summaries

R E S E A R C H A R T I C L E Open Access Antibiotic use for Vibrio infections: important insights from surveillance data Kam Cheong Wong 1,2, Anthony M. Brown 2, Georgina M. Luscombe 2, Shin Jie Wong 1and Kumara Mendis 1* Abstract Background: There is a paucity of data on the in vivo efficacy of antibiotics for lethal Vibrio species. Analyses of long-term surveillance datasets may provide insights into use of antibiotics to decrease mortality.

Methods: The United States Centers for Disease Control and Prevention (CDC) Cholera and Other Vibrio Illness Surveillance (COVIS) dataset from 1990 to 2010, with 8056 records, was analysed to ascertain trends in antibiotics use and mortality.

Results: Two-thirds of patients (5243) were pr escribed antibiotics - quinolones (56.1 %), cephalosporins (24.1 %), tetracyclines (23.5 %), and penicillins (15.4 %). Considering all Vibrio species, the only class of antibiotic associated with reduced odds of mortality was quinolone (od ds ratio 0.56, 95 % CI 0.46-0.67). Patients with V. vulnificus treated according to CDC recommendations had lower mortality (quinolone alone: 16.7 %, 95 % CI 10.2-26.1; tetracycline plus cephalosporin: 21.7 %, 16.8-27.5; no antibiotic: 51.1 %, 45.6-56.7; each p < 0.001). Cephalosporin alone was associated with higher mortality (36.8 %, 28.2-46.3). For V. cholerae non-O1, non-O139, mortality rates were lower for quinolone (0 %, 0 –2.0) or tetracycline (4.3 %, 1.2-14.5) compared to no antibiotic (9.3 %, 6.4-13.3). For all Vibrio species, mortality rates increased with number of antibiotics in the treatment regimen (p < 0.001). Treatment regimens that included quinolone were associ ated with lower mortality rates regardless of the number of antibiotics used. The main cli nical syndromes of patients with V. vulnificus infection were septicaemia (53.1 %) and wound infections (30.6 %). Mortality among V. vulnificus patients with septicaemia was significantly higher than for other clinical syndromes (p < 0.001). In a multivar iate regression model, mortality in cases with V. vulnificus was associated with presence of pre-existing conditions (ORs ranged from 4. 52 to 10.30), septicaemia (OR 2.64, 95 % CI 1.92-3.63) and no antibiotic treatment (OR 7.89, 95 % CI 3.94-15.80).

Conclusion: In view of the lack of randomized control trials, surveillance data may inform treatment decisions for potentially lethal Vibriosis. Considering all Vibrio species, use of quinolones is associated with lower mortality and penicillin alone is not particularly effective. For the most lethal species, V. vulnificus , treatment that includes either quinolone or tetracycline is associated wi th lower mortality than cephalosporin alone . We recommend treating patients who present with a clinical syndrome suggestive of V. vulnificus infection with a treatment reg imen that includes a quinolone. Keywords: Vibrio infection, Vibriosis, Antibiotics, Antimicrobials, Surveillance * Correspondence: [email protected] 1Bathurst Rural Clinical School, School of Medicine, University of Western Sydney, PO Box 9008, Bathurst, NSW 2795, AustraliaFull list of author information is available at the end of the article © 2015 Wong et al. BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated. Wong et al. BMC Infectious Diseases (2015) 15:226 DOI 10.1186/s12879-015-0959-z Background The incidence of Vibrio infections, which can cause acute diarrhoea and potentially serious complications such as hypovolemic shock and septicaemia, continues to rise in the United States [1]. Vibrio vulnificus is the most lethal species, and there are limited data on the ef- fectiveness of antibiotic use in V. vulnificus infections [2]. In 1988, the Centers for Disease Control and Pre- vention (CDC) in the United States established a surveil- lance system for human infections caused by all species of Vibrio known as “Cholera and Other Vibrio Illness Surveillance ”(COVIS) [3]. This surveillance information has been used to inform healthcare providers and edu- cate the public [4].

