Rare but Fatal Pasteurella multocida Infective Endocarditis: A Case Report and Literature Review

Pasteurella multocida is a small Gram-negative organism that usually causes a localized infection after exposure to cat or dog scratches, bites, or licking wounds. Invasive infections, such as bacteremia and endocarditis, are very rare yet serious conditions that are associated with high morbidity and mortality, particularly in patients with major comorbidities. Here, we report a case of a 47-year-old male who presented to the hospital with altered mental status two weeks after a fall and was found to have a subarachnoid hemorrhage. Further workup revealed Pasteurella multocida bacteremia and infective endocarditis. The patient had a complex hospital course with septic shock and acute congestive heart failure with poor clinical outcomes. A comprehensive review of the literature of all reported cases of definite Pasteurella endocarditis follows.


Introduction
Pasteurella multocida (P. multocida), a small, Gram-negative, nonmotile coccobacillus, is a normal commensal of many animals' oral flora, with cats and dogs representing the majority [1]. It can cause a variety of infections in humans, most commonly skin and soft tissue infections, following scratches, bites, or licking wounds [1]. However, invasive infections, such as bacteremia and infective endocarditis (IE), are very rare though serious conditions that are associated with high morbidity and mortality, especially in patients with major comorbidities [2]. Here, we report a case of a 47-year-old male with liver cirrhosis and diabetes found to have P. multocida bacteremia and endocarditis. His hospital course was complicated by septic shock, hypoxemic respiratory failure requiring intubation, septic emboli to the brain, and multiple organ failure, ultimately resulting in death.

Case Presentation
Our patient is a 47-year-old male with a history of alcohol abuse, alcoholic liver cirrhosis, hypertension, and type 2 diabetes mellitus who presented with altered mental status. Per the patient's wife, his deterioration began after a fall in the shower two weeks before presentation, followed by progressively worsening headache and multiple episodes of epistaxis. His condition continued to deteriorate and 12 hours before presentation, he developed confusion, weakness, and agitation, which prompted his presentation to the emergency department (ED).
In the ED, his vital signs were as follows: temperature 37.2 °C, heart rate 99/min, respiratory rate 20/min, blood pressure 115/66 mmHg, and oxygen saturation 99% on room air. On physical exam, he was illappearing, confused, and responding to painful stimuli only, with a Glasgow Coma Scale of 10. Skin examination was pertinent for jaundice, spider nevi, scattered ecchymoses, purpura, and scratch marks to his left lateral leg. Cardiac examination was normal except for tachycardia. Lungs were clear to auscultation, and abdominal examination was benign. The patient had +2 bilateral lower extremity pitting edema more prominent in the left side. Table 1 summarizes initial workup findings, and Figure 1 shows initial CT findings.

Imaging/Test Findings
Chest X-ray Bibasilar atelectasis and superior mediastinal prominence concerning for adenopathy or mass ( Figure 2A).

CT head without IV contrast
Left frontal hyperdense focus concerning for subarachnoid hemorrhage ( Figure 1C) and nondisplaced right nasal bone fracture.

