Abstract
Background
Necrotizing fasciitis (NF) caused by Vibrio species is a rapidly progressing, life‐threatening infection. The purposes of this study were to characterize polymicrobial Vibrio NF and compare its clinical features, microbiology, antimicrobial therapy, and outcomes with those of monomicrobial Vibrio NF, and to evaluate the effective usage of empirical antibiotics.
Methods
One hundred and ninety‐four patients surgically confirmed with Vibrio NF were retrospectively reviewed, in which 180 (92.8%) patients were infected by Vibrio vulnificus. There were 179 patients (92.3%) with a monomicrobial infection and 15 (7.7%) with polymicrobial infections. Clinical characteristics, outcomes, laboratory data, and antibiotic usage were analyzed and compared between the two groups.
Results
Twenty‐nine patients with Vibrio NF died (14.9%). Mortality was 15.6% (28/179) in the monomicrobial group and 6.7% (1/15) in the polymicrobial group. Among the 15 polymicrobial cases, 14 were caused by Vibrio vulnificus and 1 by Vibrio parahaemolyticus. Gout was more frequently observed in the polymicrobial group (4/15) than in the monomicrobial group (11/179). Vibrio isolates showed high susceptibility to third‐generation cephalosporins, fluoroquinolones, and tetracyclines. Effective antimicrobial therapy was associated with lower mortality (p = 0.002) and lower amputation rates (p = 0.004).
Conclusions
Polymicrobial Vibrio NF was uncommon but was not clinically less severe than monomicrobial Vibrio NF in this 20‐year cohort. Patients with polymicrobial infection more frequently had gout, suggesting a potential clinical association that warrants further investigation. These findings indicate that suspected polymicrobial Vibrio NF should be treated with the same urgency as monomicrobial disease, with prompt surgery, intensive care, and empirical antimicrobial therapy covering both Vibrio species and relevant copathogens.
Keywords: empirical antibiotic, necrotizing fasciitis, polymicrobial, third-generation cephalosporins, Vibrio
1. Introduction
Necrotizing fasciitis (NF) is a life‐threatening soft tissue infection with a high mortality rate of 10.3%–76% which need early diagnosis, emergent surgical intervention, intensive care, and effective antibiotic treatment [1–4]. NF is categorized as Type I (polymicrobial infection with aerobic and anaerobic bacteria), Type II (Group A β‐hemolytic Streptococcus spp. and Staphylococcus aureus), Type III (Gram‐negative pathogens), and Type IV (fungal infection) [1–8]. Staphylococcus aureus and group A Streptococcus spp. were the predominant pathogens causing NF in the United States and Europe; however, monomicrobial Gram‐negative pathogens, such as Vibrio spp., Aeromonas spp., Escherichia coli, and Klebsiella spp., were the most frequently isolated microorganisms in Asia [1–12]. Vibrio NF has been reported to present more clinical fulminant course and bullous skin progression than other pathogens, and Vibrio spp. were particularly concerning due to their rapid progression and high mortality rates of up to 18.6–42.9% [5–8].
Vibrio species naturally live in coastal areas, such as saltwater and brackish water, and can cause acute gastrointestinal diseases, necrotizing soft tissue infections (NSTIs), and primary sepsis in humans, which were typically associated with minor trauma and exposure to seawater or raw seafood [1, 3, 5–13]. Chiayi Chang Gung Memorial Hospital (CGMH) is a tertiary teaching hospital near Taiwan’s western coast where residents are often exposed to seawater, brackish water, and raw seafood, and Vibrio vulnificus (V. vulnificus) is the most frequent causative organism of monomicrobial NF [3, 9–13]. We set the Vibrio NSSTIs Treatment and Research (VTR) Group, including emergency medicine, orthopedics, infectious disease specialists, microbiologists, ICUs, plastic surgeons, and hyperbaric oxygen specialists, and have successfully decreased the mortality rate of Vibrio NF from 38% to 9.7% [5–7, 9, 12].
Although the clinical presentations of monomicrobial and polymicrobial NF were difficult to differentiate at initial presentation because of similar skin lesions, progressive erythematous changes, and pain out of proportion observed in the emergency department, we immediately performed emergent fasciotomy or limb amputation promptly based on clinical assessment, while definitive microbiological identification from blood and tissue cultures became available several days later [3, 5–7, 9, 12]. It was found that monomicrobial and polymicrobial NF exhibited significant differences in shock (hypotension at presentation, defined as systolic blood pressure < 90 mmHg), intensive care unit (ICU) admission, in‐hospital mortality, and 90‐day mortality [1, 2, 14]. Our previous studies revealed that those patients with polymicrobial Aeromonas NF had lower mortality rates than those with monomicrobial Aeromonas NF [10, 11]. Previous studies have primarily focused on monomicrobial Vibrio NF, general NSTI cohorts, or small case series involving Vibrio species; however, most studies did not specifically analyze polymicrobial Vibrio NF as a distinct subgroup [1–15]. Therefore, we focused on the exploratory and observational nature of the clinical findings between monomicrobial and polymicrobial Vibrio NF.