Clinical trials indicate that using an effective antibiotic as an adjuvant therapy to treat V. cholerae reduces the duration of diarrhoea [5, 6] and illness by almost 50 % in patients with moderate and severe dehydration [6]. Stud- ies of treatment efficacy for lethal Vibrio species such as V. vulnificus , have inherent ethical difficulties and conse- quently there are no randomised control trials (RCT) of V. vulnificus in humans [2]. Animal model in vivo stud- ies of antibiotic sensitivities to Vibrio infection may not all be applicable to humans due to differences in phar- macokinetic parameters [7]. Recommendations for V. vulnificus infections from a recent review are largely based on case reports or animal models [8]. The CDC provides recommendations on treatment regimens for V. vulnificus ,V. parahaemolyticus and V. cholerae non-O1, non-O139 [4]. However only recommendations on treat- ing V. cholerae are based on a human RCT [4]. Observational studies on lethal Vibrio infections, using established surveillance data over a long defined period of time, may provide insights about the associations be- tween the use of antibiotics and patient outcomes. For example, Purcell et al. conducted a systematic review of the use of prophylactic antibiotics in the prevention of meningococcal disease and had to rely almost entirely on surveillance data to support their use [9]. Dechet and colleagues reviewed non-foodborne Vibrio infections using COVIS data (1997 to 2006) and concluded that the optimal antibiotic treatment for Vibrio infections re- mains unknown [10].

We have analysed COVIS data from 1990 to 2010: (a) to ascertain whether the COVIS data on antibiotic use were consistent with the CDC treatment recommenda- tions, and (b) to determine the relationship between antibiotic treatment and mortality.

Methods Study design and participants Data were obtained from the CDC ’s Enteric Diseases Epidemiology Branch from case report forms submitted to the COVIS during 1990 to 2010 [1]. COVIS data are collected using a standardised form [3]. The COVIS dataset included information on demographics, the Vibrio species isolated and the source of the specimen, clinical features (symptoms and signs), mortality, and pre-existing conditions and treatments during the 30 days prior to the Vibrio illness. The dataset also in- cluded information on whether or not the patient had an antibiotic as treatment for the Vibrio illness (i.e. yes, no, unknown), and if so, the name of the antibiotic/s.

Free text records of antibiotic names and some pre- existing conditions and treatments (specifically malig- nancy, immune disorders, proton pump inhibitors and antacids) were reviewed by authors KCW and SJW inde- pendently and classified using the Systematized Nomen- clature of Medicine - Clinical Terms (SNOMED CT®) system (SNOMED Premium Version 1.0) and then reviewed jointly to reach consensus [11]. Pre-existing conditions included heart disease, diabetes, liver disease, alcoholism, malignancy, renal disease, haematological disease and immune disorders. SNOMED CT® codes were used to classify antibiotics into antimicrobial classes (e.g. quinolone, cephalosporin), antimicrobial subclasses (e.g. first, second and third generation cephalosporins) and to standardise and review pre-existing conditions and treatments (e.g. free text records of gastric surgery were reviewed and those considered irrelevant, such as hernia repair, were removed).

There were 8950 patients in the COVIS dataset, 6137 (68.6 %) of whom were recorded as having had antibi- otics as treatment for their Vibrio illness. However, the specific name of the antibiotic was not recorded for 894 (14.6 %). A sensitivity analysis, whereby results were compared for analyses which either included or excluded the 894 patients who had an unnamed antibiotic for the Vibrio illness, was performed. There were no substantial differences in terms of their epidemiological information and mortality rates, and consequently the patients with- out a named antibiotic were excluded from subsequent analyses, resulting in a final sample size of N = 8056.

Statistical analysis For the purposes of analysis, where antibiotic use was recorded in COVIS as ‘unknown ’this was recoded as ‘ no ’antibiotic used. Similarly, where data were missing or recorded as ‘unknown ’for clinical signs or symptoms, pre-existing conditions or treatments, or mortality, they were recoded as ‘absent ’or ‘no ’for analysis. Based on re- ported symptoms, patients with V. vulnificus were classi- fied into the following clinical syndrome groups: (i) septicaemia, characterised by the isolation of the organ- ism from blood AND the presence of either fever or shock; (ii) gastroenteritis, defined as the presence of blood in stool, OR both diarrhoea and vomiting, OR any gastrointestinal symptom AND the isolation of organism Wong et al. BMC Infectious Diseases (2015) 15:226 Page 2 of 9 from stool; (iii) wound infection, characterised by cellu- litis OR bullae OR fever in the absence of septicaemia, where the organism was isolated from a wound only; or (iv) other (not meeting any of the other criteria). Where a patient met the criteria for more than one clinical syn- drome, septicaemia took precedence over gastroenteritis, and gastroenteritis over a wound infection.