CT chest without IV contrast
Trace bilateral pleural effusion with compressive atelectasis and minimally displaced anterior wedge compression deformity of the superior endplate of T3 without significant height loss.   The patient received intravenous (IV) fluids and platelet transfusion, resulting in improved creatinine to 3.31 mg/dL, platelets to 22 K/mcL, and lactic acid to 1.8 mmol/L. He was then admitted to the Medical Intensive Care Unit (MICU) and started on IV vancomycin and cefepime for sepsis. Two sets of blood cultures grew Gram-negative rods 11 hours after collection. Identification of P. multocida was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The disk diffusion test revealed susceptibility to penicillin, ampicillin, ceftriaxone, and levofloxacin. Urine culture was negative for any bacterial growth. Further questioning of the patient's wife revealed a history of scratch by an outdoor cat to his left leg two weeks before presentation.
Two days later, the patient developed tachypnea, tachycardia, and increased work of breathing. Chest X-ray showed increased infiltrates concerning for moderate pulmonary edema ( Figure 2B) that was not found on the initial chest X-ray ( Figure 2A). He was intubated and started on vasopressors for septic shock.  Repeat blood culture the next day was negative. Antibiotics were switched to IV ceftriaxone 2 gm q12hr and IV metronidazole 500 mg q8hr to cover for possible meningitis and aspiration pneumonia given his worsening mentation. Four days after admission, brain MRI showed signs of subacute lacunar infarcts with distribution suggestive of embolic phenomena ( Figure 4). Spine MRI was negative for osteomyelitis, discitis, or spinal abscess. Cardiothoracic surgery was consulted and recommended repeating a TTE in one week. The patient was deemed a poor surgical candidate for surgical mitral valve replacement given his high MELD Na of 29, Child C liver cirrhosis, and subarachnoid hemorrhage. Three days later, the patient was extubated, following commands, and off vasopressors. He was then transferred to the medicine floor. However, after a few days, he developed severe pulmonary edema requiring bilevel positive airway pressure (BiPAP). Furthermore, he developed intermittent fever and anemia requiring blood transfusion. Physical exam was pertinent for diffuse anasarca, a blowing systolic murmur best heard at the lower left sternal border, and diffuse crackles bilaterally. B-type natriuretic peptide (BNP) was 1200 pg/mL and troponin I 0.22 ng/mL. ECG showed sinus tachycardia and was negative for acute ischemic changes. CT pulmonary embolism (PE) study was negative for PE but showed marked worsening bilateral infiltrates, bilateral moderate to large pleural effusions, and right heart chamber predominant cardiomegaly. The patient was started on bumetanide drip 1 mg/hr and antibiotics were switched to IV vancomycin and piperacillin-tazobactam to cover for healthcare/ventilator-associated pneumonia. He was then transferred to the MICU and was re-intubated.
A repeat TTE revealed an increase in the size of mitral valve vegetation to 2.2 cm x 1.5 cm. The MICU course was complicated by anemia and hemoptysis concerning for diffuse alveolar hemorrhage requiring blood transfusion; however, while receiving blood, the patient developed worsening oxygenation likely due to severe MR caused by the enlarging vegetation and volume overload. Blood transfusion was held, and the patient's diuretic regimen was increased.
Unfortunately, the patient's mental status did not improve and given his multiple comorbidities precluding him from aggressive interventions and prolonged complicated hospital course, his family decided to pursue comfort measures. He was palliatively extubated and transferred to the inpatient hospice service where he eventually passed comfortably.