The purposes of this study were to compare the differences and the clinical outcomes between polymicrobial and monomicrobial Vibrio NF patients, to characterize polymicrobial Vibrio NF and compare its clinical features, microbiology, antimicrobial therapy, and outcomes with those of monomicrobial Vibrio NF, and to evaluate the effective usage of empirical antibiotic regimens.
2. Materials and Methods
2.1. Study Design
From January 2002 until December 2021, the VTR Group conducted a retrospective cohort study at CGMH‐Chiayi. A total of 261 patients were diagnosed with limb Vibrio soft tissue infections after arriving at the emergency room (ER). Of these, 64 patients with non‐NSTIs were excluded (Figure 1). Three patients were excluded due to a lack of admission data: one expired shortly after arrival at the ER, and two transferred to other hospitals before admission. A total of 194 patients with Vibrio NF of extremities were included in the study.
FIGURE 1.
Flowchart of 194 patients with Vibrio necrotizing fasciitis.
2.2. Clinical Assessment
We have established the treatment strategy and protocol including emergency fasciotomy or amputation, initial empiric antibiotic therapy with a third‐generation cephalosporin with/without other regimens, and admission to the ICU for patients with fulminant clinical presentation wherein NF was diagnosed at ER. The study enrolled patients with Vibrio NF of limbs based on the following criteria: (1) The diagnosis of NF was confirmed by surgical findings, which included grayish necrotic skin, subcutaneous fat, and fascia, as well as a purulent discharge reminiscent of dishwasher odors [8, 15]; (2) histopathological examination of the tissue confirmed the diagnosis [16]; (3) Vibrio species were isolated from soft tissue lesions and blood collected immediately after the patient arrived in the ED or during surgery [8, 15]; and (4) limbs were infected by these bacteria.
Routinely, blood cultures were collected in the ER, and wound cultures were obtained during the first surgery. The patients were divided into monomicrobial and polymicrobial groups based on the infecting organism identified in their cultures. The monomicrobial NF was demonstrated by single Vibrio infection, and the polymicrobial NF was defined as Vibrio spp. combined with other bacterial isolates in patients. Vibrio spp. was considered the predominant organisms when they demonstrated heavy growth (3+ or 4+ in the semi‐quantitative grading system) and clearly exceeded the growth of other coisolated organisms in colony number and surface coverage on the agar plates. When other organisms were present only in light or moderate quantities (1+ or 2+ growth), Vibrio spp. were classified as the predominant pathogens in culture.
Based on antimicrobial susceptibility testing, effective antimicrobial usage is defined as supplying coverage to all infectious isolates, and combination therapy was defined as third‐generation cephalosporin with doxycycline or fluoroquinolones [17, 18]. The associations of effective antimicrobial therapy, combination therapy, and third‐generation cephalosporin plus doxycycline with mortality and amputation rates were analyzed. The patients’ characteristics, demographics, chronic illness history, clinical presentations with laboratory data at the time of admission to the ER, operation records, microorganisms, antibiotic regimens, usage, and outcomes were compared between the two groups.
2.3. Microbiology Laboratory Procedures
Primary culture isolates from wound and blood specimens were identified by Gram staining, serological agglutination, and conventional biochemical tests in the earlier study period. In the past decade, species identification was further confirmed using matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) with the Bruker Microflex LT/SH Biotyper system. Vibrio isolates were identified based on colony morphology on TCBS agar, Gram staining, serological agglutination with specific antisera, and biochemical characteristics. The isolates were Gram‐negative straight or slightly curved motile rods, oxidase‐ and catalase‐positive, sensitive to the vibriostatic agent O/129 (150 µg), and fermentative. Conventional biochemical tests included oxidase, H2S production, motility, indole, methyl red, Voges–Proskauer, and salt tolerance tests. Further confirmation was performed using the API 20E system (bio‐Mérieux Inc., Hazelwood, MO, USA) according to the manufacturer’s protocol. Antimicrobial susceptibility testing was performed using routine clinical laboratory methods according to the contemporaneous guidelines and breakpoint criteria of the Clinical and Laboratory Standards Institute throughout the study period.
2.4. Statistical Analysis
We used the Student’s t‐test and ANOVA for continuous variables and the Fisher exact test for categorical variables. The significance of the results was determined by p values < 0.05 with two‐tailed tests. Data were analyzed using IBM SPSS Statistics Version 20. Multivariable logistic regression analysis was performed to identify independent predictors of mortality between monomicrobial and polymicrobial NF. Unadjusted odds ratio analysis and multivariable logistic regression analysis were performed in a stepwise manner to determine the significance of effective antimicrobial therapy and clinical outcomes. Variables with p value < 0.05 in univariate analysis or with clinical relevance were included in the regression model. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported.