Skewed continuous data were reported as medians with an interquartile range (IQR). Associations between demographics, antibiotic use and mortality were ex- plored using unadjusted odds ratios with 95 % confi- dence intervals. Chi-square analyses explored univariate associations between factors such as antibiotic use and mortality. The association between the total number of antibiotics used and mortality was explored using the linear-by-linear association chi-square test. A series of univariate logistic regression models were conducted on the sub-sample of patients with V. vulnificus to deter- mine predictors of mortality. Variables in these regres- sion analyses included age, gender, year of notification, number of pre-existing conditions, clinical syndrome presentation and type of antibiotic regimen (quinolone only; quinolone and another antibiotic; at least one anti- biotic, but not quinolone; or no antibiotic at all). Un- adjusted odds ratios (OR) and 95 % confidence intervals (CIs) were produced. A multivariate logistic regression analysis was also conducted, including all of these vari- ables, to produce adjusted ORs and 95 % CIs.

All analyses were conducted using SPSS (version 21; IBM, 2012) and αwas set at p < 0.05. Ethics committee approval All data were de-identified and the CDC confirmed that ethics approval and informed consent were not applic- able for this research.

Results Of the 8056 patients, the median age was 47 years (IQR 33 to 62 years; N = 7773). Over two-thirds of the patients were male (68.6 %; 5424/7905) and 98.3 % (7921/8056) of the patients had only one Vibrio species identified. 127 (1.6 %) patients had two species and eight (0.1 %) patients had three Vibrio species identified. The most commonly identified species were V. parahaemolyticus, V. vulnificus, V. alginolyticus and the non-O group strains of V. cholerae (Table 1). The proportion of fatal cases differed by Vibrio species, the greatest being in those with V. vulnificus (Table 1). Cases of V. parahaemolyticus in- creased dramatically over time, with peaks in 1998, 2004, 2006 and 2009 –10, and there was a steady increase in cases of V. alginolyticus (Fig. 1). Peak incidence typically occurred during the summer months (June to August, 52.6 % of cases). There were 5243 (65.1 %) patients who had an anti- biotic as treatment for their Vibrio illness. The most commonly used antibiotics were quinolones (56.1 %), followed by cephalosporins (24.1 %), tetracyclines (23.5 %) and penicillins (15.4 %). The use of quinolones in- creased considerably after 1996 with peaks around 1997, 2005, and 2010, while the use of cephalosporin, tetracycline and penicillin rose only slowly from 1990 to 2010 (Fig. 2).

A total of 602 (7.5 %) patients with a Vibrio illness were recorded as deceased. Mortality was significantly associated with being male (OR 2.10, 95 % CI 1.70-2.59).

Bullae (present in 7.3 % of cases), and shock (6.5 %) were associated with significantly increased odds of mortality (OR 8.67, 95 % CI 7.11-10.58; OR 28.49, 95 % CI 23.18- 35.01 respectively). Presence of at least one of the eight pre-existing conditions (33.2 %) significantly increased risk of death (OR 16.83, 95 % CI 13.18-21.49); in par- ticular, a history of liver disease (10.6 %; OR 18.81, 95 % CI 15.63-22.63) and alcoholism (8.9 %; OR 13.50, 95 % CI 11.19-16.27).