Discussion
Pasteurella species (spp) are normal commensals of many animals' oral bacterial flora, primarily cats and dogs [1]. Human infection by Pasteurella usually causes localized skin and soft tissue infections [1]. However, infective endocarditis is rare, with only 42 cases, including ours, reported in the literature. A PubMed search was conducted using keywords "Pasteurella" and "endocarditis". Only cases that met the Modified Duke infective endocarditis criteria [3] and with microbiologically proven Pasteurella infection were included and reviewed manually. Further studies were identified from the references of the selected cases. The number of reported cases has been increasing, especially in the last two decades ( Figure 5). Males were affected more than females, comprising 62% of the reported cases. The mean age was 56.7 ± 16.5, ranging from 17 to 88 years. Table 2 summarizes the literature review of all reported cases of definite Pasteurella endocarditis. Table 3 shows a detailed review of all cases.    "Cured" in the outcome is defined as full recovery.
Our case satisfied the Modified Duke criteria for the diagnosis of infective endocarditis [3]; one major criterion: evidence of endocardial involvement, and three minor criteria: fever, blood culture, and vascular phenomena (septic emboli to the brain).
Of 31 cases (74%) who reported exposure to animals, 29 (94%) had exposure to cats, dogs, or both. One had exposure to sheep [4], and another was exposed to fish and sheep [5]. Fifteen (48%) had a known history of scratches, bites, or licking non-intact skin. Of all reported cases, seven (17%) had no history of animal exposure. P. multocida has been isolated from the respiratory tract of healthy individuals who have frequent exposure to animals [1].
Risk factors included liver disease in seven (17%), heart disease in 20 (48%), prior endocarditis in four (10%), substance abuse in 10 (24%), diabetes mellitus in two (5%), solid organ transplant/immunosuppressive therapy in one (2%), and malignancy in one (2%). However, Pasteurella IE has also been reported in six (14%) healthy individuals. Immunocompromised patients are at higher risk of severe disease and complications such as sepsis, septic shock, and multiorgan failure [2,43]. A comprehensive review of 119 cases of P. multocida bacteremia reported comorbid conditions, such as chronic liver disease, diabetes mellitus, malignancy, and immunosuppressive therapy in 67% of patients, and the mortality rate was 31% at 30 days [43]. On multivariate analysis, having major comorbid conditions was the only factor associated with mortality (OR 2.78, 95% CI 1.01-7.70: P-value 0.04) [43].
The overall mortality rate in previously reported cases of Pasteurella endocarditis was 26% (11 cases), of which 64% (7 cases) had major comorbidities. A recent analysis of 32 cases of Pasteurella endocarditis demonstrated a statistically significant association between comorbid liver disease and mortality rate despite the low number of cases [2].
Our patient had a complex hospital course consisting of sepsis, septic shock requiring vasopressors, and acute hypoxemic respiratory failure secondary to cardiogenic pulmonary edema due to severe mitral regurgitation requiring intubation, resulting in death. Diabetes mellitus and liver cirrhosis were the predisposing conditions that led to severe invasive infection in this case.
There are no clear guidelines for treating Pasteurella endocarditis, and data are limited to a small number of case reports. All patients received antibiotics except one who died shortly after presentation [17]. Pasteurella spp is often susceptible to penicillin [13,18]. Broad-spectrum cephalosporins, piperacillin-tazobactam, and ampicillin-sulbactam can be used alternatively. One case of Pasteurella endocarditis of the prosthetic mitral valve reported successful treatment with six weeks of IV penicillin without surgery [9]. Tirmizi et al. reported successful treatment of P. pneumotropica endocarditis of the native tricuspid valve with six weeks of oral ciprofloxacin [5]. One case of P. multocida endocarditis of the aortic valve prosthesis had a penicillin allergy and was successfully treated with six weeks of IV ceftriaxone [18]. Two cases reported resistance to penicillin and piperacillin-tazobactam, respectively [8,19]. Duration of treatment was variable among reported cases, and it depended on the severity, course of the disease, co-existing conditions, and antibiotic susceptibility. Carter et al. recommended initial six weeks of antibiotics therapy based on the clinical response and the average duration in previously reported patients who were successfully treated with antibiotics only [16]. Of all 29 cases (69%) who survived, 12 (41 %) received antibiotics only without surgery.
Of all reported cases, 18 (43%) required surgery. Indications for surgical intervention were severe valvular insufficiency, persistent symptoms despite antibiotic therapy, and aortic root abscess. Seventeen out of 18 (94%) cases who underwent surgery were cured while only one patient died four months after discharge due to septic shock secondary to Pseudomonas endocarditis of the native mitral and prosthetic aortic valves four weeks after a dental procedure [20]. Porter et al. suggested that surgery should be offered to all patients who have no absolute contraindications given the cure rate of 100% after surgical valve replacement [2]; however, their analysis did not consider the severity of illness, medical comorbidities, and indications for surgical intervention [16]. Moreover, they did not include the patient who died four months after surgery from Pseudomonas endocarditis [20]. Carter et al. suggested surgical intervention only if there is any indication, as with any case of other bacterial endocarditis [16]. The same study reported a patient with P. multocida endocarditis and septic arthritis successfully treated with antibiotics only despite his comorbidities.
There is no doubt that Pasteurella endocarditis is a rapidly progressive disease and is associated with high morbidity and mortality. It took approximately two weeks for our patient to develop complications following a cat scratch, one week from presentation to develop an increase in the valve vegetation size, and four weeks from presentation to death. He received a total duration of three weeks of antimicrobial therapy, but unfortunately, he was a poor surgical candidate due to significant comorbidities.
Due to its rarity, it is hard to conclude the proper management of Pasteurella endocarditis from the current literature. In the meantime, early recognition of the disease, interval echocardiograms to assess the vegetation size and possible complications, IV antibiotics, and early source control with surgical valve replacement for patients who have indications are the mainstay of treatment.

Conclusions
Infective endocarditis caused by Pasteurella spp is a rare though potentially serious and rapidly progressive disease with only 42 cases reported in the literature. It carries a high risk of morbidity and mortality, particularly in patients with comorbid conditions such as liver disease. Treatment is typically IV antibiotics, and surgery for source control should be considered on a case-by-case basis. Due to its rarity, further research is required to study the nature of disease progression, determine the appropriate duration of antimicrobial therapy, and identify the average time from symptom onset to surgery and its correlation with clinical outcomes.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.