Infective endocarditis (IE) is a serious condition, particularly in patients with congenital heart disease and prosthetic valves, where diagnosis and management are more complex. We present clinical case of 40-year-old male, who underwent repair of aortic coarctation at age seven and subsequently mechanical aortic valve replacement for active IE with multiple periannular abscesses, presented for extended diagnostics after six negative pre-operative blood cultures. Blood culture specimens were collected following established local protocols and in line with professional standards of practice.

He received empiric therapy with vancomycin, gentamicin and rifampicin. Despite this, during the fourth postoperative week he developed high-grade fever; serial blood and urine cultures remained sterile and echocardiography revealed no new vegetations. Meropenem was added without improvement, then switched to doxycycline and ceftriaxone given the possibility of rare pathogens responsible for culture-negative IE. The patient defervesced within 24 h. Further diagnostics (trans-esophageal echocardiography and labelled leukocyte scintigraphy) excluded active IE. He completed a six-week antibiotic regimen, was anticoagulated with warfarin, and at discharge had normal prosthetic aortic valve function and satisfactory cardiac parameters.

A 40-year-old patient with a history of coarctation of the aorta repair at the age of 7, consistent with congenital heart disease requiring lifelong monitoring [1, 2] was admitted for continuation of treatment and extended diagnostics of infective endocarditis (IE). He had undergone urgent surgical replacement of a bicuspid aortic valve due to active endocarditis with multiple periannular abscesses. A mechanical valve was implanted under cardiopulmonary bypass. All six blood cultures obtained prior to surgery remained negative for microbial growth, fulfilling major criteria for culture-negative endocarditis [3]. The initial empiric antibiotic regimen consisting of vancomycin 1000 mg every 8 hours and gentamicin 240 mg every 24 hours intravenously was modified at the referring center by adding rifampicin 300 mg every 12 hours orally and adjusting the vancomycin dose according to the measured drug levels. After surgical management the patient was transferred to our hospital receiving combined triple antibiotic therapy according to recommendations from the referring center. At the time of admission, blood pressure and heart rate were within the normal range, the patient reported fatigue and reduced exercise tolerance but denied dyspnea nor chest pain. Following dental consultation, tooth 36 was extracted under amoxicillin prophylaxis due to suspicion of being a potential source of infection.  Low-grade fevers persisted for two days and were attributed to post-extraction inflammation in the context of declining inflammatory markers. Multiplex PCR excluded SARS-CoV-2, influenza A/B, and RSV infection. 

Figure 1:A. Significant aortic regurigitation (colour Doppler ultrasound picture). B. Significant aortic regurigitation. C. D.  Visible vegetation on the aortic valve.On the fourth week post operation, the patient developed high-grade septic fever (up to 39.5°C). Laboratory testing excluded HIV, HBV, HCV, EBV, and CMV infection. Blood and urine cultures were repeatedly sterile. Echocardiography revealed no new vegetations, in line with Duke criteria assessment [3]. The site of temporary pacing lead insertion appeared unremarkable.           

According to the local guidelines suggesting broad-spectrum Gram negative coverage, including pathogens from the HACEK group [4], meropenem was added but yielded no clinical improvement. Despite the development of a rash, treatment continued under cetirizine coverage. After 4 days with no clinical nor laboratory improvement and written consultation with a clinical pharmacist, meropenem was replaced with doxycycline and ceftriaxone. This management was due to the concept of rare pathogens such as Coxiella burnetii, Bartonella spp., Aspergillus spp., Mycoplasma pneumoniae, Brucella spp., and Legionella pneumophila, Tropheryma whipplei could be involved in the pathogenesis of infective endocarditis. [5] Doxycycline is an anti-infective agent recommended in many of these pathogens and a limited data from a large prospective analysis [6] suggested primarily for Coxiella and Bartonella species infection culture-negative IE. Unfortunately, serological testing for these pathogens was not performed for unknown reasons, most likely due to lack of availability in the treating centre. Within 24 hours after meropenem discontinuation the patient became afebrile.      

To eliminate potential infection sources, tooth 14 was also removed. For further diagnostics (transoesophageal echocardiography [TEE] and 

labelled leukocyte scintigraphy), the patient was transferred to the Department of Coronary Artery Disease and Heart Failure at John Paul II Hospital in Krakow.              

Both TEE and scintigraphy excluded active IE. At readmission, the patient remained afebrile and in good general condition (BP 95/70 mmHg, HR 70 bpm), reporting only fatigue. Physical examination was unremarkable.           

Ceftriaxone was replaced with ciprofloxacin, and doxycycline was continued. The planned total duration of antibiotic therapy was six weeks. Warfarin was reintroduced and ACE inhibitors and spironolactone were discontinued due to hypotension.       

Control echocardiography at discharge revealed normal LV systolic function (EF 55%), mild mitral and tricuspid regurgitation, SPAP 30 mmHg, and normal function of the mechanical aortic prosthesis (gradient 12/7 mmHg). No fluid collections were present.       

This case underscores the challenges in diagnosing and managing culture-negative IE in patients with prosthetic valves and congenital heart disease. It highlights the importance of multidisciplinary collaboration, advanced imaging, and empiric adjustment of antimicrobial therapy targeting atypical pathogens when standard treatment fails.