3. Results
Twenty‐nine patients died with a mortality rate of 14.9% (29/194), and 18 patients had received amputation with an amputation rate of 9.3% (18/194). There were 179 patients (92.3%) with a monomicrobial infection, and 15 patients (7.7%) with a polymicrobial infection. All Vibrio isolates were susceptible to ceftazidime, ceftriaxone, levofloxacin, and tetracycline.
3.1. Characteristics of the Monomicrobial and Polymicrobial Groups
Patients were classified into monomicrobial and polymicrobial groups according to culture results, with the polymicrobial group defined by the isolation of Vibrio species together with additional microorganisms from blood or wound cultures. The two groups showed similar baseline characteristics, ICU requirements, limb involvement, and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scores (Table 1). Culture findings demonstrated that NF was most commonly associated with V. vulnificus, which was identified in 179 patients (92.3%). Positive Vibrio cultures were identified from blood specimens only in 50 monomicrobial and 1 polymicrobial cases, from wound specimens only in 68 and 7 cases, respectively, and from both blood and wound specimens in 61 and 7 cases, respectively. Mortality was 15.6% (28/179) in the monomicrobial group and 6.7% (1/15) in the polymicrobial group. The single fatal polymicrobial case involved V. vulnificus with Aeromonas hydrophila and Enterococcus faecalis. The isolates of Vibrio species in the polymicrobial group were 14 of V. vulnificus and 1 of V. parahaemolyticus.
TABLE 1.
Patient characteristics and demographic data for monomicrobial and polymicrobial Vibrio necrotizing fasciitis.
| Variable | Monomicrobial (n = 179) | Polymicrobial (n = 15) | p value |
|---|---|---|---|
| Age (years) | 65.9 ± 13.5 | 61.1 ± 9.7 | 0.188 |
| Gender (male) | 130 (72.6) | 12 (80.0) | 0.536 |
| Involved lower limbs | 92 (51.4) | 9 (60.0) | 0.791 |
| Need ICU a care | 104 (58.1) | 8 (53.3) | 0.720 |
| LRINEC b score | 3.0 ± 2.3 | 3.5 ± 3.2 | 0.457 |
| Positive culture | |||
| Blood | 50 | 1 | |
| Wound | 68 | 7 | |
| Blood and wound | 61 | 7 | |
| Vibrio species (dead) | |||
| Vibrio vulnificus | 165 (22) | 14 (1) | |
| Vibrio parahaemolyticus | 5 (1) | 1 (0) | |
| Vibrio cholerae non‐O1 | 6 (4) | 0 | |
| Vibrio fluvialis | 2 (1) | 0 | |
| Vibrio mimicus | 1 (0) | 0 | |
| Chronic underlying diseases | |||
| Chronic alcoholism | 17 (9.5) | 1 (6.7) | 0.717 |
| Chronic liver disease | 64 (35.8) | 4 (26.7) | 0.479 |
| Viral hepatitis | 49 (27.4) | 4 (26.7) | 0.953 |
| HBV | 22 (12.3) | 2 (13.3) | 0.906 |
| HCV | 35 (19.6) | 2 (13.3) | 0.556 |
| Liver cirrhosis | 28 (15.6) | 1 (13.3) | 0.349 |
| Chronic kidney disease | 11 (6.1) | 0 (0) | 0.323 |
| Cancer | 10 (5.6) | 1 (6.7) | 0.862 |
| Cerebrovascular disease | 4 (2.2) | 1 (6.7) | 0.298 |
| Cardiovascular disease | 56 (31.3) | 5 (33.3) | 0.870 |
| Diabetes mellitus | 52 (29.1) | 6 (40.0) | 0.374 |
| Gout | 11 (6.1) | 4 (26.7) | 0.004 ∗ |
Note: Data were presented as the mean (standard deviation) or frequency (%).
aICU, intensive care unit.
bLRINEC, Laboratory Risk Indicator for Necrotizing Fasciitis.
∗ p < 0.05.
The polymicrobial group had a higher incidence of lower limb infections than the monomicrobial group, but it was not statistically different. The polymicrobial group had a higher incidence of gout than the monomicrobial group (26.7% vs. 6.1%; p = 0.004), in which one patient from the monomicrobial group and one patient from the polymicrobial group died. Among the four patients in the polymicrobial group with a medical history of gout, three patients were coinfected with Gram‐positive pathogens and one patient was coinfected with Gram‐negative pathogens.
3.2. Comparison of Laboratory Test Results and Clinical Outcomes of the Two Groups
We compared initial disease severity, laboratory findings, treatment timing, and clinical outcomes between the monomicrobial and polymicrobial groups. No significant differences were observed in the interval from symptom onset to emergency department presentation, presenting clinical features, laboratory findings, time from diagnosis to first surgery, mortality, amputation, number of debridement operations, or length of hospital stay (Table 2). The mortality and amputation rates in the polymicrobial group were lower than those in the monomicrobial group, but this difference was not statistically significant. The number of operations, hemorrhagic bullae formation, skin necrosis, and hospital stays were similar in both groups (Figures 2 and 3).
