A Case Series of Vibrio Vulnificus Infections in New Orleans, Louisiana

A Case Series of Vibrio vulnificus Infections in New Orleans, Louisiana

John Humphrey, MD; Lauren Richey, MD, MPH

Objective: The objective of this study is to describe cases of V. vulnificus infection and to review the literature, emphasizing salient aspects of infection for practicing physicians.

Methods: A retrospective review of all patients aged 5 years and older who grew V. vulnificus from a blood or tissue culture from 2005 to 2011 at Tulane University Medical Center and Interim Louisiana Public Hospital.

Results: Six patients were identified over the study period. All were male and had a history of liver disease. Four developed primary septicemia and two developed wound infection with secondary septicemia. One received doxycycline as part of his antimicrobial therapy, which along with ceftazidime, is the recommended therapy for V. vulnficus infection. Four patients died despite aggressive care.

Conclusions: V. vulnificus infection is an uncommon but often fatal cause of severe sepsis and wound infection. Physicians must recognize the clinical presentations of this infection in order to initiate early and appropriate therapy.

INTRODUCTION contrast, is defined by a cutaneous point of pathogen entry, usually following wound exposure to coastal waters or by Vibrio vulnificus infection is the leading cause of death handling raw seafood.7 This may occur in healthy individu- related to seafood consumption in the United States and als, although secondary septicemia and death is far more carries the highest case-fatality rate of any enteric disease.1,2 common in those with liver disease.3 Treatment consists This gram-negative, curved bacillus is found naturally in of early antibiotics and aggressive surgical debridement seawaters around the world, including the Gulf of Mexico.1,3 of necrotic tissue when present.8,9 Recommended therapy Approximately half of the 100 annual cases in the United is a combination of a third-generation cephalosporin with States occur in the Gulf Coast region of Alabama, Florida, doxycycline.4 Louisiana, Mississippi, and Texas.4 More than 85% of infec- Research has significantly advanced our understanding tions occur during warmer months from May to October, of V. vulnificus infection. However, the sporadic and infre- when water temperatures above 22oC allow for increased quent nature of infection has resulted in limited knowledge V. vulnificus proliferation.1,4-6 Cultural food preferences and about the disease among the general medical community accessibility to the Gulf of Mexico additionally place this and the public.9 As a consequence, the incidence of infection region at higher risk of infection.1,6 has risen over the years, and a large number of patients do V. vulnificus causes a spectrum of disease that can be not receive recommended therapy.2,5-7 The objective of this categorized as gastrointestinal illness, primary septicemia, study is to determine the epidemiologic characteristics of or wound infection.3 Primary septicemia and wound infec- V. vulnificus infection at two academic hospitals in New tion comprise more than 90% of reported cases.1,6,7 Gastro- Orleans – a major city situated in the high-risk Gulf Coast intestinal illness is probably underreported because of its region of Louisiana.6 Following this is a review of the litera- self-limited course.6,8 In nearly all cases, gastrointestinal ture pertaining to these cases, including the epidemiology, illness and primary septicemia result from ingestion of risk factors, clinical presentation, treatment, outcome, and contaminated seafood.8 Penetration of bacteria across the prevention of V. vulnificus infection. Through this case series intestinal wall to cause sepsis, however, occurs almost ex- and systematic review, the reader will gain a better under- clusively in those with an underlying chronic disease, the standing of the features of V. vulnificus infection that are most common of which is cirrhosis.9 Wound infection, in important for the diagnosis and management of the disease.