The association between antibiotic classes (use of at least one antibiotic of a particular class in a treatment regimen) and mortality is presented by Vibrio species in Table 2. Considering all patients, regardless of Vibrio species, the only class of antibiotic associated with re- duced odds of mortality was quinolone (OR 0.56, 95 % Table 1 Vibrio species, mortality and gender distribution; United States cases during 1990 to 2010 (N = 8056) Vibrio species Total n (%) Mortality n (%) Male n (%) V. parahaemolyticus 3474 (43.1) 29 (0.8) 2243 (66.1) V. vulnificus 1599 (19.8) 491 (30.7) 1367 (86.4) V. alginolyticus 874 (10.8) 11 (1.3) 589 (69.1) V. cholerae non-O1, non-O139 763 (9.5) 41 (5.4) 474 (62.9) V. fluvialis 445 (5.5) 13 (2.9) 243 (56.0) V. cholerae O1 269 (3.3) 4 (1.5) 137 (51.1) V. mimicus 211 (2.6) 5 (2.4) 116 (55.0) V. hollisae a 131 (1.6) 1 (0.8) 79 (61.2) P. damsela b 63 (0.8) 3 (4.8) 45 (71.4) V. cholerae O139 28 (0.3) 0 (0.0) 15 (57.7) V. furnissii 19 (0.2) 1 (5.3) 13 (76.5) V. metschnikovii 14 (0.2) 1 (7.1) 7 (53.8) V. cincinnatiensis 2 (<0.1) 0 (0.0) 1 (50.0) Species not identified 279 (3.5) 9 (3.2) 169 (61.7) Other, no further information 28 (0.3) 0 (0.0) 16 (64.0) Total n/a 602 (7.5) 5424 (67.3) N.B. some patients had more than one species isolated, so numbers total to N=8199Proportions here are of the total patients, not total species identifiedInformation on gender was missing for n=151aFormerly Vibrio hollisae , now Grimontia hollisae [2] bFormerly Vibrio damsela , now Photobacterium damsela Wong et al. BMC Infectious Diseases (2015) 15:226 Page 3 of 9 CI 0.46-0.67). This association held for those patients with V. vulnificus (OR 0.58, 95 % CI 0.46-0.73), and V. cholerae (non-O1, non-O139) (OR 0.12, 95 % CI 0.04- 0.40). Cephalosporin was associated with an increased odds of mortality (OR 2.60, 95 % CI 2.16-3.13) overall, and notably for V. parahaemolyticus (OR 6.41, 95 % CI 2.89-14.24). For those patients with V. vulnificus infec- tion, use of the antibiotics quinolone, cephalosporin and tetracycline was associated with significantly lower mor- tality rate while use of penicillin was equivocal.

There was a statistically si gnificant positive associ- ation between the mortality rates and the number of antibiotics used in a treatment regimen (linear by linear association = 172.90, p < 0.001). Irrespective of Vibrio species, a treatment regimen that included a quinolone was always associated with lower mortality rate regard- less of the total number of antibiotics in the treatment regimen (Fig. 3a). Whether or not the treatment regimen included a cephalosporin, tetracycline, or penicillin was not associated consistently with the mortality rate (Fig. 3b, c, d).

Tables 3 and 4 show the mortality associated with vari- ous antibiotic regimens (including CDC recommenda- tions) for treating Vibrio vulnificus and Vibrio cholerae non-O1, non-O139 infections. Mortality rates for V. vul- nificus were significantly lower in those patients taking quinolone only or tetracycline combined with a third generation cephalosporin as per CDC recommendations (Table 3). Using quinolone as a reference, comparison between the CDC recommended combination (i.e. tetra- cycline and third generation cephalosporin) and other combinations that included quinolone, showed no statis- tically significant differences, except the comparison with taking a cephalosporin alone or a penicillin alone or no antibiotic (p = 0.002, p = 0.024, p < 0.001 respect- ively; Table 3). For V. cholerae (non O1 and non-O139) , only use of quinolone alone was associated with a sig- nificantly lower mortality rate (Table 4). 0 50 100 150 200 250 300 350 400 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Number of cases V. parahaemolyticus V. vulnificus V. alginolyticus V. cholerae non-O1, non-O139 V. cholerae O1 V. cholerae O139 Fig. 1 Patients with Vibrio infections over time, 1990 –2010, in United States 0 50 100 150 200 250 300 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Number of patients Year Quinolones Cephalosporins Tetracyclines Penicillins Fig. 2 Patterns of antibiotic use in the United States for patients with Vibrio illness: 1990 to 2010 (N = 5243) Wong et al. BMC Infectious Diseases (2015) 15:226 Page 4 of 9 Considering only V. vulnificus, 53.1 % (839/1581) had septicaemia, 4.5 % (71) had gastroenteritis, 30.6 % (484) had a wound infection, and 11.8 % (187) had other clin- ical presentation. Eighteen cases were excluded because they could not be classified as information on the sam- ple source was missing. Cases with septicaemia were more likely to fatal (40.6 %, 341/839), followed by 28.9 % (54) of those with other presentation, 28.2 % (20) of those with gastroenteritis and 14.3 % (69) of those with wound infections (p < 0.001). A series of logistic regres- sion analyses with single predictor variables was con- ducted, with year of notification dichotomised into 1990 to 1996 versus 1997 to 2010 to reflect the significant in- crease in quinolone use from 1996 observed in Fig. 2.

