A Case Report of Invasive Klebsiella pneumoniae Liver Abscess Syndrome Treated with Ceftazidime-Avibactam in Combination with Meropenem

Introduction

Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) infections present a significant challenge for clinicians due to the limited availability of effective therapeutic drugs, often resulting in adverse outcomes and high mortality rates. The Centers for Disease Control and Prevention in the United States have identified CR-hvKP as an urgent threat.¹ China is considered the main endemic region for CR-hvKP, reporting the highest number of cases globally. In this report, we describe a case of invasive Klebsiella pneumoniae liver abscess syndrome caused by a CR-hvKP infection. The patient exhibited a bloodstream infection, liver and lung abscesses, and purulent meningitis, eventually developing a brain abscess. Following treatment with a combination of meropenem and ceftazidime-avibactam (CAZ-AVI), the patient achieved a favorable clinical outcome.

Case Report

A 49-year-old male with a history of diabetes was admitted to the intensive care unit due to abdominal pain and a fever lasting one week, followed by a coma that persisted for 10 hours. Computed tomography (CT) scans revealed infectious lesions in both lungs and a low-density lesion in the right lobe of the liver (Figure 1). Brain magnetic resonance imaging (MRI) showed patchy long T1 and T2 signals in the bilateral basal ganglia, corpus callosum semioval region, genu, and splenium of the corpus callosum, with high signals on diffusion-weighted imaging (Figure 2). Blood tests indicated a white blood cell count of 27.20 x 10⁹/L, procalcitonin of 31.52 ng/mL, and C-reactive protein of 351.00 mg/L. Blood cultures identified sensitive Klebsiella pneumoniae (extended-spectrum β-lactamase-negative). Cerebrospinal fluid (CSF) analysis revealed glucose levels of 5.0 mmol/L, white blood cells of 9457.00 x 10⁶/L, 84% polymorphonuclear cells, and protein levels exceeding 3000.0 mg/L. The CSF bacterial culture was negative. CSF metagenomics next-generation sequencing (mNGS) detected Klebsiella pneumoniae with 6638 sequence reads and virulence genes, including iutA (936 reads), iucA (586 reads), iucD (443 reads), iroB (242 reads), iucC (159 reads), iucB (148 reads), ompA (98 reads), rmpA2 (21 reads), and rmpA (17 reads). Resistance genes identified included SHV-217 (22 reads), indicating resistance to carbapenems, cephalosporins, and penicillins. The liver abscess pus culture was negative. Bronchoalveolar lavage fluid targeted NGS (tNGS) identified Klebsiella pneumoniae with 62,239 sequence reads. The resistance gene detection revealed the presence of the carbapenemase gene blaKPC, and the KPC type of this case is carbapenemase gene - Class A carbapenemase gene. Klebsiella pneumoniae carbapenemases (KPCs) are β-lactamases commonly produced by blaKPC gene-harboring bacteria of the Enterobacteriaceae family, including Klebsiella pneumoniae, Escherichia coli and Enterobacter spp and that are sporadically found in non-fermenting bacteria.² This gene encodes a class A serine β-lactamase (class A SBL), which hydrolyzes the β-lactam ring of antibiotics, conferring resistance to most β-lactams, including carbapenems. The bronchoalveolar lavage fluid bacterial culture confirmed multi-drug-resistant Klebsiella pneumoniae, resistant to third-generation cephalosporins and carbapenems but sensitive to CAZ-AVI and amikacin. And the genetic analysis showed that the strain isolated of bronchoalveolar lavage fluid belonged to sequence type 11 (ST11) and serotype K2, ST11-K2. The patient was diagnosed with CR-hvKP infection, manifesting as invasive Klebsiella pneumoniae liver abscess syndrome.

Figure 1 Comparative changes in pulmonary infection (A) and liver abscess lesions (B) before and after treatment. The arrows in Figure 1 represent the changes of liver abscess lesions before and after treatment.

Figure 2 Changes in intracranial lesions on cranial MRI at various time points during the disease (days 1, 37, 50, 72, and 90, respectively). MRI, magnetic resonance imaging.

