Inducible β-lactamase-mediated resistance to third-generation cephalosporins  Ronald N Jones, Fernando Baquero, Gaetano Privitera, Matsuhisa Inoue, Bernd Wiedemann  Clinical Microbiology and Infection  Volume 3, Pages S7-S20 (April 1997) DOI: 10.1111/j.1469-0691.1997.tb00643.x Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions

Figure 1 Hypothetical model for control of the expression of inducible ampC genes in Gram-negative bacteria [24–26, 29, 30]. The proposed interconnected pathway for recycling muropeptides and for their involvement in β-lactamase induction is illustrated. ○ GlcNac; anhMurNac; □ MurNac; • Ala; ♦ Glun; ▪ DAP. (A) The recycling pathway. As shown, murein is degraded by known enzymes in the periplasm to muramyl peptides. The muropeptide GlcNac-anhMurNac-tripeptide, tetrapeptide and pentapeptide are transported into the cytoplasm through AmpG. Disaccharides are cleaved by β-N-acetyl-glucosaminidase into monosaccharides. The muropeptides are then degraded into GlcNac-anhMurNac and free tripeptide, tetrapeptide or pentapeptide by AmpD. Free tripeptide can then be added directly to UDP-N-acetylmuramic acid by an as yet unidentified enzyme, thereby reintroducing it into the biosynthetic pathway for murein synthesis. Derepression can occur because of mutations in the ampD or ampR gene. The ampR mutations change the AmpR protein into an activator. The ampD mutations alter the AmpD protein to an inactive enzyme, which results in an accumulation of the muramyl peptides in the cytoplasm. (B) Muropeptides as inducers of β-lactamase. Intracellular accumulation of GlcNac-anhMurNac-tripeptide as a result of the presence of the β-lactam antibiotics or of anhMurNac-tripeptide as the result of inactivation of ampD triggers production of C.freundii AmpC β-lactamase. The muropeptides presumably bind to the transcriptional regulator AmpR and convert it into an activator for ampC expression. (C. freundii ampR and ampC are expressed from a plasmid.) Clinical Microbiology and Infection 1997 3, S7-S20DOI: (10.1111/j.1469-0691.1997.tb00643.x) Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions

Figure 2 Relationship between crftazidime use and susceptibility of Entevobacter cloacae to ceftazidime 2. With permission of Diagn Microbiol Infect Dis. Clinical Microbiology and Infection 1997 3, S7-S20DOI: (10.1111/j.1469-0691.1997.tb00643.x) Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions

Figure 3 Ceftazidmie resistance among clinical isolates in Germany (PEG 1990). Clinical Microbiology and Infection 1997 3, S7-S20DOI: (10.1111/j.1469-0691.1997.tb00643.x) Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions

Figure 4 Median MICs for 10 E. cloacae strains during 7-day serial passage with a cephalosporin. The median MIC represents the sixth MIC observation when the MICs for the 10 strains on each day of testing are listed from the lowest to the highest value. The values in parentheses are the number of strains among the 10 strains tested for which the MIC was in the resistant range (⩾ 32 mg/L) for the 7-day serial passage. * ceftriaxone; ○ ceftazidime; ○ cefpirome; ○ cefepime. The upper and lower broken lines in the figure are cut-offs for resistance and susceptibility (NCCLS criteria), respectively. With permission of Am Soc Microbiol J Div 46. Clinical Microbiology and Infection 1997 3, S7-S20DOI: (10.1111/j.1469-0691.1997.tb00643.x) Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions

Figure 5 C-3'quaternary ammonium cephems 50. Clinical Microbiology and Infection 1997 3, S7-S20DOI: (10.1111/j.1469-0691.1997.tb00643.x) Copyright © 1997 European Society of Clinical Infectious Diseases Terms and Conditions