The Sea “Flesh Eating Bacteria” – Vibrio Vulnificus

Vibrio Vulnificus is one of those board questions that pops up occasionally. The stem usually goes along the liens of “a cirrhotic eats raw oysters/goes to the beach and has a severe skin and soft tissue infection.” This is usually followed by a question about the etiology. There have been some news stories regarding this organism and presentation, with one I recall happening in my hospital while I was in residency (1). There is not much to say about this organism, as it mimics necrotizing fasciitis. If there is a takeaway here, is getting the right exposure history and getting the right antibiotics onboard while calling a surgeon.

Environmental Factors

Vibrio vulnificus is part of the natural flora of coastal marine environment worldwide (2) and it has been isolated from water and seafood, notably oysters. Temperature and salinity tends to be correlated with the density of V. vulnifucus. For instance, in one study of 226 lots of oysters (3) found that V. vulnificus were higher in higher temperatures (above 13^OC) and lower salinity. The highest densities occurred in the warmer months:

In high salinities, even in warm temperatures, there was no significant growth of V. vulnificus (notably, in the Carolinas):

In another study from Chesapeake Bay, multiple regression analysis found that V.  vulnificus growth increased with lower salinities and with isolation from samples closer to the bottom (4). The highest percentage of V. vulnificus grown were in the months of May to December, constituting 8% of overall bacterial growth. Exposures to this organism typically occurs in recreational water in costal states, usually in the Gulf Coast, Atlantic Coast states, and Pacific Coast states (5):

In general, activities associated with Vibrio cases included swimming, diving, and wading in water (70.9%), walking or falling on the shore or rocks (32.8%), and boating, skiing, or surfing (19.6%). In a more recent report of non-foodborne Vibrio infections (6), the Gulf Coast region reported the largest incidence of V. vulnificus infections (72%) with the majority of those being reported between May and September:

Furthermore, as previously stated, exposure to recreational water activities were associated with Vibrio infections across several species:

Virulence Factors:

While I am not a fan of learning virulence factors or anything of that sort, two important mechanisms come to mind. First, is the role of iron, as one review noted (2), excess iron is associated with increased growth rates of clinical strains. In another study cited by that same review, injecting mice with iron lowered the LD50 of vibrio vulnificus. While out of the scope of this review, this would suggest the important role of iron in its pathogenesis. This could explain why patients with hemochromatosis have high mortality with this infection. While there is some in vitro studies suggesting that iron chelators may inhibit growth of Vibrio alone or in combination with antibiotics (21, 22) this has not been clinically tested as of yet.

The other virulence factor that plays a major role in cytotoxicity is RtxA1, which form pores in cellular membranes. It has been found that rtxA mutants have lower reduction in spread to the liver (2), as well as dramatically reduced cytotoxicity in some instances (for instance, look at citation 11, with the cytotoxicity of the rtxA mutation being significantly lower). One reason to mention this now is that some antibiotics actually have some sort of inhibitor effect on this, suggesting their role in therapy goes beyond bactericidal activity.

Clinical Characteristics:

The most important one to recognize is skin and soft tissue infection. For instance, in one analysis of several cases (6) the most common reported signs were fever (72%), cellulitis (85%), and bullae (48%) when compared to other Vibrio organisms:

In another cohort (7), wound infections accounted for 17 out of 62 cases and had a mortality rate of 24%. The characteristic lesions of V. vulnificus are hemorrhagic bullous necrotic lesions:

Patients with cirrhosis or HCC were also more likely to present with septic shock without hemorrhagic bullae compared to those who did present with both shock and bullae (8):

In this cohort, however, more patients presented with bullae  overall, 68% vs 32%. Here, factors associated with mortality included high APACHE score, and septic shock at arrival, with 30% of patients with bullae dying within 48hrs of presentation. Notably surgery within 24hr was associated with improved outcomes in those who have lesions:

In another retrospective study from Taiwan (9), 84 patients with Vibrio vulnificus infections were analyzed. 67% of patients presented with some sort of cutaneous lesion, and overall 50% had necrotizing fasciitis. Primary septicemia was seen at presentation in 23.8% of patients. Notably, within this cohort, the highest mortality was in those who presented with spontaneous bacterial peritonitis, followed by necrotizing fasciitis and septicemia:

A report on food-borne illnesses (18) found that V. vulnificus resulted in a mortality rate of 39% when food-related exposure was the main source.

Scoring Systems – MELD and LRINEC

As mentioned previously, liver disease is associated with worsened mortality. Furthermore, the LRINEC score (laboratory risk indicator for necrotizing fasciitis) has been proposed for the early detection of Vibrio nec fasc. This score employs six laboratory variables at the time of presentation, including CRP, total leukocyte count, Hbg, serum sodium, serum creatinine, and glucose. If score is >6, there is a higher risk of presence of necrotizing fasciitis. In one retrospective study (19) of 70 patients found that the mean LRINEC scores were similar in patients who died and who survived (notably, those who survived were more likely to have a score >6):

Despite this, multivariate analysis found that band forms, segmented forms, albumin, systolic blood pressure <90, platelets <80k, and albumin <2 were predictive of higher mortality:

