Pharmacodynamics of ceftazidime/avibactam against extracellular and intracellular forms of Pseudomonas aeruginosa.

Objectives: When tested in broth, avibactam reverses ceftazidime resistance in many Pseudomonas aeruginosa that express ESBLs. We examined whether similar reversal is observed against intracellular forms of P. aeruginosa . Methods: Strains: reference strains; two engineered strains with basal non-inducible expression of AmpC and their isogenic mutants with stably derepressed AmpC; and clinical isolates with complete, partial or no resistance to reversion with avibactam. Pharmacodynamic model: 24 h concentration-response to ceftazidime [0.01-200 mg/L alone or with avibactam (4 mg/L)] of bacteria in broth or bacteria phagocytosed by THP-1 monocytes, with calculation of ceftazidime relative potency ( C s : concentration yielding a static effect) and maximal relative effect [ E max : cfu decrease at infinitely large antibiotic concentrations (efficacy in the model)] using the Hill equation. Cellular content of avibactam: quantification by LC-MS/MS. Results: For both extracellular and intracellular bacteria, ceftazidime C s was always close to its MIC. For ceftazidime-resistant strains, avibactam addition shifted ceftazidime C s to values close to the MIC of the combination in broth. E max was systematically below the detection limit (-5 log 10 ) for extracellular bacteria, but limited to -1.3 log 10 for intracellular bacteria (except for two isolates) with no effect of avibactam. The cellular concentration of avibactam reflected extracellular concentration and was not influenced by ceftazidime (0-160 mg/L). Conclusions: The potential for avibactam to inhibit ß-lactamases does not differ for extracellular and intracellular forms of P. aeruginosa , denoting an unhindered access to its target in both situations. The loss of maximal relative efficacy of ceftazidime against intracellular P. aeruginosa was unrelated to resistance via avibactam-inhibitable ß-lactamases.

Carcinoid tumor and membranous glomerulonephritis: coincidence or malignancy-associated glomerulonephritis?

Membranous glomerulonephritis is known to be associated with malignancies. A 43-year-old man with a history of chronic renal insufficiency secondary to 20-year-old membranous glomerulonephritis was operated on for an infrarenal aneurysm. During surgical intervention, multiple nodular liver lesions were detected. Histologic examination of these lesions showed metastases of a carcinoid tumor. Despite extensive examination, the primary tumor site could not be detected. The patient remained asymptomatic 3 years postoperatively without any treatment for carcinoid tumor. This clinical report is the second case of a membranous glomerulonephritis associated with a carcinoid tumor. Whether the association is merely a coincidence or a real malignancy-related glomerulopathy remains unclear. Because survival of 23 years after the onset of symptoms of carcinoid tumor has occurred, it is possible that our patient already had an asymptomatic carcinoid tumor at the time the diagnosis of membranous glomerulonephritis was made. Comparison with other paraneoplastic glomerulonephritis as well as diagnosis of a carcinoid tumor in renal insufficiency are discussed.