Carbapenem-resistant Enterobacterales (CRE) pose a significant public health concern. CRE could be carbapenamse producers or non-producers. In the Kingdom of Saudi Arabia, bla OXA-48 and bla NDM represent the majority of carbapenemase isolates. There are very limited treatment options for carbapenemase-producing CRE caused by bla NDM. Ceftazidime-avibactam plus aztreonam (CZA-ATM) or cefiderocol as monotherapy are considered the treatment of choice for these infections. Here, we report a case of a 70-year-old man presented with surgical site infection of above knee amputation stump. The cultures revealed carbapenem-resistant Klebsiella pneumoniae positive for bla NDM and bla OXA-48 resistant to CZA-ATM therapy and intermediate susceptibility to tigecycline. He was started on CZA-ATM both adjusted for renal function, and high dose tigecycline with daily wound dressing and irrigation. By day 20 of the antibiotic regimens, he had clinical and microbiological cure based on repeated wound cultures. This case identifies a rare incidence of CRE skin and soft tissue infection positive for bla NDM and bla OXA-48 resistant to CZA-ATM in a background of limited targeted options, but successfully treated with CZA-ATM and high-dose tigecycline. Such therapeutic approach might be useful in few circumstances when no other antibiotic options are available to treat extensively drug-resistant Klebsiella pneumoniae.

The prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has been increasing in recent years. Chinese Infectious Disease Surveillance of Pediatrics (ISPED) showed that in 2022, its resistance rate to meropenem was 18.5%. However, there is limited data available on the treatment of CRKP infection in neonates. In this study, we present a case involving a premature infant infected with OXA-48-producing Klebsiella pneumoniae. The combined susceptibility test revealed a significant synergistic effect between ceftazidime-avibactam(CAZ-AVI), and aztreonam(ATM). The infection was successfully treated with a combination of CAZ-AVI, ATM, and fosfomycin. This case represents the first reported instance of sepsis in a premature infant caused by OXA-48-producing Klebsiella pneumoniae in China. The objective of our study is to evaluate the effectiveness and safety of combination therapy in treating CRKP infections in premature infants. We hope that the findings of this study will provide valuable insights for clinicians in their treatment approach.

Among carbapenem-resistant Enterobacterales, metallo-beta-lactamase producing strains represent a growing therapeutic challenge. While the association of aztreonam and ceftazidime-avibactam has been investigated in recent years for the treatment of infections involving these strains, little to no clinical data support the use of this association for the treatment of bone and joint infections. We report two cases of complex bone and joint infections involving metallo-beta-lactamase-producing Enterobacterales, successfully treated at our referral center with aztreonam and ceftazidime-avibactam for 12 weeks in continuous infusions through elastomeric infusors.

BACKGROUND: Escherichia hermannii (E. hermanni) is always accompanied by other bacterial infections in humans. In previous reports, most E. hermannii-related infections were caused by sensitive strains. Here, for the first time, we report the case of a patient with New Delhi metallo-β-lactamase (NDM)-positive E. hermannii bloodstream infection.
METHODS: The patient was a 70-year-old male admitted to our hospital due to a 4-day fever, with a history of malignant tumor, liver cirrhosis, and chronic obstructive pulmonary disease. After admission, his blood culture tested positive for E. hermannii. The drug resistance analysis showed positive for NDM resistance, with susceptibility to aztreonam, levofloxacin, and amikacin. The blood culture turned negative after 8 days of aztreonam treatment. The patient\'s symptoms improved, and he was discharged after 14 days of hospitalization.
CONCLUSIONS: This is the first report of a bloodstream infection caused by an NDM-positive E. hermannii strain. The anti-infection regimen used in this case provides a new reference regimen for clinical practice.

Objective: To describe the impact of pharmacy driven penicillin allergy assessments on de-labeling penicillin allergies and antibiotic streamlining opportunities for hospitalized patients. Design: Multi-center, retrospective case-series study. Setting: A health system of 4 non-teaching hospitals. Participants: Patients aged 18 years and older with a physician order for a pharmacist penicillin allergy assessment. Exclusion criteria consisted of patients with anaphylaxis or a type II penicillin allergy, anaphylaxis of any cause within 4 weeks, refusal of penicillin allergy skin test (PAST), antihistamine use within 24 hours, penicillin intolerance, immunosuppression or immunosuppressive medications, or skin conditions that could interfere with PAST. Interventions: The primary endpoint evaluated the number of de-labeled penicillin allergies after pharmacists provided penicillin allergy assessments. Secondary endpoints evaluated the percent of patients with antibiotics deescalated to beta-lactam antibiotics and classification of notable interventions made by pharmacists. Measurements and Main Results: There were 35 patients who met inclusion criteria. Twenty-four patients underwent both penicillin allergy skin testing and oral (PO) amoxicillin challenge. Five patients had allergies de-labeled only after a pharmacist interview. Four patients received only the PO amoxicillin challenge and 2 patients received only PAST. Penicillin allergies were de-labeled from the electronic health record (EHR) in 31 (89%) patients despite all testing negative for a penicillin allergy from PAST or a PO amoxicillin challenge. Four patients had the allergy re-added to the chart on subsequent admissions. No patients experienced a reaction from PAST, PO amoxicillin challenge, or subsequent beta-lactam antibiotics. Twenty-eight (80%) patients had their antibiotic therapy changed as a result of the allergy assessment. Seventeen patients were de-escalated onto beta-lactam antibiotics and aztreonam was stopped in 6 patients. Conclusion: Results from this study suggests that pharmacists expanding their scope of practice with PAST is a safe and effective allergy de-labeling tool. Pharmacist-driven penicillin allergy assessments could provide antibiotic cost savings and avoid aztreonam use. The study supports the need to emphasize education for patients and caretakers regarding allergy testing results to avoid relabeling in future hospital visits.

