In vitro Antibacterial Activity and Resistance Prevention of Antimicrobial Combinations for Dihydropteroate Synthase-Carrying Stenotrophomonas maltophilia

Abstract

Background: Stenotrophomonas maltophilia (S. maltophilia) is a multidrug-resistant gram-negative bacillus that is known to be an opportunistic pathogen, particularly in a hospital environment. The infection has a high morbidity and mortality. Sulfamethoxazoletrimethoprim (SXT) is the first-line agent recommended for its treatment. The global spread of dihydropteroate synthase (sul) genes has resulted in an increased resistance rate. However, the appropriate therapy for infections caused by sul-carrying S. maltophilia has not yet been established. Objective: Our study aimed to identify the optimal antibiotic combinations that could both show high antibacterial activity against sul-carrying S. maltophilia and the ability to prevent the emergence of resistance at clinical dosage regimens. Methods: Time-killing experiments and mutant prevention concentration (MPC) experiments were conducted to evaluate the antibacterial effect and ability to prevent resistance to minocycline, tigecycline, moxifloxacin, and ticarcillin/clavulanic acid (T/K), both alone and in combination, at clinically relevant antimicrobial concentrations. Results: Minocycline, tigecycline, and T/K all exhibited bacteriostatic activity to sul-carrying S. maltophilia. The combination of minocycline plus T/K and tigecycline plus T/K neither enhanced the bactericidal ability nor prevented drug-resistant mutations. Moxifloxacin, at 2 mg/L, showed good bactericidal activity to most S. maltophilia, but bacterial regrowth at 24 h was observed in two strains. When combined with T/K, moxifloxacin showed good bactericidal activity in all moxifloxacin-sensitive strains. The concentrations of moxifloxacin alone were lower than most MPCs of the tested sul-carrying strains. When combined with T/K, the mean steady-state concentrations (MSC) of moxifloxacin could prevent 70% of resistance, and the peak concentration (C max ) prevented 95% of resistance. Conclusion:The combination of moxifloxacin and T/K can achieve a good in vitro bactericidal effect and prevent the emergence of resistance at clinical dosage regimens, and may be an optimal therapeutic strategy for S. maltophilia infections, especially for vulnerable immunocompromised and critically ill patients.

Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme

“…Therefore, we can simultaneously use Equations (7) and (8), or other equations established like similar method, to quickly and complementarily predict the rough MPCs from the MIC as references when need. This was further verified by another forty-six data pairs (MIC, MPC) ( Table S7 ) from another five papers [ 42 , 43 , 44 , 45 , 46 ], with an acceptable probability of 91.3%. Conversely, the larger prediction accuracy further confirmed that the MPC of an antimicrobial agent can be roughly calculated from its corresponding MIC.…”

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations, Rules and Laws, and a Preliminary Scheme

“…These data pairs include the MIC and the corresponding MPC, of various antimicrobial agents with different classes against representative pathogenic bacteria, and shown in Table S5. After this, using another forty-six data pairs (MIC, MPC) (Table S6) reported from other papers [38][39][40][41][42], this correlation was further verified by comparison the calculated MPC with the tested one.…”

“…Thereby, we can simultaneously use equations ( 7) and ( 8), or other equations established like similar method, to quickly and complementarily predict the rough MPCs from the MIC as references when need. This was further verified by another forty-six data pairs (MIC, MPC) (Table S6) from another five papers [38][39][40][41][42], with an acceptable probability of 91.3%. Conversely, the larger prediction accuracy further confirmed that the MPC of an antimicrobial agent can be roughly calculated from its corresponding MIC.…”

Drug Combinations to Prevent Antimicrobial Resistance: Some Correlations and Laws, and their Verifications, thus Proposing Some Principles and a Preliminary Scheme

“…To obtain more intuitive visual effects, the correlation analyses were further performed using Microsoft Excel software after these data pairs (MIC, MPC) were respectively transformed into the natural logarithm (log10) of the MIC and the MPC. After this, using another forty-six data pairs (MIC, MPC) (Table S7) reported from other papers [42][43][44][45][46], this correlation was further verified by comparing the calculated MPC with the tested one.4.1.4.…”

“…Thereby, we can simultaneously use equations ( 7) and (8), or other equations established like similar method, to quickly and complementarily predict the rough MPCs from the MIC as references when need. This was further verified by another forty-six data pairs (MIC, MPC) (Table S7) from another five papers [42][43][44][45][46], with an acceptable probability of 91.3%. Conversely, the larger prediction accuracy further confirmed that the MPC of an antimicrobial agent can be roughly calculated from its corresponding MIC.…”