It is well known that intravenous drug users (IDUs) commonly suffer medical complications from the drug(s) they abuse. Besides drug side effects, there are often complications caused by associated processing impurities and unsafe methods of administration. These complications include infections, toxic necrosis, and embolic disease.1 Injection associated infection not only leads to frequent admissions2 but is also the most common cause of death in IDU patients.3 The most common bacterial organism associated with skin infections in IDU patients is Staphylococcus aureus.4 Yet, numerous other organisms have also been reported, including coagulase-negative Staphylococcus species, Streptococcus species, Klebsiella species, Pseudomonas species, Escherichia coli, and Proteus species.5 Here we present a case of sepsis in an IDU, which was believed to have originated from a large shallow ulcer on his left leg.
The patient is a 48-year-old man who presented to a local Veteran's Administration (VA) emergency room with a 2-day history of malaise and abdominal pain and a 1-day history of subjective fevers, nausea, and vomiting. He thought that his symptoms might be related to a progressively enlarging left lower leg ulcer that had been present for 2 months. He denied any other symptoms or illness before this presentation. His evaluation at the VA was notable for fever at a temperature of 103°F, tachycardia of 106 beats per minute, and a large necrotic left leg ulcer. Blood cultures were drawn; he was given intravenous (IV) ceftriaxone and clindamycin and then transferred to Madigan Army Medical Center (MAMC) for further care.
His medical history was notable for previous IV heroin abuse, chronic hepatitis C infection, and emergent splenectomy for a lacerated spleen in 1998. He had no known drug allergies, and his only medication was oral methadone as part of a drug rehabilitation program. He initially denied recent illicit drug or alcohol use, but after repeated questioning about his drug use history, he espoused recent heroin use without concomitant alcohol use. He was not homeless and did not share needles. He had been using his leg ulcer as a site for both venous access to inject heroin and for "skin-popping" heroin under the ulcer's border. Unlike his previous skin-popping ulcers, this one did not heal. At the edges of the ulcer, the skin would become necrotic and turn black. He would debride dead tissue using his fingernails and then repeat skin popping under the new border.
Upon arrival to MAMC, his vital signs were a temperature of 100.6°F, a heart rate of 103 beats per minute, a blood pressure of 110/56 mm Hg, respiratory rate of 18 breaths per minute, and an oxygen saturation of 96% on room air. His examination was notable for a midline scar over the abdomen, and a 12 × 4-cm shallow ulcer with a discrete necrotic border surrounded by a large area of erythema and tenderness tracking up to the left midthigh and down to the left ankle (Fig. 1). His right leg had numerous well-healed, round, depressed scars (Fig. 2). There was no cardiac murmur, evidence of embolic phenomenon, or other sequelae concerning for endocarditis. His laboratory values were notable for leukocytosis to 11,900 white blood cells with 27% band forms and a mild elevation of aspartate aminotransferase, 175 U/L, and alanine aminotransferase, 131 U/L. A roentgenogram of his chest did not show any abnormalities and left leg roentgenograms demonstrated soft tissue edema of the leg but were otherwise unremarkable. While undergoing evaluation, he had a hypotensive episode with blood pressures of 87/52 mm Hg which responded to IV fluid boluses without the use of pressor agents. Because of his history of IV drug use and a probable portal of entry through the skin, his antibiotic treatment was changed to IV nafcillin and gentamicin to treat sepsis, his leg wound infection, and possible endocarditis. A subsequent transthoracic echocardiogram established that all 4 valves were clear of vegetations or pathology.
The patient quickly improved and was afebrile and hemodynamically stable within 24 hours. The day after admission, the VA laboratory called to report that his initial blood cultures contained gram-negative rods. There was suspicion that the cultures contained a Capnocytophaga species, as the isolated organism demonstrated a fusiform morphology (Fig. 3). The laboratory personnel were having significant difficulty identifying the organism. The MAMC laboratory had also cultured a slender fusiform gram-negative rod that was difficult to identify using standard preparations. Upon further questioning, the patient reported he owned a Chihuahua that often slept at his feet and would frequently lick his hands. He repeatedly denied that it had ever directly licked or contacted the ulcer.
The patient was transitioned to oral amoxicillin/clavulanate and educated on hygiene and wound care. On hospital day 4, he was discharged to home with encouragement to stop his drug abuse and return to his treatment program. Although the organism species was not confirmed at the time of discharge, he continued to improve clinically with resolution of his leukocytosis. Several days later, his initial blood cultures were identified as Capnocytophaga canimorsus and the wound cultures as Fusobacterium nucleatum and a Pasteurella species.
Capnocytophaga canimorsus is an unencapsulated member of the Flavobacteriaceae family.6 It was initially identified in 1976 in association with sepsis secondary to a dog bite. At the time, it was classified as CDC dysgonic fermenters group 2 (DF-2) separate from the dysgonic fermenters group 1 (DF-1), which was a different group of cultures isolated from human oral flora samples. Within the DF-2 group, C. canimorsus and Capnocytophaga cynodegmi have since been individually identified and classified. Both Capnocytophaga species appear as thin gram-negative bacilli, with tapered ends, as was reported in this case. Some of the common errors and difficulties associated with identification, that is, confusion with F. nucleatum, have been described in the literature. Substrate adjustments and tests for strict anaerobic growth versus microaerophilia and indole reactions can help differentiate the 2 species.7,8
Risk factors for infection with C. canimorsus are male sex, middle age, splenectomy, alcohol abuse, dog bite, and corticosteroid use.7 Various case reviews include patients who have been infected by cat bite, dog or cat scratches, and atraumatic animal contact and rarely occur without animal contact.9 Although there is a prior report of C. canimorsus infection in an IV drug user, that patient presented 2 days after a dog bite. Of interest, that reported patient had also undergone splenectomy for a traumatic injury. Unfortunately, his course was more progressive with the development of disseminated intravascular coagulation (DIC) and death.10 Reported cases of life-threatening infections in C. canimorsus of both immunocompetent and immunocompromised hosts can be found in the literature.11 Yet, there is a significantly greater risk to immunocompromised or asplenic patients.
