Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea

Accepted Manuscript Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteremia: a prospective multi-center cohort study in Korea Shinwon Lee, Kyoung-Ho Song, Sook-In Jung, Wan Beom Park, Sun Hee Lee, YeonSook Kim, Yee Gyung Kwak, Young Keun Kim, Sung min Kiem, Hye-In Kim, Eu Suk Kim, Kyung-Hwa Park, Nam Joong Kim, Hee-Chang Jang, Hong Bin Kim, the Korea INfectious Diseases (KIND) study group PII:

S1198-743X(17)30355-5

DOI:

10.1016/j.cmi.2017.07.001

Reference:

CMI 997

To appear in:

Clinical Microbiology and Infection

Received Date: 17 March 2017 Revised Date:

1 July 2017

Accepted Date: 2 July 2017

Please cite this article as: Lee S, Song K-H, Jung S-I, Park WB, Lee SH, Kim Y-S, Kwak YG, Kim YK, Kiem Sm, Kim H-I, Kim ES, Park K-H, Kim NJ, Jang H-C, Kim HB, the Korea INfectious Diseases (KIND) study group Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteremia: a prospective multi-center cohort study in Korea, Clinical Microbiology and Infection (2017), doi: 10.1016/j.cmi.2017.07.001. 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 Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteremia: a prospective multi-center cohort study in Korea

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Shinwon Leea,*, Kyoung-Ho Songb,*, Sook-In Jungc, Wan Beom Parkd, Sun Hee Leea, YeonSook Kime, Yee Gyung Kwakg, Young Keun Kimh, Sung min Kiemi, Hye-In Kimj, Eu Suk Kimb, Kyung-Hwa Parkc, Nam Joong Kimd, Hee-Chang Jangf,#, Hong Bin Kimb,#, and the

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Korea INfectious Diseases (KIND) study group

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Department of Internal Medicine, Pusan National University School of Medicine and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Koreaa; Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Koreab; Department of

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Infectious Diseases, Chonnam National University Medical School, Gwangju, Republic of Koreac; Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Koread; Division of Infectious

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Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Republic of Koreae: Department of Internal Medicine, Chonnam National

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University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Koreaf; Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Koreag; Department of Internal Medicine, Yonsei University Medical School, Wonju, Republic of Koreah; Department of Internal Medicine, Inje University College of Medicine, Busan, Republic of Koreai; Department of Internal Medicine, Daegu Fatima Hospital, Daegu, Republic of Koreaj

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*

These authors contributed equally to this study. These authors contributed equally to this study.

Address correspondence to Hong Bin Kim, [email protected]

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#

Department of Internal Medicine, Seoul National University College of Medicine and Seoul

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Fax: +82.31-787-4052, Tel: +82.31-787-7021

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National University Bundang Hospital, 173 Gumi-ro, Seongnam, Republic of Korea

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Running title: Cefazolin vs. nafcillin for MSSA bacteremia

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Abstract: 239

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Main body: 2382

Keywords: Staphylococcus aureus; cefazolin; nafcillin; bacteremia; inoculum effect

ACCEPTED MANUSCRIPT ABSTRACT Objectives: No randomized controlled trials have evaluated the comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA)

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bacteremia. Methods: A prospective observational cohort study including all S. aureus bacteremia was conducted at 10 hospitals. Patients (≥15 years) with MSSA bacteremia who received

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cefazolin or nafcillin as definitive antibiotics were included. The rates of treatment failure (premature discontinuation of antibiotics due to adverse effects, switching of antibiotics due

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to clinical failure, all-cause mortality within one month, or recurrence) were compared between the cefazolin and nafcillin groups. Propensity score matching analyses were performed to balance the factors influencing the selection of antibiotics. Results: Among the 242 included cases, the bones and joints (36.8%) were the most common

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sites of infection and 60.7% of the patients had sepsis. The overall treatment failure rate was 43.8% (106/242). All-cause mortality within one month was 6.2% (15/242). After propensity score matching, the treatment failure rate of cefazolin was lower than that of nafcillin (30.4%

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[24/79] vs. 49.4% [39/79], p=0.015) due to a higher rate of discontinuation due to adverse events. When the data were limited to patients with sepsis, the treatment failure rates of both

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groups were not significantly different. Approximately 22% (24/110) of MSSA isolates exhibited cefazolin-inoculum effect (CIE) that had significant impact on the failure rate and mortality of the cefazolin group. Conclusions: Cefazolin might be recommended as an adequate and better-tolerated treatment for MSSA bacteremia in the absence of CIE.

ACCEPTED MANUSCRIPT INTRODUCTION

Staphylococcus aureus is a major pathogen in community- and health care-associated infections, and methicillin-susceptible S. aureus (MSSA) continues to contribute to the

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overall burden of S. aureus infections, representing 50% to 99% of clinical S. aureus strains [1-4]. Bacteremia is a serious S. aureus infection that causes high mortality [5-8].

