and development in this

area. Such actions may temper unnecessary resource utilization, optimize use of current and future

data, and hopefully will improve treatment outcomes in individuals with CF.

ACKNOWLEDGEMENTS

This work was funded by the European Cystic Fibrosis Society, Cystic Fibrosis Foundation, Cystic

Fibrosis Trust, Cystic Fibrosis Canada, and Cystic Fibrosis Australia.

Figure 1. Disposition of citations from the initial PubMed search yield.

Figure 2. Mean ppFEV1 changes from combination IV antimicrobial treatment initiation for PEx

stratified by in vitro bacterial susceptibility test results. Left: Responses to combined IV ceftazidime/

tobramycin treatments stratified by whether ceftazidime was administered three times daily in short infusions

(left) or continuously infused and (right) and by Pa isolate ceftazidime susceptibilities (susceptible: MICs ≤4

mcg/mL, intermediate: MICs 8–32 mcg/mL, resistant: MICs >32 mcg/mL).[22] Center: Responses to all IV

treatments and IV tobramycin/ceftazidime treatments by susceptibilities of most resistant Pa isolates to each

drug (isolates susceptible to all, some, or none of administered antimicrobials).[17] Left: Responses to

combined IV antimicrobial treatments by Pa isolate susceptibilities (isolates susceptible to all, some, or none

of administered antimicrobials).[23] Error bars are 95% confidence intervals (CI); numbers in parentheses

indicate sample sizes; MIC, minimum inhibitory concentration; Pa, Pseudomonas aeruginosa; ppFEV1,

percent predicted forced expiratory volume in 1 second; R/S, resistant/susceptible; TID, three times daily.

Figure 3. A directed acyclic graph (DAG) of the relationship between CF bacterial isolate

antimicrobial susceptibility and antimicrobial clinical response. A “back door path” suggestive of

confounding [43] exists between an individual’s bacterial isolate susceptibilities and their potential for

clinical response to antimicrobial treatment. The probability of having bacterial isolates with reduced

susceptibility is influenced by an individual’s history of antimicrobial treatment,[44,46] which in turn is

influenced by both their age and the aggressiveness of their CF lung disease.[47] The nature of an

individual’s FEV1 response to antimicrobial treatment is influenced by their age [48] as well as their lung

disease stage [49], which is in turn influenced by their lung disease phenotype.[50] In addition, it has been

shown that antimicrobial treatment history markedly affects the diversity of the airway microbial community

[47], which may in turn also influence antimicrobial response.

Table 1. PEx antimicrobial treatment: relationships between AST results and clinical response.

Authors, Year Country Design Antimicrobials studied; AST-related conclusionsPICO

Question ReferenceMcLaughlin et al., 1983a McLaughlin et al., 1983b USA Randomized,

blindedIV azlocillin/tobramycin, ticarcillin/tobramycin, and azlocillin; “Patients with sputum bacteria that were resistant to one or both of the antibiotics… fared no worse in terms of pulmonary function” 1 13,14

Schaad et al., 1986 Switzerland RandomizedIV netilmicin/azlocillin, netilmicin/ticarcillin; “No significant correlation between severity of CF, antibiotic susceptibility of the initial Pseudomonas isolates, or measured netilmicin concentrations and… clinical improvements”.

1 15

Bosso et al., 1988 USA Randomized IV aztreonam, tobramycin, azlocillin. “Patients with antibiotic-resistant Pa or P. cepacia… responded as well to treatment as those with only susceptible isolates.” 1 16

Wolter et al., 1999 Australia Retrospective IV ceftazidime/tobramycin; No statistically significant differences in ppFEV1 and FVC responses between patients with tobramycin- or ceftazidime-resistant versus susceptible Pa isolates 1 17

Master et al., 2001 Australia Randomized, blinded

IV tobramycin, tobramycin/ceftazidime; The proportion of events with PFT response to IV tobramycin treatment was 84.7% although >80% of baseline Pa isolates had tobramycin MICs above the tobramycin parenteral breakpoint.

1 18

Smith et al., 2003 USA Retrospective IV tobramycin/ceftazidime; In vitro tobramycin and/or ceftazidime resistance did not significantly impact ppFEV1 response to treatment 1 19

Aaron et al., 2005 Canada/Australia

Randomized, blinded

Two IV antimicrobials ± inhaled tobramycin; Time to next PEx and changes in ppFEV1, FVC, and dyspnea scores did not differ between subjects treated with antimicrobials chosen by physicians versus those chosen by multiple combination bactericidal testing (MCBT).