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MATERIAL AND METHODS Case 2 An 11-year-old boy developed fever, abdominal pain, A retrospective chart review of all patients who grew and lower extremity pain and swelling one day after wading Vibrio vulnificus from a blood or tissue culture from August in the Gulf of Mexico in June.10 He had a history of cirrhosis 2005 to October 2011 at two university teaching hospitals, due to hepatitis C and took pantoprazole for esophageal Tulane University Medical Center and the Interim Louisiana reflux disease. His initial temperature was 98.9oC, respira- Public Hospital (ILPH), was performed. All subjects aged tory rate 20 breaths/min, heart rate 144 beats/min, and 5 years and older were included in the study. Institutional blood pressure 137/62 mm Hg. Faint purpura was present Review Boards at both study hospitals approved the study on the bilateral lower extremities, along with marked edema protocol. and tenderness to palpation. Large, hemorrhagic bullae developed within 12 hours (see Figure 1), and he developed CASES hypotension requiring vasopressors and intubation. Labo- ratory data are listed in Table 1. Vancomycin Gentamycin Case 1 and pipercillin-tazobactam were administered, however, A 50-year-old man presented to the emergency depart- suspicion for V. vulnificus infection prompted antibiotic ment (ED) in September with fever, worsening dyspnea, and change to ceftazidime and ciprofloxacin. Bilateral fasciotomy lower extremity swelling for four days. His medical history of the lower extremities was performed within 24 hours included cirrhosis due to hepatitis C and alcohol use. Initial of admission. He died due to overwhelming sepsis after vital signs included temperature of 95.5oC, respiratory rate seven days of hospitalization. V. vulnificus grew from blood 18 breaths/min, heart rate of 116 beats/min, and blood cultures taken at admission and from the lower extremity pressure 152/98 mm Hg. Scleral icterus, bilateral pulmonary fasciotomy sites. crackles, and pitting edema of the lower extremities were noted on physical exam. Laboratory data are listed in Table Case 3 1. Vancomycin and Pipercillin-tazobactam was empirically An 87-year-old man developed abdominal pain, diar- administered. Within hours of admission, he developed rhea, and fever after eating raw oysters 12 days prior to ED hypotension requiring vasopressors and intubation. He presentation in November.11 He had a history of metastatic died after six hours due to V. vulnificus sepsis diagnosed by prostate cancer with hepatic metastasis and had been receiv- blood cultures drawn at admission. His mode of exposure ing daily prednisone for the past nine months. In addition, to the pathogen was unknown. he had received was taking dexamethasone and taxotere chemotherapy seven days prior to presentation. He also had a multi-year history of daily alcohol use but no documented history of abnormal liver function. His initial temperature was 39.5oC, respiratory rate 18 breaths/min, heart rate 89 beats/min, and blood pressure 121/73 mm Hg. There were no notable findings on physical exam. Laboratory results are listed in Table 1. He was noted to be neutropenic, and cefepime and vancomycin were administered upon hospital admission. Blood cultures from admission grew V. vulnificus and Enterococcus casseliflavus. Ceftazidime and levofloxacin were administered for treatment of V. vulnificus, while E. casseliflavus was treated with ampicillin over the same time period. He was discharged home after six days of hospitalization to complete a 14-day course of these antibiotics.

Case 4 A 48-year-old man was admitted to the hospital in No- vember with coffee-ground emesis and melanotic stools for five days. He had a history of cirrhosis due to hepatitis C and was undergoing evaluation for liver transplantation. His initial temperature was 38oC, respiratory rate 24 breaths/ min, heart rate 123 beats/min, and blood pressure 114/70 mm Hg. No significant findings were seen on physical exam. Laboratory data are listed in Table 1. Vancomycin and Pipercillin-tazobactam was administered empirically. Figure 1: Hemorrhagic bullae characteristic of V. vulnificus During esophageal endoscopy on the first day of admission, infection from Case 2. he developed refractory hypoxia and hypotension requiring intubation and vasopressor support. V. vulnificus grew from

198 J La State Med Soc VOL 164 July/August 2012 Table 1: Demographics, lab data at admission, treatment, and outcomes of the six patients with Vibrio vulnificus infections Characteristic Case 1 2 3 4 5 6 Sex Male Male Male Male Male Male Age 50 11 87 48 64 50 Race African- Hispanic Caucasian African- Caucasian Caucasian American American Diagnosis Primary Wound Primary Primary Primary Wound septicemia infection septicemia septicemia septicemia infection Month of illness 10 6 11 11 10 6 Mode of exposure Unknown Swimming Raw oyster Unknown Raw oyster Wound in Gulf of consumption consumption exposure to Mexico seafood Medical history Cirrhosis + + + + + Hepatitis C + + + Malignancy + Renal disease -- -- + Immunosu- + pressant use Alcoholism + + + + + Proton pump + + + inhibitor use Initial lab data WBC (per mm)3 3,200 6,500 1,400 8,400 12,000 16,700 Bands (%) 26 16 5 15 42 3 Platlet 61 48 231 58 64 52 (100,000/mm)3 Creatinine 2.9 2.4 1.5 1.7 3.9 5.4 (mg/dL) ALT (U/L) 81 111 76 277 15 58 Initial Antibiotics Piperacillin- Piperacillin- Cefepime Piperacilin- Ceftazidime, Ceftazidime treating V. Tazobactam Tazobactam, Tazobactam Doxycycline vulnificus gentamycin Subsequent -- Ceftazidime, Ceftazidime, Ciprofloxacin -- Doxycycline, Antibiotics Ciprofloxacin Levofloxacin, Tobramycin treating V. Ampicillin vulnificus Surgical + + + debridement Hypotension + + + + + < 12 h after admission Outcome Death Death Recovery Death Death Recovery