Before obtaining pathogen and drug sensitivity results, we initially administered intravenous meropenem combined with vancomycin. After receiving definitive pathogen and drug sensitivity results, we switched to intravenous CAZ-AVI (2.5 g/dose, three times daily) monotherapy on day 15 of the disease course. Following this treatment, the temperature of the patient gradually stabilized, his consciousness cleared, and the ventilator was removed. The patient was then transferred from the ICU to a general ward for continued care. Follow-up CT scans showed significant absorption of the pulmonary infection and liver abscess lesions (Figure 1). Repeat CSF analysis revealed glucose levels of 5.00 mmol/L, white blood cells of 26.00 x 10⁶/L, 24% polymorphonuclear cells, and a negative CSF bacterial culture. Repeat CSF mNGS detected Klebsiella pneumoniae with only two sequence reads. After treatment, the patient experienced no fever, headache, abdominal pain, cough, or other symptoms, showing both clinical and radiographic improvement. CAZ-AVI monotherapy was continued. However, due to unsatisfactory control of intracranial infection lesions on brain MRI (Figure 2) and the gradual formation of brain abscesses, on day 37 of the disease course, we switched the treatment to a combination of intravenous meropenem (2.0 g/dose, three times daily) and CAZ-AVI (2.5 g/dose, three times daily). The total treatment duration for this patient is 90 days. Repeat CSF indicators showed improvement compared to previous results, and follow-up brain MRI indicated absorption and reduction of brain abscesses (Figure 2). Currently, the general condition of the patient is good, and he is undergoing regular follow-up in our department. The changes in the CSF of the patient and the treatment course are depicted in Figure 3.

Figure 3 Illustration of changes in the CSF, cranial MRI findings, and treatment course of the patient. Abbreviations: CSF, cerebrospinal fluid; WBC, white blood cells; DH, multiple nuclear cells; TP, protein; GLU, glucose; MER, Meropenem; VAN, Vancomycin; CAZ/AVI, ceftazidime/avibactam.

Discussion

The acquisition of carbapenem resistance genes by hypervirulent Klebsiella pneumoniae has led to the emergence of CR-hvKP, presenting a significant challenge to clinical anti-infective treatment. This dual phenotype of hypervirulence and multi-drug resistance often complicates therapy, leaving patients with limited antimicrobial regimens and leading to unfavorable clinical outcomes and high mortality rates. Early detection of pathogenicity and drug resistance is crucial for selecting appropriate antimicrobial agents and improving the prognosis of the patient. China is recognized as the primary endemic region for CR-hvKP, reporting the highest number of cases globally. Epidemiological surveys of carbapenem-resistant Enterobacteriaceae in China have shown that the predominant enzyme genotype carried by Klebsiella pneumoniae is KPC-2, accounting for 84% of cases, followed by NDM-1, which accounts for 10%. Additionally, various subtypes of enzyme genotypes, such as KPC-12 and NDM-5, have been isolated in China.³

CAZ-AVI is a combination of the third-generation cephalosporin ceftazidime and the novel non-β-lactam β-lactamase inhibitor avibactam. Avibactam can inhibit class A, C, and some class D enzymes, providing CAZ-AVI with antimicrobial activity against most Enterobacteriaceae and high sensitivity to carbapenem-resistant Enterobacteriaceae carrying the KPC-2 genotype.^4,5 Multiple international guidelines consistently recommend CAZ-AVI as a first-line treatment for resistant gram-negative bacterial infections.^6,7 A meta-analysis of the efficacy and safety of CAZ-AVI in treating carbapenem-resistant Enterobacteriaceae bloodstream infections, including data up to 2021, showed that the 30-day mortality rate in the CAZ-AVI group was significantly lower than in other regimens and polymyxin-based regimens.⁸ Notably, although in vitro antimicrobial susceptibility results indicated resistance to carbapenems, we chose CAZ-AVI combined with meropenem because the patient developed multiple brain abscesses during the illness. Meropenem is a classic drug for treating central nervous system (CNS) infections due to its good blood-brain barrier permeability. Currently, data on the clinical efficacy of CAZ-AVI in treating CNS infections is limited. However, the largest study to date on CAZ-AVI-based combination therapy for CNS infections caused by CR-hvKP has confirmed its effectiveness.⁹ Previous retrospective cohort studies have also shown that CAZ-AVI combined with in vitro non-sensitive antimicrobial drugs (such as carbapenems, fosfomycin, and tetracyclines) significantly reduces mortality risk in critically ill patients with CR-hvKP infections.¹⁰ This case report suggests that CAZ-AVI combined with in vitro non-sensitive antimicrobial drugs (carbapenems in this case) is safe and effective for treating severe multi-site infections caused by CR-hvKP, including CNS infections. It provides a clinical reference for the treatment of similar patients.