Semisynthetic penicillins, such as nafcillin or oxacillin, are recommended as first-line

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antibiotics and cefazolin as an alternative [9]. Although cefazolin is widely used for MSSA infections because of its convenient dosing and tolerability, treatment with semisynthetic

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penicillin is generally preferred for patients with serious S. aureus bacteremia, due to its narrower spectrum and lower inoculum effect compared with cefazolin [10-12].

However, semisynthetic penicillins have been shown to cause a significantly higher rate of

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side effects than cefazolin in some studies (Supplementary Table 1) [10, 13]. No prospective studies have compared cefazolin with semisynthetic penicillins in the treatment of MSSA bacteremia, and there is little evidence concerning the comparative outcomes of

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semisynthetic penicillin versus cefazolin. However, an increasing number of retrospective studies have compared cefazolin with semisynthetic penicillins, and have demonstrated no

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consensus in clinical outcome (Supplementary Table 1) [10, 11, 14-17]. Furthermore, the clinical impact of the cefazolin inoculum effect (CIE) on cefazolin treatment against MSSA infections has not been well investigated [18, 19]. The purpose of the current prospective observational study was to evaluate the comparative outcomes of cefazolin versus nafcillin for MSSA bacteremia. Additionally, we evaluated the clinical impact of CIE on treatment outcomes.

ACCEPTED MANUSCRIPT MATERIALS AND METHODS

Study design, setting, and participants. A prospective observational cohort study was conducted to evaluate the comparative outcomes of cefazolin versus nafcillin. This study is

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one of the priori planned sub-studies within the prospective S. aureus bacteremia cohort study, “Korea INfectious Diseases Study Group - Staphylococcus aureus Bacteremia 2013 (KINDSAB 2013) cohort” with project name, ‘Establishment of Network for Clinical Research of

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Staphylococcus aureus Infection’. The KIND-SAB 2013 cohort prospectively and

consecutively recruited all S. aureus bacteremia cases between September 2013 and March

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2015 at 10 general hospitals across South Korea if the cases did not match any exclusion criterion (Supplementary Table 2). The study recommended guidelines to each participating hospital but the sites were not obligated to follow the guidelines [3].

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Among the S. aureus bacteremia patients who were included in the KIND-SAB 2013 cohort, all adult (≥15 years) patients with MSSA bacteremia who received cefazolin or nafcillin as definitive antibiotics were included in this comparative study. We excluded cases if cefazolin

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or nafcillin were co-administered with other antibiotics, were discontinued within two days or were not dosed appropriately (Supplementary Table 3). The KIND-SAB 2013 cohort and this

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study were approved by the institutional review boards at each participating hospital.

Variables. The exposures in our study were cefazolin or nafcillin treatment for MSSA bacteremia. The patients who received cefazolin or nafcillin as definitive antibiotics were assigned to the cefazolin or nafcillin group, respectively. Definitive antibiotics were defined as antibiotics administered after a report of antibiotic susceptibility of the isolates. The main outcome of our study was treatment failure (a composite outcome), which was considered present if at least one of following four criteria were observed: 1) switching antibiotics due to

ACCEPTED MANUSCRIPT the clinician’s opinion that treatment had failed; 2) premature discontinuation of antibiotics due to adverse effects; 3) all-cause mortality within one month; or 4) recurrence or relapse of MSSA infection within three months after treatment completion [10, 20-22]. MSSA sepsis

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was defined as a Sepsis-related Organ Failure Assessment (SOFA) score ≥ 2, i.e., significant organ dysfunction [23, 24].

Measurement of the cefazolin inoculum effect. The CIE of MSSA isolates obtained from

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the cases was measured as described elsewhere [19, 25]. Briefly, the cefazolin MICs obtained with a high inoculum (HI, ~5×107 CFU/ml) were compared with those obtained with a

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standard inoculum (SI, ~5×105 CFU/ml) to identify the strains with CIE which was defined as an increase in the MIC to ≥16 µg/ml with a high inoculum from the susceptible range of the MIC with a standard inoculum [19].

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Statistical analysis and propensity score matching. SPSS version 22, (SPSS, Inc., an IBM Company, Chicago, IL, USA) and Stata version 13 (Stata Corp LP, USA) were used for statistical analyses. Student’s t-test, χ2 test, or Fisher’s exact test were performed, depending

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on the type of variable for univariable analyses. Correlations were assessed using the Spearman correlation coefficient. Multivariable analyses were performed by logistic

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regression analysis using a generalized linear mixed model and univariable pre-selection method to evaluate the effect of cefazolin on treatment failure and independent risk factors for treatment failure. Cefazolin treatment and variables with p values less than 0.2 in the univariable analysis were included in the multivariable analyses. Bivariate and multinomial logistic regression analyses using a generalized linear mixed model were performed to take the random effects of the individual hospitals into account.

ACCEPTED MANUSCRIPT To balance the possible preference for nafcillin over cefazolin for serious infection and adjust on other confounding factors, we performed propensity score matching analysis because definitive antibiotics were decided by the physicians in charge of the included patients.