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peripheral blood cultures drawn at the time of admission, group. Indeed, the one child that developed infection in our and he died two days later due to overwhelming sepsis. His series had advanced cirrhosis. Additionally, all patients in mode of exposure to V. vulnificus was unknown. our study were male. In other studies, male predominance of up to 6:1 has also been observed.1,7 This may, in part, be Case 5 due to differences in risk factors and occupational exposure.1 A 64-year-old man presented to the ED in October with Estrogen may be a factor as well, and it has been linked with fatigue and left lower extremity pain for three days after protection during lipopolysaccharide-mediated endotoxic consuming raw oysters. He was awaiting liver transplan- shock.1,12 Finally, four of six cases occurred in October or tation for severe alcoholic cirrhosis and took omeprazole November, the tail end of the high incidence seasons as for esophageal reflux disease. His initial temperature was defined by the Centers for Disease Control and Prevention 36.7oC, respiratory rate 16 breaths/min, heart rate 110 beats/ (CDC). As mentioned, warmer water temperatures promote min, and blood pressure 60/40 mm Hg. Purpura and hemor- V. vulnificus growth and allow for higher pathogen density rhagic bullae were present on the bilateral lower legs to the in seawater and oysters. Other factors, such as salinity and level of the knee. Laboratory data are presented in Table 1. turbidity, are thought to play a role in gene expression and Ceftazidime and doxycycline were administered empirically Vibrio virulence, although the clinical relevance of these out of suspicion for V. vulnificus infection. Vasopressors findings is unclear. and mechanical ventilation were necessary for blood pressure and respiratory support, respectively. He underwent Risk Factors extensive surgical debridement of the lower extremities A number of risk factors have been associated with V. for necrotizing fasciitis within 24 hours of admission but vulnificus septicemia, many of which share the common died the following day. V. vulnificus grew from blood and endpoint of immune suppression. More than 80% of patients wound cultures. with septicemia have one or more chronic medical condi- tions, including kidney disease, diabetes, cancer, hemato- Case 6 logic disorders, achlorhydria, or most commonly, liver dis- A 50-year-old man presented to the ED in June with ease due to alcohol or hepatitis C virus infection.3,8,13,14 More right lower extremity pain and swelling for one week after than 60% of patients with septicemia have liver disease.7 injuring his leg on a metal pot during a seafood boil. His Those with cirrhosis, for example, are 80 times more likely history included a long period of heavy alcohol use. Initial to develop sepsis and 200 times more likely to die following temperature was 38.7oC, respirations 24 breaths/min, heart raw oyster consumption than those without liver disease.15 rate 121 beats/min, and blood pressure 92/54 mm Hg. A Aside from immune dysfunction in patients with cirrhosis, purpuric rash and hemorrhagic bullae were present on the elevated serum iron in these patients is used by V. vulnificus right leg, in addition to scleral icterus. Ceftazidime and li- for growth. Also, portal hypertension allows the pathogen nezolid were was administered empirically, and tobramycin direct access to the portal circulation by redirecting it away was added thereafter, as he required increasing intensive from the hepatic reticuloendothelial system.16 Nevertheless, care, including vasopressor support. Blood cultures grew this predisposition is likely dependent on both host and V. vulnificus, and doxycycline was added for additional pathogen factors, as recent data have suggested that some treatment alongside ceftazidime. He required multiple patients with liver disease may be at greater risk of infection debridements and skin graft reconstruction of the right leg than others given the relatively low incidence of infection over the course of his 32-day hospitalization, and he was despite the large number of patients with liver disease.15 eventually discharged in stable condition. Blood and wound In this series, five of six patients had a history of liver cultures grew V. vulnificus from initial admission and wound disease. Hepatitis C virus infection was present in three debridement, respectively. patients, while five had a history of alcoholism. The only patient who did not have a history of liver disease, however, DISCUSSION did carry the risk factor of immunosuppression, which is an independent risk factor for systemic infection. Achlor- Epidemiology hydria due to proton pump inhibitor use was present in As this series illustrates, V. vulnificus causes an uncom- three cases. The acidic environment of the stomach is the mon but often lethal infection. Although only six cases were first line of defense against V. vulnificus when it enters the identified over the six-year period of review, the high num- gastrointestinal tract and attenuating this barrier may be ber of at-risk individuals, along with the high case fatality harmful. However, V. vulnificus is known to possess sev- rate (66% in our study), makes the early recognition and eral virulence factors that allow it to neutralize acid, and treatment of this disease a public health priority. Adults ac- the extent to which this factor plays a role is uncertain.3 counted for five of the six patients in our series and compose Chronic renal disease was present in one patient in our the vast majority of reported cases in the literature. Infec- study and is reported in approximately 7% of patients with tion in children is very unusual, primarily due to the low primary septicemia or wound infection in other studies.2,13 prevalence of cirrhosis or other chronic illnesses in this age Presumably, this is related to immune dysfunction, as well as mediated by uremia and the buildup of unfiltered toxic