The crude odds of mortality amongst those with V. vul- nificus increased significantly with the number of pre- existing conditions (see Table 5). In comparison to wound infections, all other clinical syndromes conferred increased odds of dying. Compared to quinolone alone, an antibiotic regimen without quinolone, and no anti- biotic use at all were associated with increased odds of mortality. The multivariate analysis on mortality for pa- tients with V. vulnificus infection showed the same patterns for number of pre-existing conditions. Gastroenteritis no longer conferred significantly greater odds of dying over wound infections, but septicaemia and other clin- ical syndrome did. In the adjusted model, quinolone alone remained superior in comparison to no antibiotic treatment.

Discussion Using this large surveillance dataset covering more than two decades, we determined that the two most import- ant factors associated with mortality are the particular Vibrio species and the class of antibiotic used. Quin- olone is the only class of antibiotic associated with lower mortality in all Vibrio species, regardless of the number of antibiotics used in a treatment regimen. In potentially lethal V. vulnificus infections, the use of quinolone alone or the combination of tetracycline and third generation cephalosporin had the lowest mortality which is in-line with the current CDC recommendations.

Penicillin was the least effective antibiotic for vibriosis according to our analysis . In 1984, the USA National Institutes of Health recommended use of penicillin or tetracycline to treat V. vulnificus based on in vitro sen- sitivity studies [12]. Morris cautioned that in vitro data can be misleading, and recommended against using penicillin as a single antibiotic to treat V. vulnificus in- fections in humans [13]. In 2002, Tang conducted a study on mice and reported that quinolones as single antibiotics were as effective as cefotaxime-minocycline (third generation cephalosporin and tetracycline) in combination [7]. However Tang cautioned that results of animal models may not be applicable to humans due to differences in pharmacokinetic parameters [7]. Our findings support Morris ’s caution against penicillin as a single antibiotic (i.e. penicillin was not associated with reduced mortality) and substantiate Tang ’s previous find- ings in animals (i.e. third generation cephalosporin and Table 2 Mortality and antibiotic use, by type of Vibrio illness (N = 8056) All Vibrio species Alive n = 7454 Deceased n = 602 Crude Odds Ratio (95% CI) Received at least one antibiotic 65.1% 64.6% 0.98 (0.82-1.16) At least one quinolone 37.4% 24.9% 0.56 (0.46-0.67) At least one cephalosporin 14.5% 30.6% 2.60 (2.16-3.13) At least one tetracycline 14.5% 25.1% 1.98 (1.63-2.40) At least one penicillin 9.5% 15.8% 1.78 (1.41-2.25) V. parahaemolyticus n = 3445 n = 29 Received at least one antibiotic 56.5% 65.5% 1.46 (0.68-3.15) At least one quinolone 39.8% 37.9% 0.93 (0.44-1.97) At least one cephalosporin 6.6% 31.0% 6·41 (2.89-14.24) At least one tetracycline 7.3% 20.7% 3.29 (1.33-8.16) At least one penicillin 4.6% 3.4% 0.75 (0.10-5.53) V. vulnificus n = 1108 n = 491 Received at least one antibiotic 86.6% 68.2% 0.33 (0.26-0.43) At least one quinolone 37.1% 25.5% 0.58 (0.46-0.73) At least one cephalosporin 42.3% 33.2% 0.68 (0.54-0.85) At least one tetracycline 47.5% 27.3% 0.42 (0.33-0.52) At least one penicillin 18.5% 17.7% 0.95 (0.72-1.25) V. alginolyticus n = 863 n = 11 Received at least one antibiotic 76.0% 36.4% 0.18 (0.05-0.62) At least one quinolone 29.7% 18.2% 0.53 (0.11-2.46) At least one cephalosporin 23.6% 18.2% 0.72 (0.15-3.35) At least one tetracycline 10.0% 0.0% n/a At least one penicillin 19.1% 9.1% 0.42 (0.05-3.33) V. cholerae non-O1, non- O139 n = 722 n = 41 Received at least one antibiotic 66.1% 39.0% 0.33 (0.17-0.63) At least one quinolone 39.3% 7.3% 0.12 (0.04-0.40) At least one cephalosporin 9.4% 19.5% 2.33 (1.04-5.25) At least one tetracycline 12.3% 19.5% 1.72 (0.77-3.85) At least one penicillin 9.6% 7.3% 0.75 (0.23-2.48) n/a not applicable Wong et al. BMC Infectious Diseases (2015) 15:226 Page 5 of 9 tetracycline in combination are more effective). More re- cently Shaw and colleagues evaluated the antimicrobial susceptibility of V. vulnificus recovered from two commer- cial environmental areas and found that V. vulnificus dem- onstrated resistance to penicillin [14], which may further confirm the inefficacy of penicillin.

