The present study shows that the fT>MIC is not the major PK/PD index that correlated with efficacy in terms of overall cure after a long treatment duration. In contrast, the AUC/MIC ratio, or the daily dose, was the index that best correlated with the animal survival rate. It is clear that the antimicrobial treatment duration and the actual treatment endpoint used may be important determinants for the interpretation of the experimental data and their relevance to clinical practice. Experimental studies investigating the impact of PK/PD indices during short-term treatment on bacterial killing in the infected tissues provide relevant knowledge with respect to the first day(s) of treatment. At the same time, studies on the effect of long-term treatment on maximum animal survival are relevant for better understanding of the impact of PK/PD indices in infections requiring treatment for a relatively long duration. The role of beta-lactams in this respect is important, as relatively long treatment of serious infections caused by gram-negative bacteria with beta-lactams is common (15). Remarkably, the fAUC/MIC needed for 100% animal survival was about 100, a value that correlates with clinical efficacy for other classes of drugs as well, in particular, the quinolones (18).
Antimicrobial Pharmacodynamics In Theory And Clinical Practice (Infectious Disease And Therapy) Down
The apparent discordance between bacterial and fungal co-infection in patients with COVID-19 at presentation and the use of antibacterial therapy has potential negative effects, namely in antimicrobial resistance. Several studies have attempted to differentiate patients with and without concomitant bacterial infections using laboratory data. The use of procalcitonin in a group of hospitals was not effective as tool to encourage antibiotic discontinuation compared to clinical judgment [295]. Mason and colleagues compared hospitalized cohorts of 619 patients with COVID-19 and 106 with community-acquired bacterial pneumonia (CABP) to determine if inflammatory markers could be used to rule out bacterial co-infection [296]. They found marked differences in white blood cell counts between groups (6.78 COVID-19 vs. 12.48 CABP), and that CRP declined in 48-72 hours with antibiotic therapy in the CABP cohort but not the COVID-19 group, suggesting that these can be used to guide antibiotic discontinuation when initiated empirically in COVID-19 patients. Initiating and continuing empiric antibiotics at the time of admission may lead to superinfections that are antibiotic resistant; one study found antibiotic use in the first two days of admission for COVID-19 to be a risk factor for superinfection [292]. Immunomodulatory therapies are recommended for many patients with severe and critical illness from COVID-19, including corticosteroids, IL-6 antagonists, JAK inhibitors, and others [297]. Most of the prospective studies that support these recommendations have not reported higher rates of infection in patients receiving immunomodulators, but follow-up is limited in most cases and late infections may be missed.
In chronic bronchitis, antibiotic therapy overcomes the symptoms caused by waves of planktonic cells released from the biofilm during exacerbations of the disease but fails to eradicate infection as sessile cells are inherently less affected [116]. Due to these facts not only time to eradication of symptoms is an endpoint in clinical trials with antibiotics against exacerbations, but also time to relapse is increasingly used as endpoint. In healthy lungs, there is a transient microbiome of micro-aspirated upper airway microbial flora being cleared by normal lung defense mechanisms [117]. Chronic exposure to cigarette smoke results in higher loads of NTHi and S. pneumoniae in lungs [118], and these potential pathogenic microorganisms have been detected in approximately 25% of patients with chronic obstructive pulmonary disease (COPD) during stable disease [119]. COPD and subsequent AECBs (with related presence of released planktonic cells) are associated with biofilms [120,121,122,123], with a relevant role for H. influenzae. In addition, COPD patients with frequent exacerbations show an increase in inflammation in the upper airways contributing to the progression of the disease [124]. Antibiotics active against planktonic cells and able to interfere or decrease biofilm development may offer clinical advantages [125]. Additionally, the use of antibiotics may also reduce inflammatory parameters [107]. Cefditoren showed to interfere biofilm formation in a study comparing cefditoren (0.03 mg/l) with amoxicillin/clavulanic acid (1/0.5 mg/l) that concluded that both compounds were able to reduce biofilm formation by the 10 pneumococcal isolates tested, with significant higher reductions in the case of cefditoren [126]. With respect to inflammation, one study comparing cefditoren and levofloxacin found that the use of both antimicrobials was associated with significant reductions of IL-6 and KL-6, two mediators of lung inflammation and epithelial damage [107, 127].
