Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.

/pdf/progress-in-alternative-strategies-to-combat-antimicrobial-ixbfruwn.pdf

Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics

Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major health threat, but the economic impact of carbapenem resistance in K. pneumoniae infections remains largely uninvestigated. Methods We constructed a retrospective cohort of all patients hospitalized at West China Hospital in 2017 who had CRKP- or carbapenem-susceptible K. pneumoniae (CSKP)-positive clinical samples. Propensity score matching (PSM) was used to control the impact of potential confounding variables, including demographics, comorbidities, and treatment, and to observe the impact of factors other than length of stay (LOS). Patients who survived were subjected to subgroup analyses stratified by infection type. Results There were 267 patients with CRKP and 1328 with CSKP. Patients with CRKP had a higher crude in-hospital mortality rate (14.61% vs 5.65%, P < .05) and longer LOS (median, 31 vs 19 days; P < .05). PSM for demographics, comorbidities, and treatment generated 237 pairs. Patients with CRKP had higher medical costs than those with CSKP during the entire hospitalization (median, in US dollars, $22962 vs $11755, respectively; P < .05) and during the period after infection (median, $9215 vs $6904, respectively; P < .05). When LOS was matched, patients with CRKP still had high excess costs compared to those with CSKP (median, $22917 vs $13851, respectively, for the entire hospitalization, P < .05; $9101 vs $7001, respectively, after infection, P < .05). For infection type, the sample size generated sufficient power to compare only the patients with pneumonia. For surviving patients, high excess costs were observed in those with pneumonia caused by CRKP as compared to CSKP ($21890 vs $11698, respectively, for the entire hospitalization, P < .05; $9773 vs $5298, respectively, after infection, P < .05). Medicines other than antibacterial agents and nonmedicinal therapies contributed most (57.8%) of the excess costs associated with CRKP. Conclusions Carbapenem resistance in K. pneumoniae was associated with increased medical costs not accounted for by the cost of antimicrobial therapy.

In-hospital Medical Costs of Infections Caused by Carbapenem-resistant Klebsiella pneumoniae.

Multidrug resistant Enterobacterales have become a serious global health problem, with extended hospital stay and increased mortality. Antibiotic monotherapy has been reported ineffective against most drug resistant bacteria including Klebsiella pneumoniae, thus encouraging the use of multidrug therapies as an alternative antibacterial strategy. The present works assessed the antibacterial activity of colistin against K. pneumoniae isolates. Resistant isolates were tested against 16 conventional antibiotics alone and in combination with colistin. The results revealed that all colistin resistant isolates demonstrated multidrug resistance against the tested antibiotics except amikacin. At sub-inhibitory concentrations, combinations of colistin with amikacin, or fosfomycin showed synergism against 72.72% (8 of 11 isolates). Colistin with either of gentamicin, meropenem, cefoperazone, cefotaxime, ceftazidime, moxifloxacin, minocycline, or piperacillin exhibited synergism against 81.82% (9 of 11 isolates). Combinations of colistin with either of tobramycin or ciprofloxacin showed synergism against 45.45% (5 in 11 isolates), while combinations of colistin with imipenem or ceftolozane and tazobactam displayed 36.36% (4 of 11 isolates) and 63.64% (7 of 11 isolates) synergism. In addition, combinations of colistin with levofloxacin was synergistic against 90.91% (10 of 11 isolates). The results revealed that combinations of colistin with other antibiotics could effectively inhibit colistin resistant isolates of K. pneumoniae, and thus could be further explore for the treatment of multidrug resistant pathogens.

/pdf/synergistic-antibacterial-effects-of-colistin-in-combination-3jt8wqz6cy.pdf

Synergistic antibacterial effects of colistin in combination with aminoglycoside, carbapenems, cephalosporins, fluoroquinolones, tetracyclines, fosfomycin, and piperacillin on multidrug resistant Klebsiella pneumoniae isolates

Aminoglycosides are a family of rapidly bactericidal antibiotics that often remain active against resistant Gram-negative bacterial infections. Over the past decade, their use in critically ill patients has been refined; however, due to their renal and cochleovestibular toxicity, their indications in the treatment of sepsis and septic shock have been gradually reduced. This article reviews the spectrum of activity, mode of action, and methods for optimizing the efficacy of aminoglycosides. We discuss the current indications for aminoglycosides, with an emphasis on multidrug-resistant Gram-negative bacteria, such as extended-spectrum β-lactamase-producing Enterobacterales, carbapenemase-producing Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Additionally, we review the evidence for the use of nebulized aminoglycosides.