For V. cholerae (non-O1, non-O139), quinolone was the only class of antibiotic associated with lower mortality rate. For V. parahaemolyticus, quinolone and penicillin appeared to have equivocal odds ratios for mortality; while cephalosporin and tetracycline were associated with higher mortality. However, the total number of deaths from V. cholerae was 41 and for V. parahaemolyticus was 29, so conclusions are limited.

Generally, the mortality rate increased along with the number of antibiotics used in the treatment regimen.

We postulated that seriously ill patients were given more than one antibiotic and were associated with increased Fig. 3 aMortality by use of quinolone in treatment regimen. bMortality by use of cephalosporin in treatment regimen. cMortality by use of tetracycline in treatment regimen. dMortality by use of penicillin in treatment regimen. ** indicates a statistically significant difference at p < 0.001, * indicates a statistically significant difference at p < 0.05. n = 3132 used one antibiotic; 1305 used two antibiotics; 652 used three antibiotics; 154 used four antibiotics Table 3 Mortality associated with various antibiotic regimens in the treatment of V. vulnificus (n=1599) Na Crude mortality % (95% CI) Comparison with Quinolone only p value CDC treatment recommendation b Quinolone only 14/84 16.7 (10.2-26.1) - Tetracycline + cephalosporin (all generations) 49/226 21.7 (16.8-27.5) 0.329 Tetracycline + 3 rdgeneration cephalosporin 39/182 c 21.4 (16.1-28.0) 0.366 Other combinations Quinolone + cephalosporin (all generations) 24/98 24.5 (17.1-33.9) 0.195 Quinolone + tetracycline 15/95 15.8 (9.8-24.4) 0.874 Quinolone + cephalosporin + tetracycline 15/87 17.2 (10.7-26.5) 0.920 Other single antibiotics Tetracycline alone 30/145 20.7 (14.9-28.0) 0.456 Cephalosporin alone (all generations) 39/106 36.8 (28.2-46.3) 0.002 Penicillin alone 18/54 33.3 (22.2-46.6) 0.024 No antibiotic 156/305 51.1 (45.6-56.7) <0.001 an=399 patients with less common antibiotic regimens not included here, thus numbers do not total to n=1599bhttp://www.cdc.gov/vibrio/vibriov.html (accessed 27 June 2014): “Doxycycline (100 mg PO/IV twice a day for 7-14 days) and a third-generation cephalosporin (e.g. ceftazidime 1-2 g IV/IM every eight hours) are generally recommended. A single agent regimen with a fluoroquinolone such as levofloxacin, ciproflox acin or gatifloxacin, has been reported to be at least as effective in an animal model as combination drug regimens with doxycycline and a cephalosporin ” cn=182 patients are a subset of the n=226 patients with a tetracycline combined with a cephalosporin Wong et al. BMC Infectious Diseases (2015) 15:226 Page 6 of 9 number of antibiotics in their treatment; hence, their mortality rate was higher possibly because they were sicker instead of due to the larger number of antibiotics used. We found that quinolone was the only antibiotic associated with reduced mortality rate regardless of the number of antibiotics in the patient ’s regimen. We have shown an increase in use of quinolone after 1996 but this may be a reflection of increased use in the wider community. Linder and colleagues have reported a three-fold increase in prescribing quinolone between 1995 and 2005 in the United States adult population [15]. This increase in quinolone prescription may not necessarily reflect increased recognition of the efficacy of this antibiotic amongst prescribers or the promulga- tion of treatment guidelines. It is likely that marketing, advertising and provision of sample antibiotics might have partly contributed to the increase in prescribing of newer antibiotics [15 –17]. We found associations between liver disease, alcohol- ism and previous ill health and mortality with all species.

