Antibiotics

Monitoring antibiotic resistance genes (ARGs) is vital to the One Health approach to tackling the antibiotic resistance crisis. It has been suggested that conifer needles can be used as passive bioaerosol samplers. Here, the use of conifer needles as biomonitors of ARGs in bioaerosols was assessed as a proof-of-concept. Needles were collected from trees surrounding pig farms, villages, and forest sites in Québec, Canada. Needles were homogenised and DNA was extracted. Results of qPCR analyses showed biomass estimates were consistent across samples. Number and quantity of ARGs was significantly lower in forest sites when compared to the farm and village, comprising a distinct resistome. Consistent with previous findings, the most common ARGs were tetracyclines and sulfonamides, which were found close to agricultural activities. Although results were limited, there is great potential for using the conifer phyllosphere as a passive bioaerosol sampler. This method represents an accessible way to promote ARG surveillance over long distances from point sources. Full article

With the wide spread of multidrug-resistant bacteria, a variety of aminoglycosides have been used in clinical practice as one of the effective options for antimicrobial combinations. However, in recent years, the emergence of high-level resistance against pan-aminoglycosides has worsened the status of antimicrobial resistance, so the production of 16S rRNA methyltransferase (16S-RMTase) should not be ignored as one of the most important resistance mechanisms. What is more, on account of transferable plasmids, the horizontal transfer of resistance genes between pathogens becomes easier and more widespread, which brings challenges to the treatment of infectious diseases and infection control of drug-resistant bacteria. In this review, we will make a presentation on the prevalence and genetic environment of 16S-RMTase encoding genes that lead to high-level resistance to aminoglycosides. Full article

Background: Rhizobium (Agrobacterium) species are plant aerobic bacteria, which in some cases can produce endophthalmitis in humans after corneal trauma. Case presentation: A 42-year-old female patient presented in the Emergency Department of the Emergency County Hospital of Craiova, Romania, reporting pain, epiphora, and blurry vision in her right eye for about five days. This initial infectious keratitis episode was successfully resolved, but after 20 days she presented again after trauma with a leaf with corneal abscess. In the conjunctival secretion, R. radiobacter was identified. Despite antibiotherapy, the patient’s state did not improve, and ultimately the eye was eviscerated. Methods: A search was performed in the ProQuest, PubMed, and ScienceDirect databases for the terms Agrobacterium, Rhizobium, radiobacter, and eye. We eliminated non-human studies, editorials and commentaries, and non-relevant content, and excluded the duplicates. Results: In total, 138 studies were initially obtained, and then we selected 26 studies for retrieval. After the selection process, we ended up including 17 studies in our analysis. Most studies reported R. radiobacter endophthalmitis after ocular surgical procedures or outdoor activities that involve exposure to soil. Conclusion: R. radiobacter is a rare cause of endophthalmitis after eye trauma that generally responds well to usual antibiotherapy, but occasionally can evolve to severe, leading to the loss of the eye. Full article

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile. Full article

A quasi-experimental study was conducted on the implementation of locally developed clinical practice guidelines (CPGs) for empirical antibiotic (ATB) therapy of common infections (bacteremia, urinary tract infection (UTI), pneumonia) in the hospitals from January 2019 to December 2020. The CPGs were developed using data from patients with these infections at individual hospitals. Relevant CPG data pre- and post-implementation were collected and compared. Of the 1644 patients enrolled in the study, 808 and 836 were in the pre- and post-implementation periods, respectively, and patient outcomes were compared. Significant reductions in the mean durations of intensive care unit stay (3.44 ± 9.08 vs. 2.55 ± 7.89 days; p = 0.035), ventilator use (5.73 ± 12.14 vs. 4.22 ± 10.23 days; p = 0.007), piperacillin/tazobactam administration (0.954 ± 3.159 vs. 0.660 ± 2.217 days, p = 0.029), and cefoperazone/sulbactam administration (0.058 ± 0.737 vs. 0.331 ± 1.803 days, p = 0.0001) occurred. Multivariate analysis demonstrated that CPG-implementation was associated with favorable clinical outcomes (adjusted odds ratio 1.286, 95% confidence interval: 1.004–1.647, p = 0.046). Among patients who provided follow-up cultures (n = 284), favorable microbiological responses were significantly less frequent during the pre-implementation period than the post-implementation period (80.35% vs. 91.89%; p = 0.01). In conclusion, the locally developed CPG implementation is feasible and effective in improving patient outcomes and reducing ATB consumption. Hospital antimicrobial stewardship teams should be able to facilitate CPG development and implementation for antimicrobial therapy for common infections. Full article

