Is Penicillin Plus Gentamicin Synergistic against Clinical Group B Streptococcus isolates?: An In vitro Study

Abstract

Group B Streptococcus (GBS) is increasingly causing invasive infections in non-pregnant adults. Elderly patients and those with comorbidities are at increased risk. On the basis of previous studies focusing on neonatal infections, penicillin plus gentamicin is recommended for infective endocarditis (IE) and periprosthetic joint infections (PJI) in adults. The purpose of this study was to investigate whether a synergism with penicillin and gentamicin is present in GBS isolates that caused IE and PJI. We used 5 GBS isolates, two clinical strains and three control strains, including one displaying high-level gentamicin resistance (HLGR). The results from the checkerboard and time-kill assays (TKAs) were compared. For TKAs, antibiotic concentrations for penicillin were 0.048 and 0.2 mg/L, and for gentamicin 4 mg/L or 12.5 mg/L. In the checkerboard assay, the median fractional inhibitory concentration indices (FICIs) of all isolates indicated indifference. TKAs for all isolates failed to demonstrate synergism with penicillin 0.048 or 0.2 mg/L, irrespective of gentamicin concentrations used. Rapid killing was seen with penicillin 0.048 mg/L plus either 4 mg/L or 12.5 mg/L gentamicin, from 2 h up to 8 h hours after antibiotic exposure. TKAs with penicillin 0.2 mg/L decreased the starting inoculum below the limit of quantification within 4–6 h, irrespective of the addition of gentamicin. Fast killing was seen with penicillin 0.2 mg/L plus 12.5 mg/L gentamicin within the first 2 h. Our in vitro results indicate that the addition of gentamicin to penicillin contributes to faster killing at low penicillin concentrations, but only within the first few hours. Twenty-four hours after antibiotic exposure, PEN alone was bactericidal and synergism was not seen.

Is Penicillin Plus Gentamicin Synergistic Against Sessile Group B Streptococcal Isolates? An in Vivo Study With an Experimental Model of Foreign-Body Infection

“…The reduction in bacterial load was minor after 3 days of treatment, irrespective of growth form and treatment regimen. At this measured time point, we observed – in line with our previous in vitro results ( Ruppen et al, 2016b ) – a significant difference in killing of transition-form GBS between PEN monotherapy and systemic PEN–GEN combination therapy, without fulfilling the criteria for synergism ( Figure 2A ). The difference between PEN monotherapy and systemic PEN–GEN combination therapy was not observed for assays with biofilm bacteria and not after 6 days of treatment.…”

“…The rationale for this combination therapy is a postulated synergistic effect ( Schauf et al, 1976 ; Deveikis et al, 1977 ; Cooper et al, 1979 ; Baker et al, 1981 ). In contrast to these study findings, the results of our recent experiments did not confirm a synergistic effect with planktonic GBS ( Ruppen et al, 2016b , 2017a ). In view of the potential nephrotoxicity of aminoglycosides and the increasing elderly population at risk for invasive GBS disease, the decision to administer or withhold aminoglycosides is of clinical relevance.…”

“…The isolate was obtained from a patient with PJI (BE07-1b) and characterized previously (serotype Ib, multilocus sequence type 8, PEN MIC 0.032 mg/L, GEN MIC 24 mg/L) ( Ruppen et al, 2016a , b , 2017a ).…”

“…PEN (benzylpenicillin-sodium, Grünenthal Pharma AG, Mitlödi, Switzerland) and GEN (Hexal AG, Holzkirchen, Germany) were supplied from the clinical pharmacy of the University Hospital (Bern, Switzerland). Prior to administration, antibiotic concentrations in original vials were diluted until they reached the targeted value and were then measured, as described previously ( Ruppen et al, 2016b ). Antibiotic concentrations of PEN and GEN in serum and TCF samples obtained from animals were measured via high-performance liquid chromatography-mass spectrometry( Ruppen et al, 2016b ).…”

Infective endocarditis caused by Streptococcus agalactiae: time for beta-hemolytic streptococci to follow treatment recommendations for S. aureus?

“…Recently, performed time-kill assays indicated that the addition of gentamicin to penicillin contributes to faster killing of planktonic GBS without fulfilling the criteria for synergism. The in vitro effect of faster killing was seen only at low penicillin concentrations and only within the first few hours of the assay [23]. When human blood products (serum, neutrophilic granulocytes, or whole blood from healthy volunteers [≥ 65 years]) were added to experiments, no beneficial effect of adjunctive gentamicin was seen [24].…”