Activity of cefpirome combined with beta-lactamase inhibitors and affinity for the penicillin-binding proteins of methicillin-resistantStaphylococcus aureus

Abstract

The susceptibility of 47 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) to cefpirome, ceftazidime and methicillin was determined with Isosensitest media, with/without 5% NaCl and incubation at 30 degrees, 37 degrees and 44 degrees C for 24 and 48 h. At 24 h the MIC50 of cefpirome was 8 mg/l compared to 64 mg/l ceftazidime; at 48 h this increased to 32 mg/l cefpirome. The addition of 10 mg/l clavulanic acid or sulbactam lowered the MIC of cefpirome (at 48 h) by greater than four-fold in 23% and 11% of the strains, respectively. Cefpirome had primary affinity for penicillin-binding protein (PBP) 1 and 2 in five MRSA and one methicillin-susceptible Staphylococcus aureus. PBP 2a was present in all MRSA and was not saturated by 64 mg/l cefpirome. Clavulanic acid at a concentration of 10 mg/l bound to PBP 2 by greater than 50% in all strains, and when combined with cefpirome, the density of PBP 2a was also reduced but not completely abolished. The data from this study suggests that the mechanism of synergy of a beta-lactamase inhibitor plus a cephalosporin for MRSA may be due to an additive effect against PBPs and not just inhibition of a beta-lactamase. No cefpirome-resistant mutants could be selected from a methicillin-susceptible Staphylococcus aureus, but mutants were selected from an MRSA (expressing homogeneous methicillin resistance) for which MICs of cefpirome were 8 to 32 mg/l.

Reinforcement of antibiotic activity by nanoencapsulation of ampicillin against -lactamase producing and non-producing strains of methicillin-resistant Staphylococcus aureus

“…The antibacterial activity of ABPC-nanocapsules against MRSA was found to be more potent than ABPC alone ( Table 3). The mutation of PBP to PBP2' in MRSA decreases the affinity of this protein for β-lactam antibiotics (Hartman and Tomasz, 1981;Piddock et al, 1992). The binding properties of nanoparticles are strongly influenced by the zeta potential on their surface (Hu et al, 2002;McCarron et al, 1999).…”

Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins

“…The major target site for the zwitterionic 7-methoxyimino cephalosporins in E. coli is PBP3. The IC50S for the five compounds have been calculated at ^0.5 mg/L; moderate affinities were also calculated for PBP1 (Watanabe et al, 1988;Fujimoto et al, 1990;Pucci et al, 1991;Piddock, Traynor & Griggs, 1992;Tanaka, Otsuki & Nishino, 1992). In addition, cefepime was shown to have a 20-fold lower ICso value for E. coli PBP2 compared with corresponding values for cefpirome and cefclidin (Pucci et al, 1991).…”

“…Cefpirome had the highest affinity for PBP2, PBP1 and PBB3 isolated from methicillin-susceptible Staphylococcus aureus (MSSA); DQ2556 exhibited the next highest affinity (Fujimoto et al, 1990). Cefpirome and FK037 bound PBP1 and PBP2 from methicillin-resistant S. aureus (MRSA) and showed limited affinities (FK037 more than cefpirome) for PBP2a, which correlates with their antibacterial activities (Piacentini et al, 1992;Piddock et al, 1992). However, PBP2a was not saturated despite exposure to 64mg/L of cefpirome (Piddock et al, 1992).…”

“…Cefpirome and FK037 bound PBP1 and PBP2 from methicillin-resistant S. aureus (MRSA) and showed limited affinities (FK037 more than cefpirome) for PBP2a, which correlates with their antibacterial activities (Piacentini et al, 1992;Piddock et al, 1992). However, PBP2a was not saturated despite exposure to 64mg/L of cefpirome (Piddock et al, 1992).…”

Μελέτη μηχανισμού αντοχής στη methicillin στελεχών σταφυλόκοκκου από ασθενείς με ενδονοσοκομειακή λοίμωξη

“…Η συγγένεια των υπολοίπων πενικιλλινοδεσμευτικών πρωτεϊνών δεν παρουσιάζει διαφορά ανάμεσα στα δύο στελέχη. Επομένως, η διαφορετική συγ γένεια της ΡΒΡ2α ανάμεσα στα AnecA-θετικά στελέχη μπορεί να ευθύνεται για τη διαφορετική έκ φραση της αντοχής των αναφερομένων στελεχών[146,24,43,114,65].Με τη μελέτη της συγγένειας σύνδεσης των πενικιλλινοδεσμευτικών πρωτεϊνών βρέθηκε ένας ακόμη μηχανισμός αντοχής, η τροποποιημένη συγγένεια της ΡΒΡ3, που ευθύνεται για τη χαμηλή αντοχή στη μεθικιλλίνη του S. epidermidis. Επίσης, διαπιστώθηκε ότι μολονότι η ΡΒΡ2α εκφράζε ται σε όλα τα mecA-θετικά στελέχη, εντούτοις, η συγγένεια αυτής διαφέρει από στέλεχος σε στέ λεχος.…”