Disease relevance of Mecillinam

• We describe here a new mecillinam-resistant mutant of Escherichia coli, the lov mutant [1].
• Synergy between a 2:1 combination of ampicillin and amdinocillin was studied with 10 urinary isolates of Enterobacteriaceae [2].
• Lipopolysaccharide (LPS), spoT, and cya or crp mutations individually do not affect the minimum inhibitory concentration of mecillinam on Salmonella typhimurium [3].
• Amdinocillin has previously been shown to be synergistic with other beta-lactam antibiotics against many gram-negative bacteria [4].
• Management of enteric fever with amdinocillin [5].

High impact information on Mecillinam

• The effect of ppGpp is probably mediated by RNA polymerase, since sublethal doses of the polymerase inhibitor rifampicin suppress mecillinam resistance in argS, alaS and ptacrelA'-bearing strains [6].
• Although the argS and alaS mutants grow slowly, we show that there is no correlation between mecillinam resistance and either growth rate or translation speed [6].
• Mecillinam, a beta-lactam antibiotic which specifically inactivates penicillin binding protein 2 (PBP2) in Escherichia coli, prevents lateral cell wall elongation, inducing spherical morphology and cell death [6].
• Furthermore, a ptacrelA' multicopy plasmid makes a wild type strain mecillinam resistant [6].
• It possesses active PBP2, as evidenced by its rod shape in the absence of mecillinam (but not in its presence), its ability to filament when septation is inhibited, and its penicillin-binding ability [1].

Chemical compound and disease context of Mecillinam

• For serum-resistant clinical isolates of Escherichia coli were grown in the presence of various subinhibitory concentrations of mecillinam or pivmecillinam and then exposed to the bactericidal action of human serum [7].
• Protective effect of amdinocillin against emergence of resistance to ceftazidime in Enterobacter cloacae [8].
• These studies demonstrate the increased activity of some newer semisynthetic penicillins and the potential synergy obtained with mecillinam and carbenicillin against Bacteroides sp [9].
• Effects of sulfamethizole and amdinocillin against Escherichia coli strains (with various susceptibilities) in an ascending urinary tract infection mouse model [10].
• Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs [11].

Biological context of Mecillinam

• We discuss a possible role for ppGpp as transcriptional activator of cell division genes whose products seem to become limiting in the presence of mecillinam, when cells form large spheres [12].
• Pharmacokinetics of amdinocillin and pivamdinocillin in normal volunteers [13].
• Escherichia coli strains partially induced for the stringent response are resistant to mecillinam, a beta-lactam antibiotic which specifically inactivates penicillin-binding protein 2, the key enzyme determining cell shape [12].
• These results show that the ftsQAZ operon is not the ppGpp target responsible for mecillinam resistance [14].
• Second, the ppGpp pool was controlled by means of a plasmid carrying a ptac-relA' gene coding for a hyperactive (p)ppGpp synthetase, RelA'; increasing the ppGpp pool by varying the concentration of lac operon inducer IPTG resulted in a sharp threshold ppGpp concentration, above which cells were mecillinam resistant [12].

Anatomical context of Mecillinam

• Mecillinam, a beta-lactam antibiotic which binds specifically to penicillin-binding protein 2 (PBP2), blocks lateral cell-wall elongation, induces spherical morphology and ultimately kills bacteria [1].
• The lov gene product thus seems to define a link between PBP2 (the mecillinam target) and the ribosomes; we propose that this link is involved in transmitting information on the growth rate (ribosome concentration) to the peptidoglycan synthesizing apparatus [1].
• The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations [15].
• Levels of amdinocillin in human plasma and interstitial fluid following intravenous administration [16].
• Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously [15].

Associations of Mecillinam with other chemical compounds

• Although amdinocillin, alone or in combination with cefoxitin, appeared effective as second-line therapy in infections with organisms shown sensitive in vitro, the combination of amdinocillin and ticarcillin or carbenicillin was only moderately effective in initial therapy for neutropenic, febrile, cancer patients [17].
• The combination of amdinocillin plus cefoxitin was active in vitro against 71 percent of the isolates obtained before therapy as compared with 65 percent for cefoxitin alone [18].
• Parenteral amdinocillin for treatment of complicated urinary tract infections [19].
• The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid [15].
• These results suggest that the antibacterial action of mecillinam on S. typhimurium is somehow dependent on the interaction of LPS, cyclic AMP/cyclic AMP receptor protein (cAMP/CRP), and SpoT [3].

Gene context of Mecillinam

• The reported resistance to mecillinam of cya and crp mutants of Escherichia coli K-12 is probably due to the natural LPS defectiveness of this strain [3].
• Synergistic inhibition was noted for beta-lactamase-containing, mecillinam-resistant Klebsiella, Citrobacter, Serratia, and Salmonella isolates, but only 18% of beta-lactamase-containing Proteus mirabilis, Providencia rettgeri, Providencia stuartii, and Morganella morganii were synergistically inhibited by the combinations [20].
• We tried to identify regulators of the ftsQ-ftsA-ftsZ operon among mecillinam-resistant mutants, which include strains overexpressing these genes [21].
• The delta mre-678 mutant cells required three genes, the previously reported mreB gene and the two new genes, to restore the normal rod shape of the cells and normal sensitivity of growth to mecillinam [22].
• A chromosomal region of Escherichia coli contiguous to the fabE gene at 71 min on the chromosomal map contains multiple genes that are responsible for determination of the rod shape and sensitivity to the amidinopenicillin mecillinam [23].

Analytical, diagnostic and therapeutic context of Mecillinam

• Plasma amdinocillin concentrations were determined by microbiologic assay and urine concentrations by high performance liquid chromatography [13].
• We report the results of a multicenter study evaluating the safety and efficacy of amdinocillin in combination with other beta-lactam antibiotics in the treatment of 120 serious gram-negative bacterial infections [24].
• Amdinocillin (40 mg/kg per day) and penicillin (60,000 units/kg per day) were administered separately in divided doses by intramuscular injection at six-hourly intervals for five days [25].
• The morphologic results from the scanning electron microscopy study point to a synergistic or enhanced effect of amdinocillin in combination with beta-lactam antibiotics and are in accord with prior reports of the synergistic effects of amdinocillin [26].
• Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections [27].

References