Synergistic Effects of Phage–Antibiotic Combinations against <i>Citrobacter amalonaticus</i>

Manohar, Prasanth; Royam, Madhav Madurantakam; Loh, Belinda; Bozdoğan, Bülent; Nachimuthu, Ramesh; Leptihn, Sebastian

doi:10.1021/acsinfecdis.1c00117

Cited by 54 publications

(43 citation statements)

References 32 publications

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“…Several in vitro studies have shown a synergistic effect between antimicrobials and antipseudomonal bacteriophages; however, such phenomena are not always observed. This may be explained by the mechanism of action of antimicrobials and the difference in the required environmental factors for biofilm formation; the latter can also be a reason for the disparity in laboratory and clinical results ( 8 , 36 , 37 ). Case reports on the management of P. aeruginosa periprosthetic joint infection and aortic graft infection have demonstrated the synergistic effect of phages and antibiotics, including ceftazidime, which led to the resolution of biofilm-associated infections ( 10 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report

et al. 2022

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High-energy trauma with severe bone fractures can be complicated by infection, leading to the development of osteomyelitis. Pseudomonas aeruginosa is an important causative agent of such infections because of its high virulence profile and ability to develop resistance against a wide range of antimicrobials quickly. P. aeruginosa biofilms cause treatment failure and relapsing infections. Bacteriophages are viruses that can be used to treat biofilm-associated infections. Moreover, the combination of phages with certain antimicrobials have demonstrated synergistic and additive effects. We present a case of a 21-year-old patient with relapsing multidrug-resistant (MDR) P. aeruginosa femur osteomyelitis that developed after a road accident, with a proximal right femoral Grade III B open fracture and severe soft tissue damage. Despite extensive antimicrobial treatment and multiple surgical interventions with wound debridement, the infection persisted, with subsequent development of femoral osteomyelitis with a fistula. Patient care management included femoral head excision with wound debridement, intravenous (IV) ceftazidime-avibactam, and the local application of the lytic Pseudomonas bacteriophage cocktail BFC 1.10. Nine months after the intervention, the patient did not show any clinical, radiological, or laboratory signs of inflammation; therefore, hip replacement was performed. Nevertheless, recurrent P. aeruginosa infection evolved at the distal side of the femur and was successfully treated with conventional antimicrobials. In this case, wound debridement combined with antibiotics and bacteriophages resulted in bacterial eradication of proximal femoral segment, avoiding leg amputation, but failed to treat osteomyelitis in distal bone segment. An in vitro assessment of the isolated MDR P. aeruginosa strain for biofilm formation and phage susceptibility was performed. Additionally, the antimicrobial effects of ceftazidime-avibactam and BFC 1.10 were determined on planktonic cell growth and bacterial biofilm prevention was evaluated. The isolated bacterial strains were susceptible to the bacteriophage cocktail. Strong biofilm formation was detected 6 h after inoculation. Ceftazidime-avibactam combined with BFC 1.10 was most effective in preventing planktonic cell growth and biofilm formation. In both cases, the required concentration of ceftazidime-avibactam decreased two-fold. This study demonstrates the possible use of bacteriophages and antibiotics in difficult-to-treat bone and soft tissue infections, where the additive effects of phages and antibiotics were observed.

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Section: Discussionmentioning

confidence: 99%

Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report

et al. 2022

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“…The idea of the use of phage therapy and antibiotics together was previously proposed by several research teams [ 28 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. When considering such a method to combat STEC, Easwaran et al [ 46 , 63 ] tested the efficacy of phage EcSw administered in combination with kanamycin, chloramphenicol, and/or ampicillin against E. coli O157:H7.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Bacteriophage vB_Eco4-M7 and Selected Antibiotics on the Biofilm Formed by Shiga Toxin-Producing Escherichia coli

et al. 2022

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Apart from antibiotic resistance of pathogenic bacteria, the formation of biofilms is a feature that makes bacterial infections especially difficulty to treat. Shiga toxin-producing Escherichia coli (STEC) strains are dangerous pathogens, causing severe infections in humans, and capable of biofilm production. We have reported previously the identification and characterization of the vB_Eco4-M7 bacteriophage, infecting various STEC strains. It was suggested that this phage might be potentially used in phage therapy against these bacteria. Here, we tested the effects of vB_Eco4-M7 alone or in a phage cocktail with another STEC-infecting phage, and/or in a combination with different antibiotics (ciprofloxacin and rifampicin) on biofilm formed by a model STEC strain, named E. coli O157:H7 (ST2-8624). The vB_Eco4-M7 phage appeared effective in anti-biofilm action in all these experimental conditions (2–3-fold reduction of the biofilm density, and 2–3 orders of magnitude reduction of the number of bacterial cells). However, the highest efficiency in reducing a biofilm’s density and number of bacterial cells was observed when phage infection preceded antibiotic treatment (6-fold reduction of the biofilm density, and 5–6 orders of magnitude reduction of the number of bacterial cells). Previous reports indicated that the use of antibiotics to treat STEC-caused infections might be dangerous due to the induction of Shiga toxin-converting prophages from bacterial genomes under stress conditions caused by antibacterial agents. We found that ciprofloxacin was almost as efficient in inducing prophages from the E. coli O15:H7 (ST2-8624) genome as a classical inducer, mitomycin C, while no detectable prophage induction could be observed in rifampicin-treated STEC cells. Therefore, we conclude the latter antibiotic or similarly acting compounds might be candidate(s) as effective and safe drug(s) when used in combination with phage therapy to combat STEC-mediated infections.

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“…The study performed in vitro with Citrobacter amalonaticus showed synergistic effects for the use of phage MRM57 (10 3 and 10 6 plaque forming units (PFU/ml) with a sublethal dose of antibiotics with a different mechanism of action (carbenecillin, colistin, fosfomycin, gentamicin, meropenem, cefepime-tazobactam, tigecycline) except for cefotaxime at 1/10 × MIC [ 30 ].…”

Section: Phage–antibiotic Synergymentioning

confidence: 99%

Bacteriophages and antibiotic interactions in clinical practice: what we have learned so far

et al. 2022

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Bacteriophages (phages) may be used as an alternative to antibiotic therapy for combating infections caused by multidrug-resistant bacteria. In the last decades, there have been studies concerning the use of phages and antibiotics separately or in combination both in animal models as well as in humans. The phenomenon of phage–antibiotic synergy, in which antibiotics may induce the production of phages by bacterial hosts has been observed. The potential mechanisms of phage and antibiotic synergy was presented in this paper. Studies of a biofilm model showed that a combination of phages with antibiotics may increase removal of bacteria and sequential treatment, consisting of phage administration followed by an antibiotic, was most effective in eliminating biofilms. In vivo studies predominantly show the phenomenon of phage and antibiotic synergy. A few studies also describe antagonism or indifference between phages and antibiotics. Recent papers regarding the application of phages and antibiotics in patients with severe bacterial infections show the effectiveness of simultaneous treatment with both antimicrobials on the clinical outcome.

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Synergistic Effects of Phage–Antibiotic Combinations against Citrobacter amalonaticus

Cited by 54 publications

References 32 publications

Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report

Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis—A Case Report

Synergistic Effects of Bacteriophage vB_Eco4-M7 and Selected Antibiotics on the Biofilm Formed by Shiga Toxin-Producing Escherichia coli

Bacteriophages and antibiotic interactions in clinical practice: what we have learned so far

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