Fosfomycin for Multidrug Treatment of Klebsiella pneumoniae Carbapenemase Bacteremia

We report successful treatment of bacteremia caused by Klebsiella pneumoniae carbapenemase (KPC)-producing K pneumoniae in an immunocompromised patient using a novel antibiotic regimen that included oral fosfomycin. A 35-year-old man with history of mantle cell lymphoma was admitted to our tertiary care center after presenting with abdominal pain and low-grade temperatures 2 days following myeloablative autologous peripheral blood stem cell transplant. The patient developed septic shock despite initiation of broad-spectrum antibiotics, vancomycin, and piperacillin-tazobactam. Blood cultures grew multidrugresistant KPC-producing K pneumoniae, with only intermediate susceptibility to tetracycline, which was on national shortage at that time. Based on culture results and the available literature, various combinations of antibiotics, including meropenem, tigecycline, amikacin, and colistimethate, were initiated in attempts to achieve synergy and eradicate the infection, but repeat blood cultures remained positive, and the patient continued to worsen clinically. Two days after the addition of high-dose oral fosfomycin (9 g by mouth every 8 hours) in combination with intravenous (IV) doxycycline 100 mg twice daily and meropenem 1 g every 8 hours, blood cultures showed no growth. The patient was afebrile, alert, and clinically stable within 3 days of culture clearance. The final antibiotic regimen of IV doxycycline, meropenem, and high-dose oral fosfomycin continued for 2 weeks from the first negative culture. On completion of therapy, repeat cultures remained negative, all antibiotics were discontinued, and the patient was discharged home from the hospital. Other than causing clinically significant diarrhea, fosfomycin was well tolerated. Data are limited on effective antimicrobial treatment of infections caused by carbapenemase-producing K pneumoniae. Studies highlight the difficulty of eradicating KPC infections but suggest that combining antimicrobials may achieve synergy against KPC isolates. Fosfomycin has demonstrated activity against various KPC isolates, and European studies have shown successful treatment of highly resistant KPC infections with the addition of IV fosfomycin to antibiotic regimens. Because IV fosfomycin is not available in the United States, our team extrapolated an oral fosfomycin dose based on the dose of 3 g IV every 8 hours used by Sbrana et al. Taking into account the drug’s approximate 30% oral bioavailability, the patient received fosfomycin 9 g by mouth every 8 hours, with the aim of achieving adequate blood concentrations despite the inability to administer fosfomycin intravenously. Results of advanced microbiological synergy testing revealed that the KPC isolate was sensitive to meropenem and fosfomycin in combination but resistant to each drug alone, affirming our decision to add fosfomycin. The advanced synergy testing also revealed the combination of doxycycline and meropenem to be synergistic, whereas combinations including amikacin and colistimethate offered no benefit. It is impossible to pinpoint which agent or combination led to clearance of blood cultures. However, based on the timing of fosfomycin initiation and the subsequent eradication of infection, high-dose oral fosfomycin may have played a significant role in successfully treating this highly resistant KPC infection.