/pdf/aminoglycosides-for-the-treatment-of-severe-infection-due-to-2vsgqsqx.pdf

Aminoglycosides for the Treatment of Severe Infection Due to Resistant Gram-Negative Pathogens

In this study, we analyzed the clinical distribution and drug resistance of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, the minimum inhibitory concentrations (MIC), MIC50 and MIC90, and geographical distribution in Hebei Province, China. We aimed to provide epidemiological research data, formulate appropriate combined treatment schemes, reasonably select antibiotics, and standardize nosocomial infection control schemes.A total of 6328 strains of CRKP were collected from 2017 to 2019. The MIC was determined for the drug sensitivity test, and the experimental data were statistically analyzed using WHONET5.6.The detection rate of CRKP increased annually from 13.4% in 2017 to 14.5% in 2018, and 14.6% in 2019. The ratio of males to females was approximately 2:1; 53.6% were elderly, 39% were adults, 4.8% were minors, and 2.5% were newborns. The specimens collected were mainly sputum (70.9%). The resistance rate of CRKP to carbapenems and other β-lactam antibiotics was found to be increasing, with resistance rates generally greater than 90%. The resistance rate to aminoglycoside antibiotics decreased yearly to approximately 50%, and the resistance rate to quinolones remained unchanged at approximately 80%. From 2017 to 2019, the resistance rate of CRKP in Hebei Province to various antibiotics was high, and the resistance rate to β-lactam antibiotics increased each year.The situation of CRKP resistance is severe in Hebei Province, China. The resistance rate to most antibiotics is very high and shows an upward trend. Among them, the resistance rate to polymyxin is low; however, few resistant strains do exist. MIC50 and MIC90 are higher than their MICs. It mainly causes lung infection in elderly men. This study is helpful to improve the diagnosis, treatment, and prevention of CRKP infection in our province. 

/pdf/prevalence-of-carbapenem-resistant-klebsiella-pneumoniae-3o57e73c.pdf

Prevalence of Carbapenem-Resistant Klebsiella pneumoniae Infection in a Northern Province in China: Clinical Characteristics, Drug Resistance, and Geographic Distribution

The resistance of carbapenem-resistant Klebsiella pneumoniae (CRKP) to colistin has become a major challenge in clinics. The objective of this study was to investigate the synergistic and bactericidal effects of combinations of colistin with meropenem and amikacin in vitro and provide laboratory data required for the treatment of CRKP infections in the Eastern Heilongjiang Province. The minimum inhibitory concentrations of antibiotics were determined by micro-broth dilution method against 40 CRKP isolates. Ten CRKP isolates were selected to determine the minimum bactericidal concentration. The checkerboard microdilution method was performed to determine the synergic effects of colistin combinations with either meropenem or amikacin on CRKP isolates. Time kill assays were used to evaluate the effectiveness of monotherapies and colistin- meropenem or colistin-amikacin combined therapies against 6 distinct sequence types of the CRKP isolates. The minimum inhibitory concentrations of colistin, meropenem and amikacin were 2~32, 4~256, and 1~16 μg/ml, respectively. The minimum bactericidal concentration of the antibiotics was either 1 time or 2 times of the minimum inhibitory concentration. Treatments of 6 CRKP isolates at 16 μg/ml meropenem or amikacin in addition to 2 μg/ml colistin completely killed 4 of them and suppressed the growth of 2 others (sequence type 76 and 11) while none of them showed bactericidal effects in the monotherapy. Our data suggest that colistin would be a valid therapeutic option against colistin-resistant CRKP isolates when it is used in combination with either meropenem or amikacin for treatment of CRKP infections in the Eastern Heilongjiang Province.

/pdf/synergetic-effects-of-combined-treatment-of-colistin-with-59u720bpi3.pdf

Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.

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Synergetic Effects of Combined Treatment of Colistin With Meropenem or Amikacin on Carbapenem-Resistant Klebsiella pneumoniae in vitro.