2 20

Foweraker et al., 2009 UK Retrospective Two IV antipseudomonal antimicrobials. In vitro susceptibilities and antimicrobial synergy testing did not predict ppFEV1 response to combination antimicrobial treatments. 1 21

Hubert et al., 2009 France Randomized, crossover

Continuous infusion versus 3x daily IV ceftazidime with 3x daily tobramycin. Mean ppFEV1 response was not different between subjects with ceftazidime-susceptible versus with -resistant Pa isolates treated by continuous infusion but was poorer among patients with resistant isolates treated with ceftazidime intermittently.

1 22

Hurley et al., 2012 UK RetrospectiveMultiple IV antimicrobials; No association was observed between ppFEV1 or BMI change or time to next PEx and concordance between proportions of antimicrobials to which bacterial isolates were resistant (none, some, or all).

1 23

Parkins et al., 2012 UK Retrospective

Two IV antipseudomonal antimicrobials (a beta-lactam and an aminoglycoside or polymyxin); Significant univariate relationships observed between rate of investigator-defined treatment failure and numbers of antimicrobial agents administered with isolate resistance were not observed in multivariate modelling correcting for severity of initial presentation and inflammatory status.

1 24

Lam et al., 2015 Canada Retrospective Multiple antimicrobials; PEx treatment failure was not influenced by the number of antibiotics in combination treatments to which Pa isolates were susceptible. 1 25

Yau et al., 2015 Canada Randomized, blinded

Two IV antimicrobials with different mechanisms of action chosen based on susceptibility test results. No difference in ppFEV1 change was observed between subjects treated with antimicrobials chosen based on biofilm versus planktonic growth susceptibility tests.

2 26

BMI–body mass index; IV– intravenous; MIC – minimum inhibitory concentration; Pa – P. aeruginosa; ppFEV1 – percent predicted forced expiratory volume in 1 second

Table 2. Antimicrobial maintenance of chronic respiratory tract infections: relationships between AST results and clinical response.

Authors, Year Country Design Antimicrobials studied; AST-related conclusionsPICO

Question Reference

Ramsey et al., 1999Burns et al. 1999 USA Randomized,

blinded

Inhaled tobramycin; Mean ppFEV1 improvement was numerically, but not significantly greater among subjects with tobramycin-susceptible Pa isolates at baseline than those with tobramycin-resistant isolates.

1 27,28

Hodson et al., 2002Govan et al., 2002 UK, Ireland Randomized Inhaled tobramycin and colistimethate; Clinical response from baseline after 28 days of

treatment was not predicted by baseline Pa isolate susceptibilities. 1 29, 30

Moss 2001LiPuma, 2001Moss 2002

USA Open-label

Inhaled tobramycin; Mean ppFEV1 response to inhaled tobramycin treatment was not predicted by Pa isolate tobramycin susceptibility after 92 weeks of treatment. Proportions of patients with ppFEV1 increased from baseline were similar across isolate tobramycin susceptibility groups (<16 mcg/ml, 16-64 mcg/mL, >64 mcg/mL).

1 31, 32, 33

Etherington et al, 2008 UK Retrospective Multiple IV antimicrobials; Less frequent susceptibility testing had no effect on clinical responses to scheduled IV antimicrobial treatments for Pa suppression. 2 34

Moskowitz et al., 2011 USA RandomizedMultiple IV antimicrobials; No differences in mean change in ppFEV1 from baseline were observed between subjects with antipseudomonal antimicrobials selected by biofilm susceptibility testing versus traditional broth testing.

2 35

Geller et al., 2011 North America and Europe

Randomized, blinded

Inhaled levofloxacin; No association was observed between baseline levofloxacin MIC and ppFEV1 response following 28 days of inhaled levofloxacin treatment. 1 36

Mazurek et al, 2014 Europe Randomized, open-label

Inhaled tobramycin; Subjects with only tobramycin-susceptible Pa isolates (MIC <8 mcg/mL) had statistically greater mean ppFEV1 responses than those with at least one tobramycin-resistant isolate at some study visits over 1 year. Subjects with at least one tobramycin-resistant Pa isolate, however, had a positive mean ppFEV1 change from baseline at 10/11 study visits over 1 year.

1 37

IV – intravenous; MIC – minimum inhibitory concentration; Pa – P. aeruginosa; ppFEV1 – percent predicted forced expiratory volume in 1 second

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ON-LINE SUPPLEMENT

PubMed database search string.

