Role of Antibodies and Antibiotics in Aerobic Gram-Negative Septicemia: Possible Synergism Between Antimicrobial Treatment and Immunotherapy

Overbeek, B. P.; Veringa, Etèl

doi:10.1093/clinids/13.4.751

Cited by 25 publications

(14 citation statements)

References 133 publications

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“…Sub-MICs of several antibiotics may alter the surface structure of members of the Enterobacteriaceae, influencing host-parasite relationships, such as serum bactericidal activity, opsonophagocytosis and complement consumption [14,18,[23][24][25][26]. A previous study demonstrated that the serum of mice immunised with E. coli 06:K-pre-exposed to sub-MIC of aztreonam (T-mice) contained antibodies towards protein epitopes that were not recognised by the serum of mice immunised with the untreated bacteria of the same strain (NT-mice).…”

Section: Discussionmentioning

confidence: 99%

Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli

Lun

Raponi²,

Amatucci³

et al. 1997

Journal of Medical Microbiology

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Section: Discussionmentioning

confidence: 99%

Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli

Lun

Raponi²,

Amatucci³

et al. 1997

Journal of Medical Microbiology

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“…Possible synergy between antibodies and antibiotics presents intriguing possibilities for both the prevention and treatment of septicaemia and septic shock in irnmunocompetent as well as immunocompromised hosts. 26 The potential of antibiotics to improve the exposure of conserved LPS epitopes targeted by immunotherapeutic MAbs is likely to improve the clinical efficacy of such MAbs. The exposure of deeper antigenic determinants by subMICs of certain antibiotics has the additional advantage of influencing host defences, which include the promotion of opsonisation by serum complement or antibodies, thus enhancing phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Influence of subinhibitory levels of antibiotics on expression of Escherichia coli lipopolysaccharide and binding of anti-lipopolysaccharide monoclonal antibodies

Nelson

Delahooke²,

Poxton³

1993

Journal of Medical Microbiology

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Summary. The expression of Escherichia coli lipopolysaccharide (LPS) and the binding capacity of anti-LPS monoclonal antibodies (MAbs) to E. coli grown in the presence or absence of subinhibitory concentrations of various antibiotics was studied. Four E. coli strains (three clinical blood-culture isolates and an isogenic, non-capsulate mutant of the 018:Kl parent) were grown in the presence of the /3-lactam antibiotic, ampicillin, the aminoglycoside gentamicin, the fluoroquinolone ciprofloxacin and chloramphenicol. The techniques of silver staining, immunoblotting, whole-cell ELISA and flow cytometry were all used to monitor the expression of LPS on the bacteria and the binding of the anti-LPS MAbs. Treatment with ampicillin, chloramphenicol and ciprofloxacin resulted in enhanced binding of anti-core reactive MAbs to most E. coli strains. Overall, treatment with gentamicin produced the least effect on MAb binding. The presence of chloramphenicol decreased the expression of high molecular mass 0-antigen or increased the expression of low molecular mass substituted E. coli LPS or both. These results further illustrate that LPS core, especially the inner-core region, becomes more accessible to antibodies when bacteria are grown in the presence of certain antibiotics. Possible synergy between antibodies and antibiotics for treatment of septicaemia and septic shock remains an intriguing possibility.

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“…Antibodies against the lipid A (endotoxin) or core oligosaccharide portions of the LPS molecule are expected to have primarily an antiendotoxin function by neutralizing or sequestering endotoxin in the circulation (20). Their antibacterial effect is restricted because of the low accessibility of these epitopes on live bacteria, as they are masked by the abundant O side chains and/or the capsular polysaccharide (22). Conversely, it has been shown that antibodies specific to the O antigens of LPS can trigger bacterial killing by the complement system alone or, alternatively, through opsonophagocytic killing.…”

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confidence: 99%

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

Szijártó

Guachalla

Visram

et al. 2015

Antimicrob Agents Chemother

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The Escherichia coli sequence type 131 (ST131)-O25b:H4 clone has spread worldwide and become responsible for a significant proportion of multidrug-resistant extraintestinal infections. We generated humanized monoclonal antibodies (MAbs) that target the lipopolysaccharide O25b antigen conserved within this lineage. These MAbs bound to the surface of live bacterial cells irrespective of the capsular type expressed. In a serum bactericidal assay in vitro, MAbs induced >95% bacterial killing in the presence of human serum as the complement source. Protective efficacy at low antibody doses was observed in a murine model of bacteremia. The mode of action in vivo was investigated by using aglycosylated derivatives of the protective MAbs. The significant binding to live E. coli cells and the in vitro and in vivo efficacy were corroborated in assays using bacteria grown in human serum to mimic relevant clinical conditions. Given the dry pipeline of novel antibiotics against multidrug-resistant Gram-negative pathogens, passive immunization with bactericidal antibodies offers a therapeutic alternative to control infections caused by E. coli ST131-O25b:H4. Escherichia coli is a member of the intestinal commensal flora. Certain variants (pathotypes) of the species, however, can cause either intestinal or extraintestinal infections, such as urinary tract infection, meningitis, or bacteremia (1). Extraintestinal pathogenic E. coli (ExPEC) strains harbor a large array of virulence traits that enable them to cause disease outside the intestinal tract. ExPEC strains have been evolving antibiotic resistance, often a combined resistance against most of the clinically relevant antibiotics, such as fluoroquinolones, aminoglycosides, and ␤-lactam antibiotics. Typically, multidrug-resistant (MDR) strains are compromised in their fitness and virulence, which restricts their prevalence to a nosocomial setting and conversely limits their spread in the community. Some successful MDR clonal lineages do, however, retain high virulence potential (2, 3). The E. coli clonal lineage sequence type 131 (ST131)-O25b:H4, first described in 2008 (4, 5), has spread globally not only in hospitals (as do most other MDR clones) but also in the community (6-9). This clone is responsible for ϳ15% (up to 25% [10,11]) of all extraintestinal E. coli infections and represents the majority of fluoroquinolone-resistant isolates (12) and about half of the extended-spectrum ␤-lactamase (ESBL)-producing isolates (13). The progressive acquisition of additional resistance phenotypes in ST131-O25b:H4 strains leaves very few effective antibiotics for treatment of patients infected by members of this lineage (14). Even more alarming is the recent appearance of carbapenem-resistant ST131 isolates (15-17). Recently, ST131-O25b:H4 strains were shown to predominate among carbapenem-resistant E. coli isolates (18). A major clinical concern is the lack of development of novel antibiotics against Gram-negative pathogens, again leaving very limited treatment options (19). The p...

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Role of Antibodies and Antibiotics in Aerobic Gram-Negative Septicemia: Possible Synergism Between Antimicrobial Treatment and Immunotherapy

Cited by 25 publications

References 133 publications

Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli

Characterisation and protective capacity of monoclonal antibodies elicited in mice against protein epitopes of antibiotic-exposed Escherichia coli

Influence of subinhibitory levels of antibiotics on expression of Escherichia coli lipopolysaccharide and binding of anti-lipopolysaccharide monoclonal antibodies

Bactericidal Monoclonal Antibodies Specific to the Lipopolysaccharide O Antigen from Multidrug-Resistant Escherichia coli Clone ST131-O25b:H4 Elicit Protection in Mice

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