200 J La State Med Soc VOL 164 July/August 2012 metabolites. Acute kidney injury occurred in all patients, Table 2: Symptoms and Signs at Admission however, undoubtedly reflecting a state of severe sepsis and systemic inflammation. Symptom Primary Wound septicemia infection Clinical Presentation (N=4) (N=2) Primary septicemia and wound infection together ac- Fever 4 1 count for approximately 90% of reported V. vulnificus infec- Chills 3 1 tions in the literature.1,7 In our series, there were four (66%) cases of primary septicemia and two (33%) cases of wound Malaise 3 1 infection. No patients had uncomplicated gastroenteritis, Abdominal 3 1 3 which is diagnosed by stool culture. This is consistent with pain other studies and supports the theory that individuals with gastroenteritis typically do not seek medical care.12 The Nausea or 2 0 range of presentation for primary septicemia is noteworthy, Vomiting as only two of these patients developed the telltale stigmata Diarrhea 2 0 of purpura and hemorrhagic bullae on the lower extremities at the time of admission. This underscores the importance Lower 2 2 extremity pain of a patient’s clinical history and risk factors in deciding whether or not to initiate treatment for V. vulnificus infec- Lower 2 2 tion at the time of admission. Nonspecific symptoms such as extremity fever, abdominal pain, diarrhea, nausea, or lower extremity swelling pain or swelling may be the only reported symptoms at the Lower 2 1 time empiric antibiotic therapy must be selected (Table 2). extremity Vibrio organisms are rarely identified by gram-stained speci- purpura mens, although small (0.5-3 µm) curved, gram-negative rods are characteristic. However, blood cultures are frequently Hemorrhagic 1 1 positive because Vibrio organisms grow readily on most bullae media used in clinical laboratories. In our series, rapid clinical deterioration requiring in- based on multiple observational studies that have reported tubation and vasopressor support occurred in five patients, increased efficacy with addition of a tetracycline antibiotic four of whom subsequently died. Indeed, many patients such as doxycycline or minocycline.15,16,18,19 In our study, who die of septicemia do so within 48 hours of admission.7 only one patient received doxycycline as part of his initial Further history was unable to be elicited from two patients antimicrobial regimen. A previous study by Dechet found due to rapidly progressive respiratory failure requiring similar results, where less than one-third of patients with intubation, which highlights the need for thorough patient Vibrio wound infections received one of the antibiotics rec- assessment of the risk factors for V. vulnificus infection at ommended in treatment guidelines.9 It is unknown whether the outset of admission. Hypotension (systolic < 90 mmHg) this finding in our study is due to lack of clinical suspicion is associated with a poor prognosis in V. vulnificus septice- for infection or lack of knowledge about recommended mia, with more than twice the relative risk of mortality.7 therapy. Nevertheless, the rapid progression and high mor- Leucopenia is also associated with increased risk of severe tality of V. vulnificus infections demand early recognition infection and was present in three patients in our study, and initiation of appropriate effective treatment. two of whom died.3 Thrombocytopenia is a third laboratory If third-generation cephalosporins are not used, fluo- finding of significance and should not simply be attributed roquinolones such as levofloxacin or ciprofloxacin may be to underlying cirrhosis when present. In one study, nearly substituted and may be equally efficacious when used alone 50% of patients had disseminated intravascular coagula- or in conjunction with a tetracycline antibiotic both in vitro tion.3 Finally, wound infection occurred in two patients. and in vivo animal models.4,16,20,21 It is unknown, however, Although both developed secondary septicemia, the patient whether the synergistic effect with tetracycline antibiot- with documented cirrhosis died, and the patient without ics occurs when added to fluoroquinolones. Randomized diagnosed liver disease survived. As with primary septice- human trials comparing various antibiotics are lacking, mia, patients with liver disease are more likely to die as a being hindered by the sporadic and infrequent nature of V. result of infection.9 vulnficus infections. Piperacillin-tazobactam, used empirically in half of the patients in our series and frequently in Treatment patients suspected of bacterial sepsis, has been reported The CDC Centers for Disease Control and Prevention effective in vitro as well.19,22 Tetracycline antibiotics should recommends ceftazidime plus doxycycline as first-line probably be used in addition to beta-lactam antibiotics in therapy for V. vulnificus infection.4 This recommendation is this case, as well as in cases of severe infection, given the synergy demonstrated when these two classes of antibiot-

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