TABLE 2.
The clinical presentation, laboratory data, and outcomes between monomicrobial and polymicrobial Vibrio necrotizing fasciitis.
| Variable | Monomicrobial (n = 179) | Polymicrobial (n = 15) | p value |
|---|---|---|---|
| The interval from symptom onset to emergency room presentation (days) | 1.2 ± 1.1 | 1.2 ± 1.1 | 0.985 |
| Clinical presentation | |||
| Fever (body temperature > 38°C) | 78 (43.6) | 9 (60.0) | 0.219 |
| Tachycardia (heart rate > 100 beats/min) | 112 (62.6) | 11 (73.3) | 0.406 |
| Tachypnea (respiratory rate > 20 breaths/min) | 70 (39.1) | 5 (33.3) | 0.659 |
| Shock (systolic blood pressure < 90 mmHg) | 84 (46.9) | 4 (26.7) | 0.130 |
| Hemorrhagic bullae | 76 (42.5) | 5 (33.3) | 0.491 |
| Skin necrosis | 60 (33.5) | 2 (13.3) | 0.107 |
| Bacteremia | 111 (62.0) | 9 (60.0) | 1.000 |
| Vibrio vulnificus bacteremia | 102 (57.0) | 8 (53.3) | 0.793 |
| Laboratory test results | |||
| Total WBC a count | |||
| Leukocytosis (> 12000/uL) | 89 (49.7) | 8 (53.3) | 0.804 |
| Leukopenia (< 4000/uL) | 12 (6.7) | 0 (0) | 0.299 |
| Leukocytosis or leukopenia | 101 (56.4) | 8 (53.3) | 0.798 |
| Differential count | |||
| Band forms > 10% | 53 (29.6) | 4 (26.7) | 0.810 |
| Neutrophilia (> 7500/uL) | 112 (62.6) | 11 (73.3) | 0.406 |
| Lymphocytopenia (< 1000/uL) | 115 (64.2) | 9 (60.0) | 0.742 |
| Anemia (hemoglobin < 10 g/dL) | 13 (7.3) | 1 (6.7) | 0.932 |
| Thrombocytopenia (platelet count < 15 × 104 uL) | 107 (59.8) | 7 (46.7) | 0.322 |
| PT b (seconds) | 14.0 ± 5.2 | 12.7 ± 4.2 | 0.388 |
| APTT c (seconds) | 34.2 ± 11.5 | 32.1 ± 5.4 | 0.528 |
| Albumin (mg/dL) | 2.5 ± 1.4 | 2.7 ± 1.3 | 0.635 |
| Total bilirubin (mg/dL) | 2.1 ± 2.9 | 1.3 ± 0.7 | 0.374 |
| Creatine (μmol/L) | 139.7 ± 98.9 | 132.5 ± 71.6 | 0.784 |
| C‐reactive protein (mg/dL) | 65.2 ± 81.6 | 82.2 ± 130.9 | 0.466 |
| Time (hrs) from ER d to the OR e | 30.4 ± 64.8 | 34.8 ± 51.2 | 0.803 |
| Mortality cases | 28 (15.6) | 1 (6.7) | 0.703 |
| Amputation cases | 18 (10.1) | 0 (0) | 0.197 |
| Number of debridement operations | 3.0 ± 1.7 | 3.0 ± 1.8 | 0.900 |
| Length of hospital stay (days) | 32.4 ± 20.1 | 31.8 ± 15.9 | 0.918 |
Note: Data were presented as the mean (standard deviation) or frequency (%).
aWBC, white blood cell.
bPT, prothrombin time.
cAPTT, activated partial thromboplastin time.
dER, emergency room.
eOR, operation room.
FIGURE 2.
Clinical presentation of Vibrio vulnificus necrotizing fasciitis in an 80‐year‐old woman with chronic hepatitis B. (A) The right forearm and hand on arrival at the emergency department show extensive purpura and hemorrhagic bullae (white arrow). (B) Emergency fasciotomy was performed 4 h after surgical consultation. Blood and wound cultures yielded monomicrobial Vibrio vulnificus infection. Despite treatment, the patient died from progressive sepsis on hospital day 7.
FIGURE 3.
Clinical presentation of polymicrobial necrotizing fasciitis in a 67‐year‐old man with chronic hepatitis B presented with a 3‐day history of right‐hand pain and swelling. (A, B) Photographs obtained before surgery show purpura and hemorrhagic bullae over the right hand and fifth finger (black arrow). (C) Emergency fasciotomy revealed dishwater‐colored serous fluid in the wound (white arrow). Wound cultures grew Vibrio vulnificus and Kocuria kristinae. The patient underwent a second debridement 21 days after fasciotomy and was discharged on hospital day 32.
