In Vivo Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes

Abstract

c Streptococcus suis serotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such as S. suis. This study evaluated the in vitro and in vivo antimicrobial activities of CEQ against four strains of S. suis serotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (10 6 to 10 8 CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (E max ) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒT >MIC ) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (R 2 ‫؍‬ 91% and R 2 ‫؍‬ 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (P ‫؍‬ 0.006) and a 2-fold exposure time (P ‫؍‬ 0.01) were required for a 1-log kill using large inocula of 10 8 CFU/thigh. Streptococcus suis is an important pathogen in the swine industry and causes significant economic losses worldwide. Moreover, it is an emerging zoonotic pathogen causing severe infection in people who have close contact with diseased pigs or pork-derived products (1, 2). To date, 35 serotypes based on S. suis capsular antigens have been described. S. suis serotype 2 is the most virulent and the dominant pathogenic serotype. It has been associated with a variety of severe clinical infections such as meningitis, septicemia, pneumonia, arthritis, and endocarditis in both pigs and humans (3, 4). Significant public health concerns were raised due to large outbreaks of S. suis 2 in humans that occurred in China in 1998 and 2005 that caused high morbidity and mortality (5). Because suitable vaccines were not available, the control of S. suis 2 infections depended almost entirely on the use of antimicrobials. However, the occurrence of high levels of resistance of S. suis to certain antimicrobials (e.g., macrolides, lincosamides, tetracyclines, and sulfonamides) has limited the choice of antimicrobial agents for treatment (6). It has previously been reported that the majority of S. suis strains are susceptible to ␤-lactams (MIC of Յ0.03 g/ml). This suggested that these drugs may be efficacious in the treatment of S. suis 2 infections (7).Cefquinome (CEQ) is a fourth-generation cephalosporin developed solely for veterinary use and has been highly effective against a wide variety of Gram-positive and Gram-negative bacteria (8). CEQ has also been tested and was shown to be effective in animals using a standard thig...

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

“…The in vitro efficacy of CFQ for these pathogens has been reported by various workers (Batzias, 2009;Chin, Gu, Fang, & Neu, 1992;Ehinger, Schmidt, & Kietzmann, 2006;FDA, 2006;Limbert et al, 1991;Luhofer et al, 2004;Meyns, Croubels, Verheyen, Sustronck, & Maes, 2006;Murphy, Erwin, & Jones, 1994;Thomas et al, 2006). (Gu et al, 2015;Guo et al, 2015;Qiu et al, 2016;Shan, Liang, Wang, Li, & Zeng, 2014;Wang et al, 2014). In this study, % (Roberts et al, 2010;Smiet, Haritova, Heil, Fink-Gremmels, & Wijnberg, 2012;Zhang et al, 2014) have been recommended in critically ill patients and patients with compromised immune responses.…”

“…In this study, the hypothetical MIC values (0.125‐2 μg/ml), which based on MIC 90 values of 0.016‐1 μg/ml reported for susceptible pathogens above and the susceptibility breakpoint of 2 μg/ml recommended by the AVID (Working Group for Veterinary Medicines and Diagnosis of Infections) in Germany (AVID, ), were used to calculate %T > MIC. Studies recommend T > MIC values of 40%–70% for CFQ (Gu et al., ; Guo et al., ; Qiu et al., ; Shan, Liang, Wang, Li, & Zeng, ; Wang et al., ). In this study, % T > MIC values for two administration routes were calculated using V darea determined following IV administration of CFQ.…”

“…Due to its broad antibacterial spectrum and excellent efficacy, CFQ has the potential to become a valuable antibiotic in the treatment of infectious diseases in sheep. The successful therapeutic use of CFQ, time‐dependent antibiotic, requires knowledge of its pharmacokinetics and pharmacodynamics (PK/PD) (Ahmad et al., ; Gu et al., ; Guo et al., ; Thomas, Thomas, & Wilhelm, ; Wang, Shan, Ding, Liang, & Zeng, ; Zhang et al., ). For this purpose, the useful pharmacokinetic/pharmacodynamic (PK/PD) parameter, which calculated using the apparent volume of distribution and elimination half‐life and the minimum inhibitory concentration (MIC), is the percentage of time interval (%T > MIC) that plasma concentration remains above MIC (Turnidge, ).…”

Plasma and synovial fluid pharmacokinetics of cefquinome following the administration of multiple doses in horses

“…In this study, T > MIC was calculated using the hypothetical MIC values (0.125–2 μg/mL) that were established based on MIC 90 values of 0.016–2 μg/mL reported for susceptible horse pathogens (Thomas et al ., ) and the susceptibility breakpoint of 2 μg/mL. In vitro and in vivo animal data support T > MIC values of 40–70% between CFQ doses (Shan et al ., ; Wang et al ., ; Gu et al ., ; Guo et al ., ; Qiu et al ., ). This pharmacodynamic target was provided by the administration of 1, 2, 4, and 6 mg/kg doses of CFQ at 12‐h intervals, with MIC values of ≤0.25, ≤0.5, ≤1, and ≤1, respectively, for bacteria (Table ).…”

“…Cefquinome has low activity against methicillin-resistant S. aureus and very limited activity against gram-negative anaerobes, Pseudomonas aeruginosa and Rhodococcus equi in vitro (Limbert et al, 1991;Bottner et al, 1995;Thomas et al, 2006). The antibacterial activity of CFQ generally displays time-dependent characteristics (Thomas et al, 2006;Wang et al, 2014;Zhang et al, 2014a;Ahmad et al, 2015;Gu et al, 2015;Guo et al, 2015). It has been reported that the pharmacokinetics/pharmacodynamics (PK/ PD) index that correlates with the therapeutic efficacy of the beta-lactam antibiotic is the amount of time (%T > MIC) that the drug levels remain above the minimum inhibitory concentration (MIC) (Craig, 1998;Turnidge, 1998;McKellar et al, 2004).…”