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Propensity score matching was conducted using the propensity score module for SPSS and the MatchIt package for R software [26]. One-to-one nearest neighbor matching was

performed with the following covariates: age, sex, participating hospitals, site of infections,

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and severity of infections (SOFA score). MSSA bacteremic patients with sepsis according to the sepsis-3 definition in each group were then matched again by propensity score [24]. All

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tests of significance were two-tailed, and p<0.05 was considered significant.

ACCEPTED MANUSCRIPT RESULTS

Clinical characteristics. Among 1,013 S. aureus bacteremia patients satisfying the inclusion criteria of the KIND-SAB 2013 cohort, 480 patients had MSSA bacteremia. Of these 480

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MSSA bacteremia patients, 52.9% (254/480) received cefazolin or nafcillin as definitive

antibiotics, 41.3% (198/480) received antibiotics other than cefazolin and nafcillin, and 5.8% (28/480) died before the reporting of the culture and antimicrobial susceptibility results

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(Figure 1). The demographics and clinical characteristics of the patients who received

antibiotics other than cefazolin and nafcillin are described in Supplementary Table 4. Of the

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remaining 254 patients, the 242 patients who received the appropriate dose of antibiotics were included in this study (Figure 1). The mean age of the 242 included patients was 61.5 ± 15.7 years, and 63.6% (154/242) were male. The bones and joints (36.8% [89/242]) were the most common sites of infection. One hundred forty-seven patients (60.7%) had sepsis

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according to the sepsis-3 definition and 5.4% (13/242) had shock and needed a vasopressor. The treatment failure rate of the 242 included patients was 43.8% (106/242) (Table 1).

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Antibiotic selection for MSSA bacteremia. The demographics, clinical characteristics, and severity of infection of the cefazolin (n=79) and the nafcillin (n=163) groups were compared

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to identify the factors affecting the pattern of definitive antibiotics selection. Physicians preferred to prescribe nafcillin for patients with more serious infections (nafcillin vs. cefazolin, 68.1% vs. 45.6%, p=0.001) or endovascular infections (nafcillin vs. cefazolin 14.7% vs. 5.1%, p=0.028, Table 1). The median time to appropriate antibiotics and definitive antibiotics were not significantly different between both groups (Table 1). Adverse reactions that caused drug interruption were more frequent in the nafcillin group (Table 1 and Supplementary Table 5). The median proportion of cefazolin vs. nafcillin in the 10 hospitals was 35.3% (interquartile range [IQR]: 24.2-43.6, range: 12.5-61.1%). There was minimal

ACCEPTED MANUSCRIPT correlation between institutional preference for cefazolin use and the severity (SOFA score) of infections (correlation efficient 0.08, p=0.222).

Risk factors for treatment failure. Univariable and multivariable analyses of the 242

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patients with MSSA bacteremia who received cefazolin or nafcillin as definitive antibiotics were conducted to identify the risk factors for treatment failure (Table 2). Metastatic

complication and higher SOFA score at the onset of bacteremia were identified as significant

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risk factors for treatment failure in the multivariable analyses (Table 2). Patients who

received cefazolin were also less likely to experience treatment failure than those receiving

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nafcillin (adjusted odds ratio [aOR]: 0.44; 95% confidence interval [CI]: 0.22-0.86; p=0.017; Table 2). Additionally, we evaluated the independent risk factors for 90-day mortality; cefazolin use was associated with a decreased risk of 90-day mortality compared with

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nafcillin (aOR: 0.09; 95% CI: 0.02-0.54, p=0.008, Supplementary Table 6).

Propensity score matching and comparative outcomes. Age, hospital, site of infection, and severity of infection were possible factors influencing antibiotic selection, and all these

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factors were balanced through propensity score matching, resulting in the assignment of 79 patients to each group. There was no significant difference in the baseline characteristics

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between the two matched groups (Supplementary Table 7). The treatment failure rate was significantly lower in the cefazolin group (30.4% [24/79] vs. 49.4% [39/79]; p=0.015; Table 3) due to a lower rate of adverse events.

To identify the comparative outcomes of cefazolin and nafcillin for severe infections, we performed propensity score matching of patients with MSSA sepsis. In the subgroup analysis of MSSA sepsis patients, the treatment failure rates were not significantly different (Table 3).

ACCEPTED MANUSCRIPT Clinical implication of the cefazolin inoculum effect. We compared the outcomes of the CIE-positive group with those of the CIE-negative group in each propensity score-matched cefazolin or nafcillin group. Among the 158 propensity score-matched MSSA bacteremia

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cases, causative isolates were obtained for 69.2% (110/158) (58 from the cefazolin group and 52 from the nafcillin group), and 21.8% (24/110) showed CIE. Overall, the treatment failure rates were not significantly different between the CIE-positive (CIE-P) and -negative (CIE-N)

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groups (Table 4). However, a stratified analysis among the patients received cefazolin showed that the treatment failure rate (CIE-P 61.5% [8/13] vs. CIE-N 28.9% [13/45], p=0.049), rate

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of switching antibiotics due to clinical failure (CIE-P 38.5% [5/13] vs. CIE-N 11.1% [5/45], p=0.036), and rate of one-month mortality (CIE-P 15.4% [2/13] vs. CIE-N 0% [0/45],

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p=0.047) were significantly higher in the CIE-P group than in the CIE-N group (Table 4).

