Efficacy of Contezolid in the Treatment of Catheter-Related Bloodstream Infections Caused by Methicillin-Resistant Staphylococcus aureus in a Patient with Hepatorenal Syndrome and Acute Kidney Injury: A Case Report

Introduction

The Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) represents a serious complication in patients with cirrhosis in the decompensated stage, often leading to a dismal prognosis.¹ Methicillin-resistant Staphylococcus aureus (MRSA) infection further complicates the situation, negatively impacting on prognosis of patients with decompensated cirrhosis.² The mortality rate associated with MRSA bloodstream infections is approximately 32%.³ Patients with cirrhosis exhibit an increased mortality risk in the context of MRSA bloodstream infections, with a 1.9-fold higher likelihood of fatality compared to those without cirrhosis.⁴ Furthermore, it is estimated that only about two-thirds of these cases receive appropriate initial therapeutic interventions.³ Timely initiation of treatment against MRSA is crucial upon establishing a diagnosis. However, the employment of first-line agents, such as vancomycin and linezolid, for MRSA infections in HRS-AKI patients is hindered by compromised hepatic and renal functions, as well as thrombocytopenia resulting from hypersplenism.^5,6 Although daptomycin has demonstrated efficacy in treating MRSA bloodstream infections, its use is contraindicated in patients with pneumonia.⁷ Therefore, HRS-AKI patients with MRSA infection urgently need safe and effective therapeutic agents. Herein, we present a case of a continuous renal replacement therapy (CRRT) catheter-related MRSA bloodstream infection in an HRS-AKI patient with stage 3 AKI, concurrent thrombocytopenia and suspected pneumonia, who achieved favorable clinical outcomes after receiving a new oxazolidinone antibiotic contezolid.

Case Details

A 58-year-old male patient was admitted to our department with a 10-day history of nausea, abdominal distension, and oliguria. He had a 30-year history of heavy alcohol consumption and hepatitis C virus treated 3 years ago and denied recent kidney-damaging drug use. Prior to admission, the patient had received i.v. albumin for 48 hours without satisfactory response and presented with dyspnea and chest tightness.

On admission, his body temperature was 36.2°C, pulse was 82/min, respirations were 25/min, and blood pressure was 154/78 mmHg. Physical examination revealed abdominal distension with positive shifting dullness, bilateral lower extremity edema, and decreased breath sounds in both lungs. The abdominal computed tomography (CT) confirmed liver cirrhosis, splenomegaly, and ascites. Chest CT showed pleural effusion and left atelectasis. The renal ultrasound revealed no evidence of structural damage. Laboratory examination indicated an increase in serum creatinine (Scr) levels (from 850umol/L two days before admission to 1181umol/L at admission), elevated liver enzymes (glutamyl transferase at 126U/L and alkaline phosphatase at 206U/L) and normal coagulation test. Proteinuria was present, but no pathological casts. The patient was diagnosed with HRS-AKI, AKI stage 3.

Albumin and CRRT were initiated to optimize renal function and mitigate fluid overload. Cefazolin was administered. The patient’s Scr levels gradually decreased from 1181umol/L to 419umol/L (Figure 1), while urine volume increased from 500mL/d to 1650mL/d. However, on the 11th day of hospitalization, his temperature rose to 39°C with chills. Tests showed elevated C-reactive protein and neutrophils, as well as a decrease in platelet count (67×10⁹/L). The chest CT revealed bilateral lung infiltrates accompanied by pleural effusion. Based on the hypothesis of a bacterial infection, empirical treatment with Piperacillin-tazobactam (PTZ) (2.5g I.V. every 12 hours) was initiated. The blood culture at 24 hours returned positive for Gram-positive cocci, leading to the removal of the CRRT catheter as the suspected source. Further blood cultures confirmed the presence of MRSA in both blood and CRRT catheter samples, with drug sensitivity tests revealing susceptibility to vancomycin, linezolid, and rifampin. A diagnosis of catheter-related MRSA bloodstream infection was established. Despite negative sputum culture results, the presence of pulmonary infection cannot be excluded based on the findings from the CT scan of the lungs. Considering the patient’s history of HRS-AKI and stage 3 AKI, along with concurrent thrombocytopenia and the potential for pulmonary infection, treatment with vancomycin, linezolid or daptomycin were pending. An alternative oxazolidinone antibiotic called contezolid (800mg orally every 12 hours) was introduced to the anti-infection regimen with informed consent. Terlipressin, albumin, and tolvaptan were administered for HRS-AKI management. The patient’s temperature gradually returned to normal, serum creatinine levels decreased, and urine output significantly increased (2400mL/d) (see Figure 1). Liver function improved as shown by normalized bilirubin and liver enzyme levels. By day 7, infection markers had returned to normal. Contezolid and PTZ were administered for another seven days without any significant changes in platelet count (refer to Figure 1). Additionally, the patient did not report any significant adverse reactions throughout this period. The intake of medication was closely monitored by the nursing staff to ensure adherence. No infection recurrence or drug-related adverse events was observed during his follow-up. At the six-month consultation, bilirubin and transaminase levels were normal, while creatinine level was 127umol/L.

Figure 1 Antibiotics used in the patient and correlated changes with the progress of the clinical condition. Abbreviations: Plt, platelets; Scr, serum creatinine; MRSA, methicillin-resistant Staphylococcus aureus; CRRT, continuous renal replacement therapy; PTZ, piperacillin-tazobactam.

Discussion

This patient presented with a catheter-related infection caused by MRSA, which was further complicated by stage 3 AKI, HRS-AKI, concurrent thrombocytopenia, and suspected pneumonia. Therefore, the use of first-line agents such as vancomycin, linezolid, and daptomycin was limited. Consequently, combination therapy involving contezolid and piperacillin-tazobactam was administered, which led to complete recovery.