Coralmycins, such as coralmycin A and DH-coralmycin A, have novel molecular skeletons and have been reported to exhibit potent antibacterial activity against standard Gram-positive bacterial strains. Here, the in vitro antibacterial activity against an extensive clinical isolate collection, time-kill kinetics, pharmacokinetics (PK), and in vivo efficacy of coralmycins were studied. Coralmycin A showed potent antibacterial activity with an MIC₉₀ of 1 mg/L against 73 clinical methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci isolates, which was 2–8 times higher than the corresponding activities of DH-coralmycin A, vancomycin, daptomycin, and linezolid, and against 73 vancomycin-resistant Enterococcus and Streptococcus pneumoniae isolates, which was 4–16 times higher than the corresponding activities of DH-coralmycin A, daptomycin, and linezolid. Pharmacokinetic analysis after i.v. injection showed that coralmycins have a moderate volume of distribution and moderate-to-high clearance in mice. The coralmycin A and DH-coralmycin A bioavailability values were 61.3% and 11.7%, respectively, after s.c. administration. In a mouse respiratory tract infection model, coralmycin A showed bacteriostatic and bactericidal in vivo efficacies at an s.c. administration of 4 and 100 mg/kg bid, respectively; these efficacies were similar to those of vancomycin at 4 and 20 mg/kg bid, respectively. The present findings indicate that coralmycin A has great potential as a new class of antibiotic for treating infections caused by multidrug-resistant Gram-positive bacteria. Full article

Salvia africana-lutea L., S. lanceolata L., and S. chamelaeagnea L. are used in South Africa as traditional medicines to treat infections. This paper describes an in-depth investigation into their antibacterial activities to identify bioactive compounds. Methanol extracts from 81 samples were screened against seven bacterial pathogens, using the microdilution assay. Biochemometric models were constructed using data derived from minimum inhibitory concentration (MIC) and ultra-performance liquid chromatography-mass spectrometry data. Active molecules in selected extracts were tentatively identified using high-performance thin layer chromatography (HPTLC), combined with bioautography, and finally, by analysis of active zone eluates by mass spectrometry (MS) via a dedicated interface. Salvia chamelaeagnea displayed notable activity towards all seven pathogens, and the activity, reflected by MICs, was superior to that of the other two species, as confirmed through ANOVA. Biochemometric models highlighted potentially bioactive compounds, including rosmanol methyl ether, epiisorosmanol methyl ether and carnosic acid. Bioautography assays revealed inhibition zones against A. baumannii, an increasingly multidrug-resistant pathogen. Mass spectral data of the eluted zones correlated to those revealed through biochemometric analysis. The study demonstrates the application of a biochemometric approach, bioautography, and direct MS analysis as useful tools for the rapid identification of bioactive constituents in plant extracts. Full article

Whereas the clinical approach in pediatric cancer patients with febrile neutropenia is well established, data on non-neutropenic infectious episodes are limited. We therefore prospectively collected over a period of 4 years of data on all infectious complications in children treated for acute lymphoblastic or myeloid leukemia (ALL or AML) and non-Hodgkin lymphoma (NHL) at two major pediatric cancer centers. Infections were categorized as fever of unknown origin (FUO), and microbiologically or clinically documented infections. A total of 210 patients (median age 6 years; 142 ALL, 23 AML, 38 NHL, 7 leukemia relapse) experienced a total of 776 infectious episodes (571 during neutropenia, 205 without neutropenia). The distribution of FUO, microbiologically and clinically documented infections, did not significantly differ between neutropenic and non-neutropenic episodes. In contrast to neutropenic patients, corticosteroids did not have an impact on the infectious risk in non-neutropenic children. All but one bloodstream infection in non-neutropenic patients were due to Gram-positive pathogens. Three patients died in the context of non-neutropenic infectious episodes (mortality 1.4%). Our results well help to inform clinical practice guidelines in pediatric non-neutropenic cancer patients presenting with fever, in their attempt to safely restrict broad-spectrum antibiotics and improve the quality of life by decreasing hospitalization. Full article