ACCEPTED MANUSCRIPT DISCUSSION

Our observational study demonstrated that patients who received cefazolin were less likely to experience treatment failure than those who received nafcillin although the lower rate of

interrupted due to adverse events than nafcillin.

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treatment failure in the cefazolin group was due to the fact that cefazolin was less frequently

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The comparative outcomes of nafcillin versus cefazolin have not previously been evaluated through a randomized controlled study. Previous retrospective studies (Supplementary Table

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1) have suggested that cefazolin is comparable to semisynthetic penicillin for MSSA bacteremia, including complicated bacteremia of deep-seated infections [10, 11, 14-16]. McDanel et al, recently reported a large nationwide retrospective study which demonstrated that using cefazolin versus nafcillin or oxacillin for MSSA bacteremia reduced mortality [17].

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The study had the largest sample size among previous studies. However, the study might be heterogeneous in end points since the study collected data from many places over a long period of time.

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Our study was the first prospective observational study dealing with the comparative

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outcomes of cefazolin versus nafcillin treatment for MSSA bacteremia. We tried to minimize selection bias or indication bias though performing propensity score matching to adjust the imbalance between the cefazolin and nafcillin groups.

Our study also provides useful information concerning the clinical implication of the CIE of MSSA bacteremia. Nannini EC et al. warned that the CIE could be associated with cefazolin treatment failure [19]. However, there are limited data concerning the impact of the CIE in clinical practice. A previous study of our group dealt with this issue regarding the CIE, but the study failed to prove its clinical implications [18, 25]. In this study, we demonstrated that

ACCEPTED MANUSCRIPT the CIE was associated with treatment failure of MSSA bacteremia when the patients were treated with cefazolin. Therefore, we can improve the outcomes of MSSA bacteremia if we have tools to rapidly identify the CIE-positive strain. Therefore, it may be necessary to

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develop reliable method for rapid detection of CIE positivity in clinical setting which is currently not available [27].

This study had several limitations. First, there is a probability of confounding factors that

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were unexpected despite propensity score matching because our study was not randomized or controlled. In our study, the mortality rate of the nafcillin group was significantly higher than

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that of the cefazolin group prior to matching. The difference in 90-day all cause mortality between both groups was also shown in the propensity score matched analysis. It is probably due to the fact that patients in the cefazolin group were sicker, even though our study was balanced for comorbidity, site of infection, and severity of illness. Therefore, we cannot be

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sure of the superiority of cefazolin to nafcillin based on our findings until a randomized controlled trial has confirmed this issue. Second, few cases of endocarditis or septic shock patients were included and many cases with higher illness severity and septic shock were

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excluded because of using other antibiotics than cefazolin or nafcillin. In addition, the mortality rate within one month was less than 10% in our study, which is low compared with

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that observed in previous retrospective studies [14, 16, 17]. This difference might be due to the fact that the patients included in our study were less seriously ill than those included in previous studies. Therefore, these results cannot be generalized for MSSA bacteremia associated with endocarditis or higher illness severity such as septic shock. Third, we used composite end points as primary outcomes to enhance the power of this study. The importance of each component of our composite end points was not even, and significant differences might be driven by less serious outcomes [28]. Therefore, we reported each

ACCEPTED MANUSCRIPT component of a composite outcome separately to determine the direction and size of each effect [28]. Finally, only 69.2% of MSSA isolates among the 158 propensity-matched MSSA bacteremia cases were analyzed for the clinical implications of CIE.

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In conclusion, this study found that the clinical efficacy of cefazolin for MSSA bacteremia and sepsis was comparable to those of nafcillin, and that the CIE was associated with

cefazolin treatment failure for MSSA bacteremia. Cefazolin was associated with a lower risk

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of adverse events leading to treatment discontinuation. This study suggests that cefazolin versus anti-staphylococcal penicillin can improve the outcomes of MSSA bacteremia,

MSSA bacteremia and sepsis.

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particularly MSSA without CIE, and that cefazolin may be recommended as an option for

However, the evidence from this study is not sufficient to recommend cefazolin as a first-line

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therapeutic agent for MSSA bacteremia but justifies the necessity of randomized controlled trials to confirm the comparative efficacy of cefazolin versus anti-staphylococcal penicillins

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for MSSA bacteremia.

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Funding: This work was supported by Grant No. HI10C2020 from the National Strategic Coordinating Center for Clinical Research, which is run by Ministry of Health and Welfare,

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Korean Government. The measurement of the cefazolin inoculum effect of MSSA isolates was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP)

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(No. NRF-2015R1C1A1A01054293).

ACKNOWLEDGEMENTS

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Conflict of Interest: None.