HRS-AKI is a functional renal failure that occurs due to renal vascular constriction in patients with end-stage liver disease, acute liver failure, or alcoholic hepatitis. The first-line therapy for HRS-AKI is the combination of terlipressin and albumin, which effectively reduces plasma renin and serum creatinine levels, thereby enhancing the reversal rate of HRS.⁸ Renal replacement therapy (RRT) is often used as a transitional treatment before liver transplantation, but its use in HRS-AKI patients who are not suitable for liver transplantation is controversial. However, for patients with severe acidosis, hyperkalemia, or volume overload, the decision to initiate RRT should be made on an individual basis.⁹ In this case, our patient presented with severe manifestations of fluid overload upon admission, necessitating the initiation of CRRT. However, during CRRT treatment, the patient’s temperature and infection markers increased.

According to a report, patients with cirrhosis have a 5–6 times higher prevalence of bacterial infections compared to the general population.¹⁰ Hospitalization is a known risk factor for bacterial infections in cirrhotic patients.¹⁰ Furthermore, AKI can have a negative impact on immune functions, leading to persistent immune paralysis and an increased risk of subsequent infections. A large-scale retrospective study involving over 3 million patients with cirrhosis found that individuals with AKI had a higher risk of developing infections (34.6% vs 22.2%, p<0.001) and sepsis (19.3% vs 6.1%, p<0.001) compared to those without AKI.¹¹ Prompt diagnosis and treatment of infections are crucial for HRS-AKI patients. Therefore, our group immediately conducted blood, sputum, urinary, and ascitic fluid cultures to detect any possible infections. The diagnosis of catheter-related bloodstream MRSA infection was confirmed by detecting MRSA in the blood culture and in the catheter culture after removing the CRRT catheter.

MRSA is a leading nosocomial pathogen and ranks second in terms of infection-related mortality rate in China.¹² Currently, there are few available reports on the treatment of MRSA infection in patients with HRS-AKI. The presence of AKI and persistent baseline thrombocytopenia in those patients may limit the choice of antibiotics.

Glycopeptides, such as vancomycin and teicoplanin, are effective against gram-positive bacteria, including MRSA. However, they are renal toxic. It was reported that among the various comorbidities and clinical factors examined, the highest risk of vancomycin-associated AKI is posed by kidney disease (OR 2.19), followed by liver disease (OR 1.82).¹³ Considering the patient’s hepatic and renal injury, it was crucial to avoid exacerbating renal impairment by excluding glycopeptides from his treatment regimen.

It is reported that patients with impaired renal function have an increased risk of linezolid exposure.¹⁴ Those with renal insufficiency are significantly more likely to develop linezolid-related thrombocytopenia compared to those with normal renal function.¹⁴ Therefore, linezolid was not considered as the initial treatment for this patient.

Daptomycin is an alternative to vancomycin for treating MRSA bacteremia. In cases of persistent MRSA bloodstream infections, the concurrent administration of daptomycin and ceftaroline has demonstrated superior cure rates and comparatively shorter treatment durations.¹⁵ It is primarily eliminated through renal excretion, with approximately 78% being excreted in urine. In patients with impaired kidney function, daptomycin exhibits a prolonged half-life.¹⁶ However, its use for pneumonia treatment is not recommended due to inactivation by pulmonary surfactant. Therefore, daptomycin was not included in the treatment regimen as pneumonia was suspected.

Contezolid, a novel oxazolidinone antibiotic, has exhibited antibacterial activity comparable to or exceeding that of linezolid, vancomycin, and daptomycin against clinical isolates of MRSA, in vitro. The The minimum inhibitory concentration 90 (MIC₉₀) values for contezolid, linezolid, vancomycin, and daptomycin were 0.5 mg/L, 0.5 mg/L, less than 1 mg/L, and 0.5 mg/L, respectively.¹⁷ In a murine model of systemic S. aureus infection, the median effective dose of contezolid is either lower or equivalent to that of linezolid.¹⁸ The Phase III clinical trial of contezolid for treating complex skin and soft tissue infections demonstrated comparable efficacy to linezolid. Additionally, there was a low incidence of hematologic toxicity, with only 3 out of 354 cases affected.¹⁹ Contezolid also showed similar major pharmacokinetic parameters in patients with mild to moderate renal impairment (estimated creatinine clearance (CLcr) 30-<90 mL/min) and mild to moderate liver impairment compared to those with normal kidney and liver function.^20,21 The efficacy of contezolid in individuals with mild or moderate renal impairment was similar to that in individuals with normal renal function, and the rates of adverse drug events during treatment observed in both Phase 2 and 3 trials were also comparable.²² Currently, successful treatment of adult MRSA infective endocarditis with contezolid has been reported.²³ After thorough consultation with the patient, contezolid was administered for treatment. The patient demonstrated satisfactory clinical efficacy following treatment with contezolid, and no significant drug-related adverse effects were observed.

This case report has certain limitations. The patient exhibited substantial clinical improvement after contezolid therapy and the removal of the indwelling catheter, which effectively addressed the source of infection. It is crucial to understand that these results may not apply to all cases, particularly for patients who are unable to have their catheters removed or those with ongoing bloodstream infections. Therefore, the conclusions from this single case should not be broadly applied to all instances of MRSA-related bloodstream infections. Given these considerations, future research efforts should be directed towards large-scale, prospective clinical trials to further investigate the efficacy and safety of contezolid in the treatment of MRSA-related bloodstream infections.

Conclusion

The successful use of contezolid in this case highlights its potential as an innovative therapeutic option for treating MRSA infections in patients with HRS-AKI.