Multivariable logistic regression analysis was performed to adjust for potential confounding variables, such as age, liver disease, liver cirrhosis, shock, bacteremia, timing to operation, gout, and effective empirical therapy (Table 3). Shock (systolic blood pressure < 90 mmHg) was independently associated with increased mortality (aOR 3.82, 95% CI 1.75–8.36, p = 0.001), whereas effective empirical antimicrobial therapy was associated with lower mortality (aOR 0.34, 95% CI 0.13–0.88, p = 0.026). Gout was also an independent predictor of mortality (aOR 3.85, 95% CI 1.12–13.25, p = 0.033). Age and chronic liver disease were not significantly associated with mortality. Bacteremia, although common, was not associated with mortality and was excluded from the multivariable model. Polymicrobial infection was not independently associated with mortality.
TABLE 3.
Multivariable logistic regression analysis for mortality between monomicrobial and polymicrobial Vibrio necrotizing fasciitis.
| Variable | Adjusted odds ratio (aOR) | 95% confidence interval | p value |
|---|---|---|---|
| Age (per year increase) | 1.01 | 0.98–1.04 | 0.41 |
| Shock | 3.82 | 1.75–8.36 | 0.001 ∗ |
| Gout | 3.85 | 1.12–13.25 | 0.033 ∗ |
| Chronic liver disease | 0.91 | 0.33–2.55 | 0.86 |
| Polymicrobial infection | 0.58 | 0.07–4.60 | 0.60 |
| Effective empirical antimicrobial therapy | 0.34 | 0.13–0.88 | 0.026 ∗ |
∗Statistically significant (p < 0.05).
3.3. Microbiological Analysis of the Polymicrobial Group
Ten patients with polymicrobial Vibrio NF had one additional coisolated organism and five patients were coinfected with more than two pathogens. All 25 coinfective pathogens were isolated from wound specimens, of which 22 (88%) were aerobic bacteria. The most common isolates obtained from the polymicrobial group were Staphylococcus species (4, 16%), Shewanella putrefaciens (3, 12%), and Enterococcus spp. (3, 12%) (Table 4).
TABLE 4.
Summary of identified infectious microorganisms in 15 patients with Vibrio polymicrobial NF.
| Identified infectious microorganisms | Total no. | (%) |
|---|---|---|
| Gram‐positive aerobic pathogens | 9 | 36 |
| Staphylococcus spp. | 4 | 16 |
| MRSA a | 2 | 8 |
| Staphylococcus epidermidis | 1 | 4 |
| Staphylococcus saprophyticus | 1 | 4 |
| Enterococcus spp. | 3 | 12 |
| Streptococcus dysgalactiae | 1 | 4 |
| Kocuria kristinae | 1 | 4 |
| Gram‐negative aerobic pathogens | 13 | 52 |
| Shewanella putrefaciens | 3 | 12 |
| Aeromonas spp. | 2 | 8 |
| Pseudomonas aeruginosa | 2 | 8 |
| Escherichia coli | 1 | 4 |
| Enterobacter cloacae | 1 | 4 |
| Klebsiella pneumoniae | 1 | 4 |
| Morganella morganii | 1 | 4 |
| Proteus vulgaris | 1 | 4 |
| Serratia marcescens | 1 | 4 |
| Anaerobic pathogens | 3 | 12 |
| Clostridium spp. | 1 | 4 |
| Finegoldia magna | 1 | 4 |
| Peptoniphilus harei | 1 | 4 |
| Total | 25 | 100 |
aMRSA: methicillin‐resistant Staphylococcus aureus.
3.4. Antibiotic Sensitivity and Empirical Antibiotic Selection Between Two Groups
Table 5 shows that susceptibility testing was reported for individual antimicrobial agents or antimicrobial classes with varying denominators according to the number of isolates tested. In both groups, Vibrio isolates demonstrated high susceptibility to third‐generation cephalosporins, fluoroquinolones, tetracyclines, carbapenems, aminoglycosides, and sulfonamides. Ampicillin susceptibility was significantly lower in the polymicrobial group than in the monomicrobial group (50.0% vs. 90.7%, p = 0.016).
TABLE 5.
Antimicrobial susceptibility testing and the initial empiric antibiotic usage at ER between monomicrobial and polymicrobial Vibrio necrotizing fasciitis.