We registered the protocol of the KIND-SAB 2013 cohort study (KCT0001070) and this

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comparative study (KCT0001081) in the Clinical Research Information Service of the Republic of Korea, http://cris.nih.go.kr, in cooperation with the WHO International Clinical Trials Registry Platform. KIND-SAB 2013 cohort which was supported by Ministry of

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Health and Welfare, Korean Government with project name, ‘Establishment of Network for Clinical Research of Staphylococcus aureus Infection’.

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This work was summarized in an abstract (Presentation No. 1075) for the ID Week, New Orleans, LA, USA, 2016.

We thank the members of the Korea INfectious Diseases (KIND) study group and the associated staff for their cooperation in this study. In addition to the authors, the following individuals participated in the study group: Su-Mi Choi (Chonnam National University Hospital); Kyoung Un Park, Chung Jong Kim, Jeong Eun Cho, Yun Jung Choi, and Jung In Park (Seoul National University Bundang Hospital); Taek Soo Kim, Pyoeng Gyun Choe, Wan

ACCEPTED MANUSCRIPT Beom Park, Nak-Hyun Kim, Myung Jin Lee, and Su Jin Choi (Seoul National University Hospital); Jae Hyun Jeon, Dong-Kie Kim, Sae-Am Song, Min Ji Kang, and Jae Gyun Shin (Inje University Haeundae Paik Hospital); Jongyoun Yi, Sohee Park (Pusan National

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University Hospital); Hee Kyoung Choi and Myung Sook Han (Yonsei University Wonju Severance Christian Hospital); Chong Rae Cho, Hyun Suk Song, and Young Soon Lee (Inje University Ilsan Paik Hospital); Seung-Ji Kang and Hyeon-jeong Hwang, (Chonnam National

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University Hwasun Hospital); Shinhye Cheon, Jin Hee Hwang, and Seon Jin Yun (Chungnam National University Hospital); and Ki Tae Kwon and Seung Min Shin (Daegu Fatima

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Hospital).

We thank Dr. Soyeon Ahn, a biostatistician of Medical Research Collaborating Center, Seoul National University Bundang Hospital for statistical advice on this work. AUTHOR CONTRIBUTIONS

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Conceptualization: Lee S, Song KH, Kim HB, Data collection and curation: Lee S, Song KH, Jung SI, Park WB, Lee SH, Kim YS, Kwak YG, Kim YK, Kiem SM, Kim HI, Kim ES, Park

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KH, Kim NJ, Jang HC. Formal analysis: Lee S, Song KH, Jang HC, Kim HB. Funding acquisition: Lee S, Kim HB. Investigation: Lee S, Song KH. Supervision: Lee S, Song KH,

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Kim ES, Jang HC. Writing - original draft: Lee S. Writing - review & editing: Lee S, Song KH, Jang HC, Kim HB.

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Shaw E, Miro JM, Puig-Asensio M, et al. Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial. BMJ Open 2015; 5: e006723.

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Seymour CW, Liu VX, Iwashyna TJ, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis3). JAMA 2016; 315: 762-74. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus

RI PT

24

Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315: 801-10. 25

Song KH, Jung SI, Lee S, et al. Characteristics of cefazolin inoculum effect-positive

SC

methicillin-susceptible Staphylococcus aureus infection in a multicentre bacteraemia cohort. Eur J Clin Microbiol Infect Dis 2017; 36: 285-94.

Daniel E. Ho KI, Gary King, Elizabeth A. Stuart MatchIt: Nonparametric Preprocessing

M AN U

26

for Parametric Causal Inference. Journal of Statistical Software 2011; 42: 1-28. 27

Lee SH, Park WB, Lee S, et al. Association between type A blaZ Gene Polymorphism and Cefazolin Inoculum Effect in Methicillin-Susceptible Staphylococcus aureus.

28

TE D

Antimicrob Agents Chemother 2016; 60:2928-32.

Harris PN, McNamara JF, Lye DC, et al. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus

AC C

EP

definition. Clin Microbiol Infect 2016; E-pub ahead.

Figure 1. Flow diagram of study inclusion to compare outcomes of cefazolin versus nafcillin, which is a sub-study of the study ‘Korea INfectious Diseases Study Group Staphylococcus aureus Bacteremia 2013 (KIND-SAB 2013) cohort’

ACCEPTED MANUSCRIPT Table 1. Comparison of the demographics and clinical characteristics of the cefazolin group versus the nafcillin group among 242 total MSSA bacteremia cases

Cefazolin

Nafcillin

P-

Clinical Characteristics

OR (95% CI) (n=163)

Age ≥65 years

33 (41.8%)

90 (55.2%)

0.58 (0.34-1.00)

0.050

Male sex

48 (60.8%)

106 (65.0%)

0.83 (0.48-1.45)

0.517

Healthcare-associated infection

22 (27.8%)

47 (28.8%)

0.95 (0.52-1.73)

0.873

Cardiovascular disease

52 (65.8%)

117 (71.8%)

M AN U

Charlson’s comorbidity index ≥3

SC

Underlying illness

value

RI PT

(n=79)

0.76 (0.43-1.35)