For V. vulnificus the number of pre-existing conditions was associated with increased odds of mortality in both unadjusted and adjusted models. Others have found that patients with liver disease or alcoholism are at higher risk of V. vulnificus infection [10, 18, 19]. This may be Table 4 Mortality associated with various antibiotic regimens in the treatment of V. cholerae non-O1, non-O139 (n=763 a) N Crude mortality % (95% CI) Comparison with Tetracycline aloneFET p value CDC treatment recommendation b Tetracycline alone 2/46 4.3 (1.2-14.5) - Other single antibiotics Quinolone alone 0/ 192 0.0 (0.0-2.0) 0.037 Penicillin alone 1/38 2.6 (0.5-13.5) 1.000 Cephalosporin alone 2/29 6.9 (1.9-22.0) 0.638 No antibiotic 25/ 270 9.3 (6.4-13.3) 0.395 FET fisher ’s exact test an=188 patients with less common antibiotic regimens not included here, thus numbers do not total to n=763bhttp://www.cdc.gov/cholera/treatment/antibiotic-treatment.html (accessed 27 June 2014): “Antibiotic choices should be informed by local antibiotic susceptibility patterns. In most countries, doxycycline is recommended asfirst-line treatment for adults, while azithromycin is recommended as first-linetreatment for children and pregnant women ” Table 5 Predictors of death in cases of V. vulnificus in the United States during 1990 to 2010 Fatal N (%) Non-fatal N (%) Crude OR (95% CI) Adjusted OR (95% CI) Age, mean (SD) 56.6 (13.5) 58.0 (17.8) 0.995 (0.989-1.001) 0.99 (0.98-0.998) Gender Female 72 (15.2) 135 (12.6) reference reference Male 402 (84.8) 939 (87.4) 0.80 (0.59-1.09) 0.70 (0.49-1.000) Year of notification 1990 –1996 103 (21.7) 194 (18.1) reference reference 1997 –2010 371 (78.3) 880 (81.9) 0.79 (0.61-1.04) 0.99 (0.73-1.34) Pre-existing conditions 0 41 (8.6) 397 (37.0) reference reference 1 107 (22.6) 277 (25.8) 3.74 (2.53-5.53) 4.52 (2.92-6.99) 2 194 (40.9) 227 (21.1) 8.28 (5.69-12.03) 10.30 (6.72-15.78) 3 or more 132 (27.8) 173 (16.1) 7.39 (4.99-10.95) 9.31 (5.93-14.62) Clinical presentation Wound 68 (14.3) 406 (37.8) reference reference Gastroenteritis 20 (4.2) 49 (4.6) 2.44 (1.36-4.35) 1.52 (0.77-3.01) Septicaemia 333 (70.3) 493 (45.9) 4.03 (3.01-5.40) 2.64 (1.92-3.63) Other 53 (11.2) 126 (11.7) 2.51 (1.67-3.79) 1.69 (1.04-2.74) Antibiotic treatment Quinolone only 13 (2.7) 68 (6.3) reference reference Quinolone and other/s 106 (22.4) 335 (31.2) 1.66 (0.88-3.12) 1.44 (0.73-2.84) Antibiotic/s, not quinolone 208 (43.9) 534 (49.7) 2.04 (1.10-3.77) 1.84 (0.95-3.56) None 147 (31.0) 137 (12.8) 5.61 (2.97-10.62) 7.89 (3.94-15.80) Wong et al. BMC Infectious Diseases (2015) 15:226 Page 7 of 9 because V. vulnificus uses transferrin-bound iron, which is usually abundant in these patients, for growth [18, 20]. Another hypothesis about the increase mortality in the presence of liver disease is that the shunting of por- tal blood containing V. vulnificus infection around a dis- eased liver may lead to septicaemia [21]. The main clinical syndromes in patients with V. vulnificus infec- tion were septicaemia and wound infections. Mortality among V. vulnificus patients with septicaemia was sig- nificantly higher than for other clinical syndromes. A treatment regimen that included quinolone was associ- ated with lower mortality compared with cephalosporin alone or penicillin alone or no antibiotic at all. We rec- ommend that patients who present with a clinical syn- drome suggestive of V. vulnificus infection be treated with a regimen that includes a quinolone.

