Susceptibility to  -lactam antibiotics of mutant strains of Xanthomonas maltophilia with high- and low-level constitutive expression of L1 and L2  -lactamases

Abstract

Summary. Xanthomonas maltophilia produces two inducible P-lactamases, L 1 and L2, and resists the antimicrobial activity of P-lactam antibiotics, including carbapenems. L1 is a zinc-metaloenzyme with carbapenemase activity; L2 is an unusual cephalosporinase. Mutant strains with high-and low-level constitutive expression of these enzymes were derived from three reference strains of X. maltophilia. With a single exception, the mutant strains had altered expression of both enzymes, indicating that these P-lactamases share regulatory components. The exception was a mutant strain that had low-level constitutive (basal) expression of L1 enzyme but remained inducible for L2. A parent strain with low-level Blactamase inducibility was more susceptible to penicillins, cephalosporins and carbapenems than were those in which higher levels of enzyme activity were inducible. Mutations that caused high-level constitutive P-lactamase expression increased resistance to penicillins and newer cephalosporins. P-Lactamase basal mutant strains, including the one that remained inducible for L2 enzyme, were more susceptible than inducible strains to these drugs. Organisms with inducible or high-level constitutive P-lactamase expression were equally resistant to meropenem and imipenem but basal mutant strains, including the one that remained inducible for L2 enzyme, were more susceptible to meropenem than imipenem. Minimal inhibitory concentrations of meropenem, penicillins and cephalosporins, but not imipenem, were greater on Mueller Hinton agar than on IsoSensitest or Diagnostic Sensitivity Test agars. This behaviour was independent of P-lactamase inducibility, and may reflect permeability differences between cells grown on different media.

Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen

“…However, no synergistic effect against these two isolates was observed for the combination of Esc(1-8) and amikacin. No synergy was observed for Esc (1)(2)(3)(4)(5)(6)(7)(8) used in combination with ceftazidime or levofloxacin. In the presence of 20% heat-inactivated human serum, against one representative S. maltophilia isolate, Esc(1-8) demonstrated enhanced bactericidal activity (4 g/ml; 1/8 minimal bactericidal concentration [MBC]) when used in combination with colistin (0.125 g/ml; 1/2 MBC) or with amikacin (1 g/ml; 1/16 MBC).…”

“…maltophilia exhibits resistance to a broad array of antibiotics, including TMP-SMX, ␤-lactam antibiotics, macrolides, cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, chloramphenicol, tetracyclines, and polymyxins. The low membrane permeability that contributes to resistance to ␤-lactams including cefepime, ticarcillin-clavulanate, ceftazidime, and piperacillintazobactam (5,68,229) and the presence of chromosomally encoded multidrug resistance efflux pumps (6,11,54,129,196,198,269,383), ␤-lactamases (9,17,18,227,295,296,352,353), and antibiotic-modifying enzymes (174,190,195) all contribute to the intrinsic antibiotic resistance of S. maltophilia (298). The intrinsic resistance of S. maltophilia was suggested to have been acquired in natural nonhuman environments and is not due solely to the use of antibiotics in medical/clinical settings (218,298).…”

“…The N-terminal region [Esc (1)(2)(3)(4)(5)(6)(7)(8)] of the esculentin-1b peptide isolated from Rana esculenta skin secretions contains the antimicrobial properties of the peptide (214). Esc(1-18) was effective against MDR S. maltophilia clinical isolates at concentrations of 0.5 M, 8 M, and 16 M needed for a bactericidal effect when tested in sodium phosphate buffer (SPB), in 20% heat-inactivated human serum, and in 40% heat-inactivated human serum, respectively (215).…”

“…The activity of Esc (1)(2)(3)(4)(5)(6)(7)(8) in combination with conventional antibiotics used to treat S. maltophilia infections (amikacin, ceftazidime, colistin, and levofloxacin) has been assessed in synergy studies (211). Synergy studies using five clinical S. maltophilia isolates and S. maltophilia ATCC 13637 were performed in the presence of sodium phosphate buffer and human serum.…”

“…In sodium phosphate buffer, Esc(1-8) in combination with amikacin or colistin resulted in synergistic activity against five of six S. maltophilia isolates. Enhanced killing at subbactericidal concentrations [0.5-g/ml concentration of Esc (1)(2)(3)(4)(5)(6)(7)(8) and colistin] was observed for the combination of Esc(1-8) and colistin against two representative S. maltophilia isolates. However, no synergistic effect against these two isolates was observed for the combination of Esc(1-8) and amikacin.…”