0.344

9 (11.4%)

22 (13.5%)

0.82 (0.36-1.88)

0.646

15 (19.0%)

19 (11.7%)

1.78 (0.85-3.72)

0.124

6 (7.6%)

12 (7.4%)

1.03 (0.37-2.87)

0.948

4 (5.1%)

6 (3.7%)

1.40 (0.38-5.09)

0.732

4 (5.1%)

3 (1.8%)

2.84 (0.62-13.03) 0.220

1 (1.3%)

1 (0.6%)

2.08 (0.13-33.64) 0.547

14 (17.7%)

32 (19.6%)

0.88 (0.44-1.77)

0.722

Hematologic malignancy

4 (5.1%)

11 (6.7%)

0.74 (0.23-2.39)

0.779

Advanced liver disease

5 (6.3%)

15 (9.2%)

0.67 (0.23-1.91)

0.620

Metastatic solid tumor

9 (11.4%)

10 (6.1%)

1.97 (0.77-5.06)

0.154

Receipt of immunosuppressant

13 (16.5%)

30 (18.4%)

0.87 (0.43-1.78)

0.710

10 (12.7%)

20 (12.3%)

1.04 (0.46-2.33)

0.932

4 (5.1%)

24 (14.7%)

0.31 (0.10-0.92)

0.028

Endocarditis

1 (1.3%)

11 (6.7%)

0.18 (0.02-1.40)

0.110

Large vessel infection

3 (3.8%)

14 (8.6%)

0.42 (0.12-1.51)

0.171

Diabetes mellitus with complication Cerebrovascular diseases

Connective tissue diseases Ulcer disease

AC C

EP

Chronic kidney diseases

TE D

Chronic pulmonary diseases

Central or peripheral venous catheter Endovascular

Site of infection

ACCEPTED MANUSCRIPT 28 (35.4%)

61 (37.4%)

0.92 (0.53-1.61)

0.765

Bone

17 (21.5%)

35 (21.5%)

1.00 (0.52-1.93)

0.993

Joint

14 (17.7%)

26 (16.0%)

1.14 (0.56-2.32)

0.728

27 (34.2%)

38 (23.3%)

1.71 (0.95-3.08)

0.074

Respiratory tract

3 (3.8%)

16 (9.8%)

0.36 (0.10-1.28)

0.103

Intra-abdominal

2 (2.5%)

3 (1.8%)

1.39 (0.23-8.46)

0.663

0(0%)

5 (2.9%)

-

0.176

1 (1.3%)

3 (1.8%)

0 (0%)

1 (0.6%)

-

>0.999

12 (15.2%)

22 (13.5%)

1.15 (0.54-2.46)

0.722

Urinary tract Others Central nervous system

M AN U

Unknown

0.68 (0.07-6.68) >0.999

SC

Skin and soft tissue

RI PT

Bone and joint

Severity of infection 10 (12.7%)

23 (14.1%)

0.88 (0.40-1.96)

0.758

SOFA score ≥2

36 (45.6%)

111 (68.1%) 0.39 (0.23-0.68)

0.001

3 (1.8%)

0.68 (0.07-6.68) >0.999

12 (7.4%)

0.16 (0.02-126)

0.066

0.9 [0.2-2.1]

1.3 [0.5-3.0]

-

0.100

AC C

Metastatic complication

4.0 [3.0-6.0]

3.0 [3.0-5.0]

-

0.123

24 (30.4%)

82 (50.3%)

0.43 (0.24-.076)

0.003

Mortality within 1 month

2 (2.5%)

13 (8.0%)

0.30 (0.07-1.36)

0.153

13 (16.5%)

27 (16.6%)

0.98 (0.48-2.05)

0.983

2 (2.5%)

6 (3.7%)

Septic shock

1 (1.3%)

TE D

Pitt bacteremia score ≥5

1 (1.3%) Antibiotics

time

to

appropriate

EP

Median

antibiotics Day [IQR]

Median time to definitive antibiotics Day [IQR]

Treatment failure

Outcomes

Antibiotic change due to clinical failure Recurrence

0.68 (0.13-3.45) >0.999

ACCEPTED MANUSCRIPT PDA due to adverse effects Mortality within 3 months

10 (12.7%)

48 (29.4%)

0.35 (0.17-0.73)

0.004

2 (2.5%)

24 (14.7%)

0.15 (0.04-0.65)

0.004

MSSA, methicillin-susceptible Staphylococcus aureus; SOFA, Sepsis-related Organ Failure Assessment; IQR,

The bold text indicates p<0.05.

AC C

EP

TE D

M AN U

SC

*Severe renal impairment: Chronic Kidney Disease (CKD) stage 4 or 5.

RI PT

Interquartile range; PDA, premature discontinuation of antibiotics.