The US Centers for Disease Control and Prevention (CDC) dedicate a substantial proportion of their urgent and serious threats to addressing antibiotic-resistant Gram-negative bacteria [1]. Specifically, infections caused by multidrug-resistant (MDR)/extensively drug-resistant (XDR) Gram-negative pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB) or Enterobacterales (CRE), have been associated with substantial morbidity and mortality in comparison to their susceptible phenotypes due, in part, to a lack of efficacious and safe therapies [2, 3]. Although options such as the novel intravenous (IV) beta-lactam/beta-lactamase inhibitors (BL/BLI), polymyxins, high-dose/extended infusion carbapenems, novel tetracycline derivatives, and/or aminoglycosides (depending on the pathogen) exist for susceptible and invasive infections, resistance to these therapies is increasing. Furthermore, various concerns have been expressed regarding some of the aforementioned antibiotics, such as minimal real-world data, tolerability issues, sub-optimal pharmacokinetics (PK) data, and/or lack of attaining pharmacodynamic (PD) targets in deep-seated infections [4, 5]. Importantly, transitions-of-care for infections caused by resistant Gram-negative pathogens are complex due to the lack of suitable alternative therapies, including those with an available oral formulation. These organisms cause chronic infections, and the lack of efficacious oral formulations for step-down therapy following initial stabilization may often lead to prolonged IV therapy, which has been shown to have its own array of complications (i.e., delayed discharge, hospital readmissions, line complications, etc.) [6, 7]. Importantly, recent randomized clinical trials have shown non-inferiority of oral agents to parenteral therapy as step-down therapy in invasive infections [8, 9]. Therefore, effective and safe antimicrobial agents, including carbapenem-sparing regimens, with in vitro activity against MDR/XDR Gram-negative pathogens with novel mechanisms of action and availability in oral formulations are urgently needed.
Overall, clinical success occurred in 6/9 (66.7%) cases. For patients with bone/joint infections, IAI, and VAP, clinical success was observed in 4/5 (80.0%), 1/3 (33.3%), and 1/1 (100%) cases, respectively. Among the most commonly isolated pathogen (CRAB), clinical success was 4/5 (80.0%). The most common infection and isolate pair was bone/joint infections caused by CRAB, with a 3/4 (75.0%) success rate. The primary reasons for OMC utilization were due to oral availability (8/9 [88.9%]), ease of administration (7/9 [77.8%]), antimicrobial resistance to previous antibiotic(s) (5/9 [55.6%]), and/or as oral step-down therapy (4/9 [44.4%]). One patient experienced an adverse effect while on therapy that was gastrointestinal in nature; however, the adverse effect did not lead to OMC discontinuation and resolved throughout OMC continuation.
We report a case series of OMC use for MDR/XDR Gram-negative organisms in a variety of infections with an overall success rate of 66.7%. Given the dearth of oral options available for the treatment of pathogens like CRE and CRAB and OMC being documented as utilized due to its oral bioavailability and option for oral step-down therapy, the fairly high clinical success rate achieved within this case series is significant. With careful consideration to our small sample size and heterogeneity in pathogens and infection sites, OMC administered orally appears to be a promising agent for the treatment of MDR/XDR Gram-negative pathogens in certain clinical scenarios when used as part of a comprehensive antibiotic therapy regimen with infectious diseases specialist supervision and source control (when applicable).
Judicious, careful and rational use of antimicrobials is an integral part of good clinical practice. This attitude maximizes the utility and therapeutic efficacy of treatment, and minimizes the risks associated with emerging infections and the selection of resistant pathogens. The indiscriminate and excess use of antimicrobial drugs appears the most significant factor in the emergence of resistant microorganisms in recent years.
In these countries, routine microbiologic culture and sensitivity testing, especially in rural hospitals, are not performed, due to lack of personnel, equipment and financial resources. As a result antimicrobial therapy is empirical and a small collection of antimicrobials may be overused. This approach, although relatively inexpensive, may further increase the emergence of AMR and hence sub-optimal clinical outcomes [49].
Core principles of antimicrobial stewardship include the use of antibiotic prophylaxis only when there is proven efficacy, use of the narrowest spectrum of antimicrobial therapy with proven efficacy, use of the least number of agents and for the shortest length of therapy to achieve efficacy, and appropriate antimicrobial dosing to maximize efficacy and limit complications. However, the best strategies for an antimicrobial stewardship program (ASP) are not definitively established and are likely to vary based on local culture, policy and routine clinical practice [15]. Observational data support a significant association between stewardship practices and reduction of antibiotic resistance. In a retrospective before and after study design, analysis of two ICUs within a single institution (trauma and surgical) before and after the implementation of service specific antibiotic stewardship protocols, Dortch et al. demonstrated a significant reduction in the percentage of multidrug resistant gram negative pathogens isolated and a corresponding decrease in broad spectrum antibiotic use [137]. 2ff7e9595c
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