(((((((((((((("cystic fibrosis"[Title/Abstract] OR mukoviszidose[Title/Abstract] OR

mucoviscidosis[Title/Abstract] OR CF[Title/Abstract]) AND “cystic fibrosis”[MeSH Major Topic])))

AND (suscept*[ All Fields] OR resistan*[ All Fields] OR multiresistan*[ All Fields] OR multi-

resistan*[ All Fields] OR sensitiv*[ All Fields] OR density[All Fields] OR load[All Fields] OR “Drug

Resistance, Microbial”[MeSH Major Topic] OR “Microbial Sensitivity Tests”[MeSH Major

Topic]))))) AND (antibiotic [Text Word] OR antibiotics [Text Word] OR antimicrobial* [Text Word]

OR anti-microbial* [Text Word] OR "anti-bacterial agents"[MeSH Major Topic])))))))

Evaluating studies using GRADE criteria

As noted in the Methods section, study quality was assessed using the GRADE criteria with

eight domains: (a) risk of bias, (b) directness of results, (c) precision of results (d) consistency of

results, (e) risk of publication bias, (f) magnitude of effect, (g) presence of residual plausible

confounding and (h) dose-response gradient.[11,12] GRADE criteria were applied separately for

each PICO question by outcome and study design (prospective vs observational). Using the

GRADE method, randomized trials and observational studies start at high and low quality,

respectively, and can be downgraded or upgraded based on the criteria (a) through (h), above. The

total sample size for the GRADE summary table was based on the sum of all studies with their

starting patient population without specific documentation of the number of events, but these

were considered if power calculations were conducted to determine risk of imprecision. GRADE

summary tables for PICO questions #1 and #2 are provided below.

PICO Question #1: For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection predictable from AST results available at treatment?

GRADE Certainty Assessment

ImpactGRADE

Certainty

№ of studie

sStudy design

Risk of bias

Inconsistency

Indirectness Imprecision

Other consideration

s

Randomized controlled trials - Lung function response outcome [13-16,18,22,27-30,36,37]

11 randomized trials

not serious not serious seriousa not serious none

[n=2,017] No significant differences in lung function responses were demonstrated between groups in 10/11 studies. 1/11 studies demonstrated increased lung function response using continuous vs. intermittent ceftazidime if isolates were ceftazidime-resistant.

⨁⨁⨁◯MODERATE

Observational studies - Lung function response outcome [17,19, 21, 23,31,32,33]

7 observational studies

not serious not serious not serious not serious none

[n=1,075] No differences in lung function response were noted based on bacterial susceptibility at treatment start.

⨁⨁◯◯LOW

Observational studies - Treatment failure outcome [24, 25]

2 observational studies

not serious not serious not serious not serious none

[n=147] The presence of resistant bacterial isolates was associated with treatment failure in 1/2 studies but was not associated with failure in multivariable models in either study.

⨁⨁◯◯LOW

a-The majority of studies were not designed to specifically address the question of bacterial resistance and clinical response and this was a secondary or lesser objective. There was also heterogeneity in measurement of both the exposure and outcome variables and lung function. Additionally, the results crossed the no effect boundary and may not always have been powered to assess the question as the number of subjects with available data was lower than the total sample size.

PICO Question #2: For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection affected by the method used to guide antimicrobial selection?

GRADE Certainty Assessment

ImpactGRADE

Certainty

№ of studie

sStudy design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other consideration

s

Randomized controlled trials - Time to next exacerbation outcome [20]

1 randomized trials not serious not serious not serious serious a none

[n=251] Hazard ratio for next pulmonary exacerbation was 0.86 in favor of conventionally treated group (p=0.40)


Randomized controlled trials - Lung function response [26, 35]

2 randomized trials not serious not serious not serious serious b none

[n=78 total] Biofilm vs conventional susceptibility testing compared. Lung function changes were similar at end of treatment (7-14 days)


Observational studies - Lung function response [34]

1 observational studies not serious not serious not serious not serious none

[n=193] No differences in median lung function change with reduction in susceptibility testing frequency.

⨁⨁◯◯LOW

a. Effect confidence intervals cross zero, underpowered to assess the difference in outcome seen.

b. Confidence intervals cross zero, underpowered to assess lung function difference. In addition, Lung function response was a secondary outcome in both trials.

spiral.imperial.ac.uk · web viewa systematic search and review of the pubmed database was...

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