Patients who are immunosuppressed, alcoholic, or asplenic are reported to be at increased risk for a rapid, fulminant progression of C. canimorsus infections that can result in septic shock and DIC. The largest case review to date was published in 1991 and reported on the characteristics of 60 cases of C. canimorsus sepsis. They reported that 33 (55%) of the infected patients had a history of being either asplenic or alcoholic. Eighteen (55%) of the 33 patients either developed DIC or died compared with an overall mortality rate of 28% in the other reported cases.12 Additional reported complications associated with C. canimorsus infection include meningitis, brain abscess, disseminated purpuric lesions, renal failure, myocardial infarction, keratitis, gangrene of the bite site, pulmonary infiltrates, hemolytic uremic syndrome, Waterhouse-Friderichsen syndrome, endophthalmitis, and, recently, mycotic aortic aneurysm.7,13,14
The mechanism for the immunocompromised state caused by anatomic asplenism or functional hyposplenism is still under study with various theories proposed to explain the process.15-21 Recent research in mice suggests that the marginal zones of the spleen are the primary area for immunologic response and clearance of encapsulated organisms (and similar antigens) through 2 possible mechanisms. The first mechanism is based on the presence of the B-1a B-cell subset in the splenic marginal zone that produces a standing inventory of "natural" IgM antibodies. These low-specificity immunoglobulins allow for a host response to some T-cell-independent antigens.18,20 Another mouse subset of B cells identified as marginal zone B cells provides the second mechanism by lowering the threshold of cross-linked activation. This is achieved through a high density of surface receptors in the low-velocity flow state of the marginal zone.19
In addition to requiring a functional spleen for efficient clearance, C. canimorsus may also have specific mechanisms for avoiding other portions of the mouse immune system. Shin et al 21 reported on the ability C. canimorsus isolates to replicate in the presence of macrophages and the lack of an inflammatory response that would be expected of most gram-negative bacteria in his mouse model. Together, these studies suggest that the spleen is the cornerstone of immunologic response to C. canimorsus (and other organisms with a low immunogenic profile) and that C. canimorsus likely has additional immunosuppressive capability that results in increased morbidity and mortality.
The usual treatment of C. canimorsus is penicillin or amoxicillin/clavulanate, although there are reports of response to several other antibiotics to include third-generation cephalosporins, imipenem, erythromycin, vancomycin, clindamycin, doxycycline, and quinolones. V. J. Gill, whose review is often referred to in case discussions, further recommends prophylaxis with amoxicillin/clavulanate for asplenic patients after a dog bite.7 Yet, asplenic patients often present with an unknown source for their sepsis.
The most common organisms causing infection and death in asplenic patients are Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitides. Capnocytophaga canimorsus is far less frequently associated with asplenic septic shock but, as mentioned, has an extremely high associated morbidity. Numerous other microbial species, including Salmonella species, Bordetella species, other Streptococcus species, Staphylococcus species, and parasites, have also been reported as asplenic-associated infections and occasionally asplenic-associated septic shock.22
The empiric treatment of asplenic sepsis of unknown etiology is often based on covering the 3 most common organisms which also results in broad coverage of most bacterial species. Initial treatment recommendations for asplenic patients with sepsis often include a third-generation cephalosporin with the addition of vancomycin if there is significant risk of local resistance. If there is little risk of a penicillin-resistant infection, then more selective antibiotic coverage can be initiated.14,23 If the patient presented here had not rapidly improved, then vancomycin might have been added as empiric therapy until culture data were available. The risk factor of IV drug use in the setting of an unstable asplenic patient would have warranted broader empiric coverage.
Our patient presented with several nonspecific, yet associated risk factors for C. canimorsus infection: male sex, middle age, splenectomy, and animal contact. Because of his large leg ulcer and continued injection drug use, the initial treatment decisions were based on the assumption that his sepsis was caused by organisms typically associated with IV drug use. As culture data became available, the more relevant clinical associations in this case were identified. The actual mechanism of his wound inoculation is unknown. It may have been through direct contact with the dog or from the patient's contaminated hands but not from animal bite which is a more common association. Fortunately, for this asplenic patient, he did not suffer some of the more severe complications of C. canimorsus infection.
During evaluation and management, it is important to remember that IV drug abusers are at increased risk for sepsis from multiple environmental and other associated risk factors that commonly occur in this patient population, including poor hygiene, immunosuppression, malnutrition, inadequate shelter, alcoholism, animal contacts, and so on. These factors contribute not only to risk of commonly associated infections such as Staphylococcus species, but also to the uncommon but no less serious infections such as C. canimorsus. This case serves as a reminder that a complete history and evaluation, which might include consideration of asplenism and animal contacts, will lead to more accurate diagnoses, improved patient care, and more efficient use of antibiotic resources.
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