ACCEPTED MANUSCRIPT Table 2. Univariable and multivariable analyses of risk factors for treatment failure of 242 MSSA bacteremia cases that received cefazolin or nafcillin as definitive antibiotics Treatment

failure (106)

success (136)

Cefazolin use vs. nafcillin

24 (22.6%)

Univariable analysis

POR (95% CI)

55 (40.4%) 0.43 (0.24-0.76)

Median time to appropriate -

3.0 [2.0-5.0] 3.0 [1.0-4.8]

-

Median time to definitive

aOR (95% CI)

0.003

value

0.44 (0.22-0.86) 0.017

0.508

M AN U

Age, years

P-value

SC

0.8 [0.1-2.9] 1.0 [0.2-3.0] antibiotics, Day [IQR]

antibiotics, Day [IQR]

Multivariable analysis

RI PT

Clinical Characteristics

Treatment

~49

17 (16.0%)

30(22.1%)

50~64

33 (31.1%)

39 (28.7%) 1.49 (0.70-3.18)

0.296

1.31 (0.53-3.23) 0.557

65~79

42 (39.6%)

58 (42.6%) 1.28 (0.63-2.61)

0.501

1.12 (0.48-2.66) 0.785

80~

14 (13.2%)

2.75 (0.98-7.67)

0.051

1.84 (0.53-6.36) 0.337

65 (61.3%)

89 (65.4%) 0.84 (0.49-1.42)

0.509

27 (25.5%)

42 (30.9%) 0.77 (0.43-1.35)

0.355

91 (66.9%) 1.38 (0.79-2.41)

0.262

19 (17.9%)

12 (8.8%)

2.26 (1.04-4.89)

0.036

16 (15.1%)

18 (13.2%) 1.17 (0.56-2.41)

0.680

TE D

9 (6.6%)

Male sex Healthcare-associated

EP

infection

1

0.402

-

1

Charlson’s comorbidity (age

78 (73.6%)

AC C

weighted) ≥3

Cardiovascular disease Diabetes

mellitus

1.53 (0.59-3.98) 0.386

with

complication

Cerebrovascular diseases

9 (8.5%)

9 (6.6%)

1.31 (0.50-3.42)

0.582

Chronic pulmonary diseases

4 (3.8%)

5 (4.4%)

0.85 (0.23-3.09)

0.805

Connective tissue diseases

1 (0.9%)

6 (4.4%)

0.21 (0.02-1.74)

0.140

Ulcer disease

1 (0.9%)

1 (0.7%)

1.29 (0.08-20.80) >0.999

Chronic kidney diseases

27 (25.5%)

19 (14.0%) 2.11 (1.10-4.04)

0.024

0.31 (0.03-3.91) 0.367

1.47 (0.65-3.33) 0.360

ACCEPTED MANUSCRIPT Hematologic malignancy

4 (3.8%)

11 (8.1%)

0.45 (0.13-1.44)

0.167

0.29 (0.07-1.17) 0.082

Advanced liver disease

12 (11.3%)

8 (5.9%)

2.04 (0.80-5.198)

0.127

1.85 (0.62-5.56) 0.270

Metastatic solid tumor

10 (9.4%)

9 (6.6%)

1.47 (0.58-3.76)

0.419

16 (15.1%)

27 (19.9%)

12(11.3%)

18 (13.2%) 0.84 (0.38-1.82)

Receipt

of

0.72 (0.36-1.43) 0.337

Catheter-associated infection

8 (7.5%)

4 (2.9%)

2.69 (0.79-9.20)

Large vessel infection

8 (7.5%)

9 (6.6%)

1.15 (0.43-3.09)

0.654 0.102

24 (22.6%)

28 (20.6%) 1.13 (0.61-2.09)

0.700

Joint infection

17 (16.0%)

23 (16.9%) 0.94 (0.47-1.86)

0.856

Skin and soft tissue infection

27 (25.5%)

38(27.9%)

0.88 (0.50-1.57)

0.667

9 (8.5%)

10 (7.4%)

1.17 (0.46-2.99)

0.744

18 (17.0%)

16 (11.8%) 1.53 (0.74-3.18)

0.247

Metastatic complication

22 (20.8%)

11 (8.1%)

0.004

SOFA score

primary

bacteremia

0~1 2~5

10~

2.98 (1.37-6.46)

68 (50.0%)

50 (47.2%)

47 (34.6%) 2.68 (1.47-4.87)

0.001

1.95 (0.97-3.92) 0.061

21 (19.8%)

20 (14.7%) 2.64 (1.24-5.64)

0.011

1.62 (0.60-4.39) 0.343

AC C

8 (7.5%)

1

3.51 (1.47-8.37) 0.005

27 (25.5%)

EP

6~9

M AN U

Unknown,

SC

Bone infection

Respiratory tract infection

1.78 (0.44-7.24) 0.421

0.779

TE D

Endocarditis

RI PT

immunosuppressant

1

20.15 (2.40-

1 (0.7%)

-

11.93 (1.13-125.52) 0.039

<0.001 168.89)

MSSA, methicillin-susceptible Staphylococcus aureus; IQR, Interquartile range; SOFA, Sepsis-related Organ Failure Assessment.

The bold text indicates p<0.05.