Aztreonam/avibactam is a promising antimicrobial combination with additional coverage for metallo-β-lactamases compared with ceftazidime/avibactam. A carbapenem-resistant blaKPC-2-carrying Escherichia coli clinical isolate had four extra amino acids in penicillin-binding protein 3 (PBP3), which has been known to mediate reduced susceptibility to aztreonam/avibactam. This prompted us to investigate whether the strain could develop resistance to aztreonam/avibactam after exposure to the combination. A mutant with high-level resistance to aztreonam/avibactam [minimum inhibitory concentration (MIC), 512/4 mg/L] was obtained after 5-day exposure to 0.5 × MIC but it remained susceptible to ceftazidime/avibactam (MIC, 4/4 mg/L). The mutant had a single nucleotide polymorphism (SNP) in blaKPC-2 to encode KPC-21 with a Trp105Arg amino acid substitution. By cloning into E. coli BL21, blaKPC-21 could mediate reduced susceptibility to aztreonam/avibactam (MIC, from ≤0.03/4 to 1/4 mg/L), which was still below the breakpoint to define resistance. In contrast, when blaKPC-21 was cloned in E. coli 035125ΔpCMY42 with four extra amino acids in PBP3, which was generated in our previous work, the strain exhibited high-level resistance to aztreonam/avibactam (MIC, 256/4 mg/L). The above findings highlight that although aztreonam/avibactam has a broader spectrum than ceftazidime/avibactam, strains may develop resistance to the former combination but remain susceptible to the latter. The discrepancy is due to mutation of KPC-2 to KPC-21 in combination with the insertion of four extra amino acids in PBP3.

OBJECTIVE: The aim of this study was to describe our experience of a combination treatment including meropenem/vaborbactam (M/V) plus aztreonam (ATM) for bloodstream infections (BSIs) due to ceftazidime/avibactam-resistant Klebsiella pneumoniae (CAZ/AVI-R-Kp), for which gene typing was not available at the time the blood culture (BC) results were obtained.
METHODS: Between 20 July and 22 August 2021, in our hospital laboratory, the molecular test for carbapenemase gene typing was not available. All Gram-negative bloodstream infections were recorded, and characteristics of patients were analysed. Among them, three patients had positive BCs for CAZ/AVI-R-Kp, and the empirical therapy was switched to M/V plus ATM pending phenotypic testing of sensitivity to M/V. Therapy was subsequently targeted on the basis of the results of this test.
RESULTS: KPC and NDM represent the most prevalent carbapenemases in our polyclinic. Three patients with CAZ/AVI-R-Kp sepsis were treated with M/V plus ATM not knowing the carbapenemase gene. Two had an NDM-Kp infection for which, upon obtaining the result of sensitivity to M/V, combination therapy was maintained. The third had KPC-Kp infection for which ATM was discontinued, after the acquisition of an antibiogram reporting full sensitivity to M/V (MIC = 0.25 mg/L). One patient with NDM-Kp infection died due to complications of the underlying disease for which he was hospitalised.
CONCLUSIONS: Meropenem/vaborbactam plus ATM and subsequent de-escalation could represent a possible therapeutic strategy in severe CAZ/AVI-R-Kp infections when carbapenemase gene typing is not rapidly available.

In this clinician-therapeutic drug monitoring (TDM) consultant interaction, the authors describe the use of TDM in an 11-year-old female patient with cystic fibrosis receiving ceftazidime/avibactam and aztreonam for the treatment of persistent pulmonary exacerbations caused by Stenotrophomonas pneumonia. Serum drug concentrations at a steady state confirmed inadequate antimicrobial exposure, and continuous infusions of both ceftazidime/avibactam and aztreonam were required to optimize the percentage of time when free drug remained above the minimum inhibitory concentration (MIC), known as fT > MIC. After dose adjustment, this continuous infusion strategy resulted in 100% target attainment for fT > MIC. This case illustrates the importance of TDM, and the logistical issues encountered with the use of alternative dosing strategies in pediatric patients with CF.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-β-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer β-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing β-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.

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