| Variable | Monomicrobial (n = 179) | Polymicrobial (n = 15) | p value |
|---|---|---|---|
| Coinfection with Gram‐positive bacteria | 0 | 9 | |
| Coinfection with Gram‐negative bacteria | 0 | 13 | |
| Antibiotic sensitivity of Vibrio spp. ∗ | |||
| Ampicillin | 49/54 (90.7) | 2/4 (50) | 0.016 ∗∗ |
| Aminoglycosides | 77/79 (97.5) | 7/7 (100) | 0.670 |
| Third‐generation cephalosporins | 179/179 (100) | 15/15 (100) | 1.000 |
| Fluoroquinolones | 171/173 (98.8) | 15/15 (100) | 0.675 |
| Tetracyclines | 102/103 (99.0) | 9/9 (100) | 0.767 |
| Carbapenems | 79/79 (100) | 7/7 (100) | 1.000 |
| Sulfa drugs | 59/61 (96.7) | 7/7 (100) | 0.627 |
| Effective empirical antimicrobial usage | 153 (85.5) | 11 (73.3) | 0.212 |
| Monotherapy | 88 (49.2) | 8 (53.3) | 0.756 |
| Third‐generation cephalosporins | 87 (48.6) | 8 (53.3) | 0.725 |
| Fluoroquinolones | 1 (0.6) | 0 (0.0) | 0.772 |
| Combination therapy | 65 (36.3) | 3 (20.0) | 0.203 |
| Third‐generation cephalosporins + doxycycline | 61 (34.1) | 3 (20.0) | 0.265 |
| Third‐generation cephalosporins + fluoroquinolones | 4 (2.2) | 0 (0.0) | 0.559 |
| Ineffective empirical antimicrobial usage | 26 (14.5) | 4 (26.7) | 0.212 |
Note: Data were presented as frequency (%).
∗Data not all available.
∗∗ p < 0.05.
Effective empirical antimicrobial therapy was administered in 85.5% of monomicrobial cases and 73.3% of polymicrobial cases, with no significant difference between the groups. Monotherapy with third‐generation cephalosporins was the most commonly used regimen, whereas combination therapy mainly consisted of third‐generation cephalosporins plus doxycycline. Eleven patients (73.3%) in the polymicrobial group using our empirical antimicrobial regimens were found effective for coverage of both Vibrio spp. and non‐Vibrio organisms.
Those patients who received effective antimicrobial therapy, combination therapy, and third‐generation cephalosporin plus doxycycline were found to have a significant association with lower mortality. Those patients who were treated with effective antimicrobial therapy had significantly associated with lower incidence of amputation (Table 6). Unadjusted odds ratio analysis and multivariable logistic regression analysis demonstrated that effective antimicrobial therapy was associated with significantly lower mortality. Similarly, combination therapy and third‐generation cephalosporin plus doxycycline therapy were associated with reduced odds of death. Effective antimicrobial therapy was also associated with a lower risk of amputation (Table 7).
TABLE 6.
Clinical outcome and initial empiric antibiotic usage in Vibrio NF patients.
| Variable | Effective antimicrobial usage | p value | Combination therapy | p value | Third‐generation cephalosporin + DOX | p value | |||
|---|---|---|---|---|---|---|---|---|---|
| Yes (n = 164) | No (n = 30) | Yes (n = 68) | No (n = 126) | Yes (n = 64) | No (n = 130) | ||||
| Mortality | 19 (11.6) | 10 (33.3) | 0.002 ∗ | 3 (4.4) | 26 (20.6) | 0.002 ∗ | 2 (3.1) | 27 (20.8) | 0.001 ∗ |
| Amputation | 11 (6.7) | 7 (23.3) | 0.004 ∗ | 4 (5.9) | 14 (11.1) | 0.231 | 3 (4.7) | 15 (11.5) | 0.122 |
Note: DOX: doxycycline. Data were presented as frequency (%).
∗ p < 0.05.
TABLE 7.
Association between empirical antimicrobial therapy and clinical outcomes by multivariable logistic regression analysis.
| Outcome | Variable (total 194) | Univariate OR (95% CI) | p value | Multivariable aOR (95% CI) | p value |
|---|---|---|---|---|---|
| Mortality | Effective antimicrobial usage | 0.26 (0.11–0.64) | 0.002 ∗ | 0.34 (0.13–0.88) | 0.026 ∗ |
| Combination therapy | 0.18 (0.05–0.61) | 0.002 ∗ | 0.22 (0.06–0.78) | 0.019 ∗ | |
| Third‐generation cephalosporin + doxycycline | 0.12 (0.03–0.54) | 0.001 ∗ | 0.21 (0.05–0.89) | 0.034 ∗ | |
| Amputation | Effective antimicrobial usage | 0.24 (0.08–0.67) | 0.004 ∗ | 0.31 (0.10–0.98) | 0.046 ∗ |
| Combination therapy | 0.50 (0.16–1.59) | 0.231 | 0.58 (0.18–1.88) | 0.37 | |
| Third‐generation cephalosporin + doxycycline | 0.38 (0.11–1.35) | 0.122 | 0.44 (0.12–1.62) | 0.21 | |
∗Statistically significant (p < 0.05).
4. Discussion
The principal findings of this study were that patients with polymicrobial Vibrio NF had clinical characteristics, laboratory findings, and outcomes similar to those of patients with monomicrobial Vibrio NF. Among the 194 patients with Vibrio NF, 15 (7.7%) had polymicrobial infections, and only one patient in this group died. Vibrio vulnificus was the predominant Vibrio species identified in both groups. In addition, gout was more frequently observed among patients with polymicrobial infection. Several cohort studies have reported similar or even higher mortality among monomicrobial infections compared with polymicrobial disease, reflecting differences in pathogen virulence and host factors [1–3, 12, 14, 16, 19]. However, those studies specifically focusing on polymicrobial Vibrio NF remain limited [20–25]. Therefore, we compared mortality‐associated factors, clinical presentations, laboratory findings, and antimicrobial therapy between patients with monomicrobial and polymicrobial Vibrio NF. To our knowledge, this study represents one of the largest clinically focused cohorts examining polymicrobial Vibrio NF and provides additional information regarding its clinical characteristics and outcomes.