There are a number of limitations to this study that re- late to the underlying surveillance data collection. For example, non-cholera vibriosis only became nationally notifiable in USA from 2007 onwards [22]. Several per- tinent details regarding use of antibiotics were not re- corded systematically such as timing or order of antibiotic use. There were 894 patients who had an un- named antibiotic for the Vibrio infection. Cephalospo- rins could not be categorised into the four generations due to the small subgroup size. This may have contrib- uted to the paradoxical observation in Table 2 where a treatment regimen that had included a cephalosporin was associated with increased mortality rate in V. chol- era (non-O1 and non-O139) and V. parahaemolyticus in- fections, but reduced mortality elsewhere. The dataset did not detail specific cause of death, but an infection such as Vibrio is likely to have been significant. Further characterisation of liver disease (type and severity) was not possible due to the inconsistency of these data in the COVIS dataset. Finally, it is possible that the use and ef- fectiveness of different antibiotics reflect changes in the antibiotic sensitivities of the organism, however we are unable to explore this with the data available in the COVIS dataset.

Determining the optimal antibiotic regimen for a po- tentially lethal infection is difficult because randomised controlled trials may not be possible and in vitro or ani- mal models may not be easily applied in patients. In this context, systematic experience from detailed surveillance data may inform treatment decisions. However informa- tion from surveillance data is only as good as the data collected. The COVIS dataset may not have included every Vibrio cases and reporting may have been biased towards more severe cases [22]. It is important that cli- nicians provide detailed and timely data to surveillance programs such as COVIS. Publication of findings from surveillance data may help encourage clinicians to pro- vide specific data regarding antibiotic use. Surveillance authorities must be encouraged to simplify and refine the data collection tools and seek more specific informa- tion on classes of antibiotics and the time frame of their use so that the influence of these important factors can be reported and analysed.

Conclusions Surveillance of large numbers of affected individuals over longer periods of time appears to be a reasonable method of determining antibiotic use and outcome pat- terns. Vibrio infection remains a serious condition with significant mortality. Adjuvant antibiotic therapy in addition to basic care with fluids has an important role.

The use of quinolones may reduce risk of death in pa- tients with V. vulnificus and V. cholerae (non-O1 and non-O139). For V. vulnificus , which has the highest mortality rate, a treatment regimen which is in line with the CDC recommendations i.e. that includes either quin- olone alone, or tetracycline and a third generation ceph- alosporin is associated with lower mortality. Penicillin alone is not particularly effective. We recommend treat- ing patients who present with a clinical syndrome sug- gestive of V. vulnificus infection with a treatment regimen that includes a quinolone.

Competing interests No authors have any commercial or other association that might pose aconflict of interest (e.g., pharmaceutical stock ownership, consultancy,advisory board membership, relevant patents, or research funding). The University of Western Sydney and the University of Sydney have no conflict of interest in the content and publication of this paper.

Authors ’contributions All authors participated in the conceptualisation of the research objectives and methods. KCW and SJW performed the coding of variables with freetext fields using SNOMED-CT. GL managed and analysed the data. KCW, AB,and GL wrote the manuscript; and all authors reviewed and approved the manuscript.

Acknowledgements We would like to thank Dr Hazel Dalton at the School of Rural Health, University of Sydney for her assistance in the research grant application; Ms Anna Newton at the CDC for providing access to the COVIS dataset; and theUniversity of Western Sydney (UWS) for providing an Early Career ResearchGrant to KCW; and Professor Annemarie Hennessy (Dean of the School of Medicine, University of Western Sydney) for her valuable comments to our manuscript.

Declaration The content of this manuscript has not been presented in any meeting at the time of submission of this manuscript to the journal.

Funding This work was supported by the University of Western Sydney (Conjoint Early Career Research Grant awarded to author KCW).

Author details1Bathurst Rural Clinical School, School of Medicine, University of Western Sydney, PO Box 9008, Bathurst, NSW 2795, Australia. 2School of Rural Health, Sydney Medical School, University of Sydney, PO Box 1191, Orange 2800 NSW,Australia.

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