ACCEPTED MANUSCRIPT

Table 3. Treatment outcomes of the propensity score-matched cefazolin group versus nafcillin group (1:1) among 158 MSSA

Propensity score-matched MSSA bacteremia

PDA due to adverse effects Antibiotic

change

due

OR

n=79

n=79

24 (30.4%)

39 (49.4%)

0.45 (0.23-0.86)

10 (12.7%)

24 (30.4%)

to 13 (16.5%)

11 (13.9%)

P-value

Propensity score-matched MSSA sepsis (sepsis 3) Cefazolin

SC

Nafcillin

Nafcillin

OR

P-

n=36

n=36

0.015

18 (50.0%)

22 (61.1%)

0.64 (0.25-1.62)

0.343

0.33 (0.15-0.75)

0.007

8 (22.2%)

12 (33.3%)

0.57 (0.20-1.63)

0.293

1.22 (0.51-2.91)

0.658

8 (22.2%)

7 (19.4%)

1.18 (0.38-3.67)

0.772

1.00 (0.14-7.28)

>0.999

1 (2.8%)

2 (5.6%)

0.49 (0.04-5.61)

>0.999

0.38 (0.07-2.04)

0.442

2 (5.6%)

5 (13.9%)

0.37 (0.07-2.02)

0.429

M AN U

Treatment failure

Cefazolin

RI PT

bacteremia and 72 MSSA sepsis cases

TE D

clinical failure

value

2 (2.5%)

2 (2.5%)

Death within 1 month

2 (2.5%)

5 (6.3%)

Persistent bacteremia

5 (6.3%)

11 (13.9%)

0.42 (0.14-1.26)

0.114

3 (8.3%)

6 (16.7%)

0.46 (0.10-1.99)

0.478

Death within 3 months

2 (2.5%)

10 (12.7%)

0.18 (0.04-0.85)

0.016

2 (5.6%)

7 (19.4%)

0.24 (0.05-1.27)

0.151

AC C

EP

Recurrence

MSSA, methicillin-susceptible Staphylococcus aureus; OR, odds ratio; PDA, premature discontinuation of antibiotics. The bold text indicates p<0.05.

ACCEPTED MANUSCRIPT

Table 4. Outcomes of cefazolin inoculum effect-positive versus -negative MSSA bacteremia in total propensity score-matched MSSA

Total

(n=24)

(n=86)

P-

CIE-P

CIE-N

value

(n=11)

(n=41)

12 (50.0%)

33 (38.4%)

1.61 (0.65-3.99)

0.306

4 (36.4%)

20 (48.8%)

PDA due to adverse effects

4 (16.7%)

21 (24.4%)

0.62 (0.19-2.02)

0.423

2 (18.2%)

Antibiotics change due to

7 (29.2%)

10 (11.6%)

3.12 (1.04-9.40)

0.053

Death within 1 month*

3 (12.5%)

2 (2.3%)

6.00 (0.94-38.24) 0.068

Recurrence

2 (8.3%)

1 (1.2%)

Persistent bacteremia

4 (16.7%)

Death within 3 months**

3 (15.4%)

Treatment failure

OR (95%CI)

Cefazolin

P-

CIE-P

CIE-N

value

(n=13)

(n=45)

0.60 (0.15-2.37)

0.463

8 (61.5%)

13 (28.9%)

3.94 (1.08-14.31) 0.049

13 (31.7%)

0.48 (0.09-2.54)

0.477

2 (15.4%)

8 (17.8%)

0.84 (0.16-4.55)

2 (18.2%)

5 (12.2%)

1.60 (0.27-9.63)

0.630

5 (38.5%)

5 (11.1%)

5.00 (1.17-21.39) 0.036

1 (9.1%)

2 (4.9%)

1.95 (0.16-23.73)

0.518

2 (15.4%)

0 (0%)

NC

7.73 (0.67-89.17) 0.119

1 (9.1%)

0 (0%)

NC

0.212

1 (7.7%)

1 (2.2%)

3.67 (0.21-63.03) 0.401

7 (8.1%)

2.26 (0.60-8.47)

0.251

2 (18.2%)

5 (12.2%)

1.60 (0.27-9.63)

0.630

2 (15.4%)

2 (4.4%)

3.91 (0.49-30.94) 0.214

5 (5.8%)

2.31 (0.51-10.47) 0.369

1 (9.1%)

5 (12.2%)

0.72 (0.08-6.89)

>0.999

2 (15.4%)

0 (0%)

NC

EP

TE D

clinical failure

OR (95%CI)

SC

CIE-N

Nafcillin

M AN U

CIE-P

RI PT

bacteremia cases (n=110), the nafcillin group (n=52), and the cefazolin group (n=58)

OR (95%CI)

value

AC C

MSSA, methicillin-susceptible Staphylococcus aureus; CIE-P and CIE-N, cefazolin inoculum effect-positive and -negative groups, respectively; OR, odds ratio; NC, not calculable.

* and ** : All-cause mortality within 1 month and 3 months.

P-

>0.999

0.047

0.047

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT