Use of a cephalosporin/β-lactamase inhibitor combination against MDR P. aeruginosa in tibial osteomyelitis and wound infection

History and investigations
The patient was a man in his late thirties with a history of tibial malunion. Since childhood, he had undergone multiple operations and received various implants, including intramedullary gamma nails and external fixators. In the past decade, he had several episodes of Gram-positive and Gram-negative bacterial infections requiring hospital admissions and intravenous antibiotic therapies, including cloxacillin, amoxicillin/clavulanate, cefuroxime, ciprofloxacin and cefotaxime.

The patient was admitted to hospital in mid-November 2021 for osteomyelitis of the tibia. He had been experiencing fever of up to 40^oC for 5 days, with abscess formation in an old implant wound.

Upon admission, blood test showed an elevated C-reactive protein (CRP) level of >200 mg/L, and his estimated glomerular filtration rate was >90 mL/min/1.73 m². Initial wound swab culture revealed multiple bacterial isolates, including Pseudomonas aeruginosa. (Table) 

Treatment and response
Based on results of antimicrobial susceptibility testing, the patient received 26 days of piperacillin/tazobactam (4.5 g Q8H), along with surgical open drainage of the abscess, wound debridement and reaming with external fixation. Treatment with piperacillin/tazobactam led to an improvement in tibial osteomyelitis, with CRP level dropping to 114 mg/L. In mid-December 2021, the patient experienced rash and recurrent fever, and his CRP level rebounded to >200 mg/L. He subsequently developed bacteraemia due to Enterobacter cloacae, which resolved after a course of meropenem (1 g Q8H).

However, wound swab, drainage and tissue culture all revealed multidrug-resistant (MDR) P. aeruginosa isolates that were nonsusceptible to almost all tested antibiotics, except ceftazidime, cefoperazone/sulbactam, and ceftolozane/tazobactam. Corynebacterium kroppenstedtii was also recovered in tissue and wound swab culture. Although the Corynebacterium infection was treated with 10 days of vancomycin, treatment with 14 days of ceftazidime monotherapy followed by 14 days of ciprofloxacin and amikacin combination therapy did not eradicate MDR P. aeruginosa, resulting in unsatisfactory clinical improvement. In late January 2022, ceftazidime/avibactam (2.5 g Q8H) with tobramycin or colistin were started and administered over 2 months, for bone and skin grafting performed in late February 2022. (Table)

Ceftazidime/avibactam-based treatment controlled the infection, with CRP level falling to 10 mg/L. However, in late March 2022, 2 weeks after treatment completion, P. aeruginosa was detected from wound culture. In late March 2022, the patient was treated with piperacillin monotherapy, but he developed a rash. After switching to ceftazidime, multiple strains of MDR P. aeruginosa resistant to piperacillin/tazobactam and ceftazidime were isolated in the wound swab samples. Despite 2 months of combination therapy with meropenem, amikacin and ciprofloxacin, the MDR P. aeruginosa infection persisted. The CRP level in June 2022 was 11.5 mg/L. (Table)

In late June 2022, MDR P. aeruginosa nonsusceptible to nearly all tested antibiotics, including ceftazidime/avibactam, but susceptible only to ceftolozane/tazobactam, was isolated in the wound swab sample. The patient was put on a 2-week course of ceftolozane/tazobactam (3 g Q8H) in combination with fosfomycin (8 g Q8H), which resulted in clinical cure and postoperative wound recovery, with CRP level of 8.7 mg/L. During this treatment, he did not experience any adverse events (AEs). He was discharged after completing combination therapy with ceftolozane/tazobactam and fosfomycin. (Table)

After discharge, the patient was followed up in the orthopaedic trauma clinic. As of February 2023, he remained well and was able to engage in sports.

Discussion
The 2019 Antibiotic Resistance Threats Report by the US Centers for Disease Control and Prevention (CDC) identified MDR P. aeruginosa as a serious threat.¹ MDR P. aeruginosa may cause severe infections, which are associated with worse outcomes, such as higher rates of invasive procedures, longer hospital stays, and increased mortality.^2,3

The choice of empirical antibiotic treatment for bacterial infections should be guided by antimicrobial susceptibility patterns of the isolates. In case of resistance to common antibiotics, the Infectious Disease Society of America (IDSA) guidelines recommend cephalosporin/β-lactamase inhibitor combinations, such as ceftolozane/tazobactam, for difficult-to-treat P. aeruginosa infections.⁴

Ceftolozane is a cephalosporin that disrupts bacterial cell wall synthesis via inhibiting a broad range of penicillin-binding proteins, which is resistant to hydrolysis driven by AmpC-type and OXA-type non–extended-spectrum β-lactamases (ESBLs). Tazobactam is a β-lactamase inhibitor that extends the activity of ceftolozane by targeting class A serine β-lactamases and ESBLs. The two modes of action make ceftolozane/tazobactam effective in treating infections caused by MDR P. aeruginosa.^2,5

Ceftolozane/tazobactam has demonstrated clinical effectiveness against susceptible Gram-negative bacteria, including MDR P. aeruginosa. In a systematic review of 83 real-world studies (n=3,701), 27 of 39 studies showed clinical success rates of >70 percent (range, 45.7–100.0 percent), and 14 of 19 studies showed microbiological success rates of >70 percent (range, 31–100 percent). In addition, 45 studies showed mortality rates of 0–50 percent, while 31 studies reported mortality rates of ≤20 percent.⁶

In our patient, P. aeruginosa was isolated from the infection site 2 weeks after completion of treatment with ceftazidime/avibactam plus colistin. Importantly, the isolates showed resistance to commonly used antibiotics, including piperacillin/tazobactam and ceftazidime. Although susceptibility to ceftolozane/tazobactam was identified at the time of hospitalization, it was unavailable in Hong Kong at the time due to global supply chain crisis. MDR P. aeruginosa was not completely eradicated after 2 months of combination therapy with meropenem, amikacin and ciprofloxacin.

Multiple failed attempts of antibiotic treatment may lead to development of resistance of clinical P. aeruginosa isolates. Some in vitro studies have shown synergistic effects of combining older antibiotics (eg, fosfomycin, aminoglycosides and polymycins) with cephalosporin/β-lactamase inhibitor combination.^7-9 These treatment options could be considered for hospitalized patients with persistent MDR P. aeruginosa, like our patient who had been receiving treatment for his infection for >6 months.

Our patient was started on ceftolozane/tazobactam once its supply had resumed in Hong Kong, along with fosfomycin. After 2 weeks of treatment, he achieved clinical cure and was discharged. Although nausea, vomiting and diarrhoea were commonly reported AEs associated with ceftolozane/tazobactam, our patient tolerated ceftolozane/tazobactam well and did not experience any AEs during treatment.⁵

As illustrated in our patient’s case, positive clinical outcomes can be achieved with the use of ceftolozane/tazobactam in MDR P. aeruginosa infection. This combination is one of the preferred antibiotics for treatment of infections due to MDR P. aeruginosa, including strains resistant to piperacillin.