Polymicrobial Vibrio NF was uncommon in our cohort, accounting for 15 of 194 cases (7.7%). These polymicrobial cases frequently involved additional Gram‐positive and Gram‐negative organisms, while the clinical characteristics, laboratory findings, and outcomes were broadly comparable to those of monomicrobial Vibrio NF. These findings indicate that polymicrobial Vibrio NF represents an uncommon but clinically important presentation that requires prompt recognition and management. Because the present study was based on clinical and culture data, the biological mechanisms underlying the coexistence of multiple microorganisms could not be determined.
By performing early fasciotomy, empiric third‐generation cephalosporin antibiotic therapy and ICU care, the mortality rate in the Vibrio polymicrobial group was lower than those in the monomicrobial group (6.7% vs.15.6%); nevertheless, the two groups did not show statistically significant differences in mortality rate, chronic underlying diseases, and lab data. Although crude mortality was numerically lower in the polymicrobial group than in the monomicrobial group, this difference should be interpreted with caution because the polymicrobial group included only 15 patients and one mortality event. The present study was underpowered to detect clinically meaningful differences in mortality between groups. Therefore, these findings should not be interpreted as evidence that polymicrobial Vibrio NF has a more favorable prognosis or is clinically less severe than monomicrobial infection. Instead, our results suggest that polymicrobial Vibrio NF should be managed with the same degree of clinical urgency as monomicrobial disease until larger studies provide more definitive evidence.
In the present cohort, Vibrio isolates demonstrated high susceptibility to aminoglycosides, third‐generation cephalosporins, fluoroquinolones, tetracyclines, carbapenems, and sulfonamides. Effective empirical antimicrobial therapy was administered in 153 (85.5%) patients with monomicrobial Vibrio NF and 11 (73.3%) patients with polymicrobial Vibrio NF. Because polymicrobial infections commonly involved additional Gram‐positive and Gram‐negative organisms, adequate empirical antimicrobial coverage should include both Vibrio species and potential copathogens. In our cohort, the empirical antimicrobial protocol provided appropriate coverage for both Vibrio and most coisolated organisms in the majority of polymicrobial cases. Although the frequency of initially inadequate empirical antimicrobial therapy was higher in the polymicrobial group than in the monomicrobial group (26.7% vs. 14.5%), antimicrobial regimens were subsequently adjusted according to culture and susceptibility results under the guidance of infectious disease specialists. Consequently, no significant differences in antimicrobial usage or mortality were observed between the two groups in univariable analyses. The susceptibility patterns observed in our cohort were generally consistent with previous reports from Taiwan, where Vibrio species remain highly susceptible to third‐generation cephalosporins, aminoglycosides, fluoroquinolones, and tetracyclines [5–11, 22, 26]. In contrast, studies from the Maryland Coastal Bays in the United States have reported higher resistance rates to third‐generation cephalosporins and carbapenems among some Vibrio isolates [27]. These findings highlight potential geographic differences in antimicrobial susceptibility and support the importance of regional surveillance to guide empirical antimicrobial therapy.
In multivariable logistic regression analysis, shock was independently associated with increased mortality (aOR 3.82, 95% CI 1.75–8.36, p = 0.001), whereas effective empirical antimicrobial therapy, combination therapy, and third‐generation cephalosporin plus doxycycline therapy were associated with lower mortality. The application of the effective antimicrobial agents under the supervision of infectious disease specialists can improve the outcomes of patients with Vibrio NF, especially when NF patients presented shock at ER; however, because treatment allocation was not randomized, these associations should not be interpreted as evidence of causality.
Third‐generation cephalosporins, particularly ceftriaxone, were the most commonly prescribed empirical antimicrobial agents in our institution, and our previous studies demonstrated that ceftriaxone‐containing regimens were associated with favorable outcomes in patients with NF presenting with bloodstream infection and hemorrhagic bullae [7–9, 13, 26]. In the present cohort, third‐generation cephalosporins and fluoroquinolones showed excellent in vitro activity against Vibrio isolates and were considered appropriate empirical agents for suspected Vibrio NF. However, because polymicrobial infections may involve additional Gram‐positive organisms, Gram‐negative organisms, and anaerobes, antimicrobial therapy was adjusted according to culture and susceptibility results when necessary [28–31]. The principal clinical implication of the present study is that empirical antimicrobial therapy for suspected polymicrobial Vibrio NF should provide coverage for both Vibrio species and clinically relevant copathogens until culture and susceptibility results become available. However, no conclusions can be drawn regarding the independent effect of infectious disease specialist involvement because this factor was not specifically evaluated, and these findings should be interpreted cautiously because of the retrospective observational design of the study. In addition to antimicrobial therapy, early surgical intervention, intensive care management, and multidisciplinary care likely contributed substantially to patient outcomes.