What about MELD scoring? One retrospective (20) study of 39 patients evaluated this, along with the LRINEC score for the prediction of mortality. In this cohort, only 5 patients died at the end of the study period. Patients who had higher admission MELD and MELD-Na scores on admission, as well as when accounting the extreme scores and the difference:

AUC for mortality risk was 0.929 (95% CI 0.818-1.0), MELD-Na score 0.871( 95% CI 0.662-1.00) and change in MELD 0.971 (95% CI0.662-1.00). Moreover, higher MELD, MELD-Na, and change in MELD scores were associated with increased mortality, though the same was not true for the LRINEC score:

Treatment:

In vitro data (10) suggested that the newer quinolones, including levofloxacin, sparfloxacin, and lemofloxacin, had anti-bacterial activity up to 48hr after inoculation. Moxifloxacin had regrowth after around 24hr. The combination of cefotaxime and minocycline also had ongoing activity against Vibrio for 48hrs:

The in vivo portion of the study evaluated 15 rats and found that both moxifloxacin and cefotaxime/minocycline were significantly more likely to survive.

The same applied to all the quinolones, though the difference between quinolones themselves did not reach statistical significance:

In a similar study (11), the combination of cefotaxime/ciprofloxacin had significantly higher survival at 96hr in a group of 90 rats (17/20) compared to cefotaxime (0/20), cefotaxime/minocycline (7/20; p-value <0.001 and p-value 0.003 respectively).

One interesting aspect of this study was the evaluation of the effect of antibiotics against rtxA1 expression, which is one of the important cytotoxic virulence factors. Cytotoxicity was inhibited more effectively by ¼ MIC of ciprofloxacin than by ¼ MIC of cefotaxime or ¼ MIC of minocycline (p-value <0.05). Transcription of rtxA1 was also inhibited by these antibiotics, suggesting their effect may also be due to in part due to their effect on one of the main cytotoxic virulence factors:

Tigecycline has also been used in salvage therapy in one instance (12). In vitro data (13) suggest some degree with activity, with high concentration of tigecycline (up to 2 times MIC) had bacterial growth up until 48hrs:

Combination of tigecycline and cefotaxime also had better survival benefit over other combinations when compared to other combinations in rats infected with high inoculum of bacteria:

In another animal study (14), survival in mice treated with tigecycline/ciprofloxacin (71%) was higher than mice treated with cefotaxime/minocycline (42%, p-value 0.04). The combination of tigecycline/cefotaxime had a survival of 67% at 96h which was higher than cefotaxime/minocycline, but not statistically significant (p-value 0.09). Survival between the tigecycline/ciprofloxacin, ciprofloxacin, and tigecycline groups were not statistically significant:

The same study found that the combination of tigecycline/ciprofloxacin did not exhibit synergy in the in vitro part of the study. The pharmacokinetics and dynamics of tigecycline suggest that this may not be an appropriate monotheraphy for V. vunlificus sepsis as tigecycline enters tissues rapidly after administration, resulting in low serum levels.

What about clinical data? A retrospective analysis (8) found that therapy with third generation cephalosporine plus a tetracycline was associated with improved outcomes in those who had hemorrhagic lesions. There was a trend towards improvement with a third gen cephalosporine and another antibiotic in patients with no lesions:

Antibiotic therapies were evaluated in a retrospective study of 89 patients who received surgical therapy within 24 hours (15). Group 1 were patients who were treated with a third-generation cephalosporin, group 2 was a third-gen cephalosporin/minocycline, while group 3 was a fluroquinolone +/- minocycline. In general, patients who received a combination of a third-gen cephalosporin and minocycline had lower case fatality rate when compared to a group 1. Both groups 2 and 3 had similar outcomes:

Notably, there was no difference in the need for limb amputation or ICU requirements between groups:

This suggests the combination of either ceftriaxone + either minocycline or doxycycline is a good initial therapy if this Vibrio vulnificus septicemia is suspected. A quinolone such as levofloxacin is a reasonable alternative. Duration of therapy is unclear, however it will likely depend on the presence of ongoing bacteremia and good source control (i.e. if there is still necrosis, it may not be a good idea to stop antibiotics just yet).

Earlier, I mentioned that patients who had early surgical intervention actually had a better outcome if they presented with hemorrhagic bullae. In one study of 121 patients (16), patients were divided into 3 groups according to the time from admission to surgical treatment: <12hrs, between 12-24hrs, and >24hrs after admission. Case-fatality rate in this cohort was 29%, with those patients who underwent surgery <12hrs after admission having a lower mortality risk compared to those who had surgery either 12-24hrs after admission (aHR 0.064, 95% CI 1.6 x 10^-7 to 0.25, p-value 0.037). There was no difference between the groups where surgery was done after 12 hrs (p-value 0.849). In another retrospective analysis of 67 patients (17), those who had first fasciotomy within 24hrs exhibited greater survival when compared to those who had any procedure beyond 24hrs (4.9% vs 23% in-hospital mortality, p-value 0.005). Notably, those who had fasciotomy beyond 24hrs were more likely to present with hemorrhagic bullae and shock, muddling these results.

References:

1. https://www.tcpalm.com/story/news/local/indian-river-lagoon/health/2017/06/06/vibrio-infects-texas-man-new-tattoo-he-dies-couple-months-later/374592001/
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