One notable finding of this study was that a history of gout was more frequently observed among patients with polymicrobial Vibrio NF. Several mechanisms have been proposed to explain the potential association between gout and susceptibility to polymicrobial infection, including chronic inflammation, metabolic comorbidities, and skin barrier disruption. Some studies have also reported associations between gout and Gram‐positive skin and soft tissue infections, including Group A Streptococcus and Staphylococcus aureus [32–36]. Although a history of gout was more frequently observed in the patients with polymicrobial Vibrio NF, this finding was based on only four cases and should be interpreted cautiously, and these hypotheses remain speculative because the present study did not evaluate gout severity, tophus formation, skin lesions, serum uric acid levels, medication use, or other relevant clinical factors. Clinically, patients with gout, particularly those with skin barrier disruption or soft tissue vulnerability, may require careful evaluation following wound exposure, seawater exposure, or seafood‐related injury in coastal regions.
There were several limitations to the present study. First, this was a retrospective observational study conducted at a single institution and was therefore subject to potential selection bias and unmeasured confounding. In addition, the relatively small number of polymicrobial Vibrio NF cases (n = 15) limited the statistical power and precision of between‐group comparisons. Therefore, nonsignificant findings should be interpreted cautiously, as they may reflect insufficient power to detect clinically meaningful differences rather than true equivalence between the monomicrobial and polymicrobial groups. Second, the study did not include detailed molecular, genetic, or functional investigations of the bacterial isolates, including minimum inhibitory concentration distributions, resistance mechanisms, genotyping, or polymerase chain reaction‐based analyses. Therefore, the contribution of specific Vibrio virulence mechanisms and potential pathogen–pathogen interactions in polymicrobial infections could not be assessed, and no mechanistic conclusions can be drawn from the present clinical and culture‐based data. Further studies incorporating molecular and genomic approaches are warranted to better characterize the microbiological characteristics and potential interactions of polymicrobial Vibrio infections. Third, only 29 mortality events occurred overall, including one in the polymicrobial group. The limited number of outcome events may have reduced the stability and precision of the multivariable logistic regression estimates and increased the risk of model overfitting. Although variables were selected based on clinical relevance and univariable findings, the limited event‐to‐variable ratio warrants cautious interpretation of the multivariable results. Therefore, the results of the multivariable models should be interpreted cautiously and require validation in larger cohorts.
5. Conclusions
Polymicrobial Vibrio NF was uncommon but was not clinically less severe than monomicrobial Vibrio NF in this 20‐year cohort. Patients with polymicrobial infection more frequently had gout, suggesting a potential clinical association that warrants further investigation. These findings indicate that suspected polymicrobial Vibrio NF should be treated with the same urgency as monomicrobial disease, with prompt surgery, intensive care, and empirical antimicrobial therapy covering both Vibrio species and relevant copathogens.
Author Contributions
Jiun‐Liang Chen: conceptualization. Hung‐Yen Chen: conception and design of the study and drafting the article. Chun‐Hao Chen: acquisition of data. Hung‐Yen Chen: analysis and interpretation of data. Chien‐Hui Hung & Shu‐Fang Kuo: design and coordination. Hsing‐Jung Li: revising it critically for important intellectual content. Cheng‐Ting Hsiao: final approval of the version to be submitted. Tsung‐Yu Huang: writing review and editing.
Funding
This work was supported by grants from the Chang Gung Memorial Hospital in Taiwan (Grant numbers CMRPG6P0031, CMRPG6N0061, CMRPG6L0071, and CMRPG6H0641 to Tsung‐Yu Huang).
Disclosure
All authors read and approved the final manuscript for publication.
Ethics Statement
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Chang Gung Medical Foundation (Numbers: 202301943B1, 202300428B1, 202001656B0, and 201801530B1B0).
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors thank all the participants who participated in this study.
Chen, Jiun‐Liang , Chen, Chun‐Hao , Chen, Hung‐Yen , Hsiao, Cheng‐Ting , Kuo, Shu‐Fang , Hung, Chien‐Hui , Li, Hsing‐Jung , Huang, Tsung‐Yu , Tsai, Yao‐Hung , Antibiotic Selection and Outcomes in Patients With Monomicrobial and Polymicrobial Vibrio Necrotizing Fasciitis, Canadian Journal of Infectious Diseases and Medical Microbiology, 2026, 9414923, 11 pages, 2026. 10.1155/cjid/9414923
Academic Editor: Shweta Negi
Contributor Information
Tsung-Yu Huang, Email: r12045@cgmh.org.tw.
Yao-Hung Tsai, Email: orma2244@adm.cgmh.org.tw.
Shweta Negi, Email: kshwetakal@wiley.com.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.