Data specific to the epidemiology and burden of sepsis in low- and middle-income countries are limited. This study aimed to determine the epidemiology and burden of adult patients with sepsis at Siriraj Hospital during 2019. Randomly selected adult patients who had blood cultures performed at our center during January–December 2019 were enrolled. A Quick Sepsis-related Organ Failure Assessment (qSOFA) score was used to determine the presence of sepsis. Demographic data and clinical outcome data were collected, and the annual incidence of sepsis or septic shock and death was estimated. Of the 987 subjects who had blood cultures performed, 798 had infections, 341 had sepsis, and 104 had septic shock. The prevalence of sepsis or septic shock was 34.9% among blood cultured patients, and 42.7% among those with infections. The prevalence of septic shock was 30.5% among subjects with sepsis. Approximately 63% of sepsis subjects were hospital-acquired infections. The factors independently associated with 28-day mortality in sepsis were receiving an immunosuppressive agent (adjusted odds ratio [aOR]: 2.37, 95% confidence interval [CI]: 1.27–4.45; p = 0.007), septic shock (aOR: 2.88, 95% CI: 1.71–4.87; p < 0.001), and proven infection (aOR: 2.88, 95% CI: 1.55–5.36; p = 0.001). Receiving appropriate, definitive antibiotic therapy (ABT) was independently associated with lower mortality in sepsis (aOR: 0.50, 95% CI: 0.27–0.93; p = 0.028) and septic shock subjects (aOR: 0.21, 95% CI: 0.06–0.72; p = 0.013). Achievement of mean arterial pressure (MAP) ≥ 65 mmHg (aOR: 0.09, 95% CI: 0.01–0.77; p = 0.028) and urine output ≥ 0.5 mL/kg/h (aOR: 0.15, 95% CI: 0.04–0.51; p = 0.006) were independently associated with lower mortality in septic shock patients. The incidence and mortality of sepsis remains high. Appropriate choice of definitive ABT and achievement of MAP and urine output goals may lower mortality in patients with sepsis or septic shock. Full article

Temocillin is active against Gram-negative bacteria, including many extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. We studied its pharmacokinetics in plasma and ascitic fluid after intravenous administration of a loading dose of 2 g over 30 min, followed by continuous infusion of 6 g/24 h, to 19 critically-ill patients with septic shock associated with complicated intra-abdominal infection. We established a pharmacokinetic model describing unbound temocillin concentrations in plasma and ascitic fluid and performed Monte-Carlo simulations to evaluate the probability of target attainment (PTA) of unbound concentrations (100% fT > MIC, i.e., unbound concentrations remaining above the MIC during 100% of the time) for the applied and hypothetical dosing regimens. The temocillin AUC in ascitic fluid was 46% of the plasma AUC. Plasma unbound concentrations were best described by a two-compartment model, and an additional compartment was added to describe unbound concentration in ascitic fluid, with renal clearance as a covariate. Dosing simulations showed that 90% PTA was achieved in the plasma with the current dosing regimen for MIC ≤ 16 mg/L (EUCAST susceptibility breakpoint) but not in the ascitic fluid if renal clearance was ≥40 mL/min. Hypothetical dosing with a higher (a) loading dose or (b) infused dose allowed to reach target concentrations in ascitic fluid (a) more rapidly or (b) sustainably, but these simulations need to be evaluated in the clinics for safety and efficacy. Full article

Analytical methods for the drug substance and degradation products (DPs) are validated by performing forced degradation studies. Forced degradation studies of Velpatasvir (VEL) drug substance and Velpatasvir copovidone solid dispersion (VEL-CSD) were performed under the stressed alkaline, acidic, oxidative and thermal conditions according to ICH guidelines ICH Q1A (R2). VEL is labile to degrade in stressed alkaline, acidic, and oxidative conditions. It is also photolabile and degraded during photostability studies as described by ICH Q1B, and showed no degradation on exposure to extreme temperature when protected from light. A sensitive stability indicating HPLC-UV method was developed and validated for the separation of VEL and eight DPs. The DPs of VEL are separated using gradient elution of mobile phase containing 0.05% Trifluoroacetic acid (TFA) and methanol over symmetry analytical column C18 (250 mm × 4.6 mm, 5 µm) with a flow rate of 0.8 mL min⁻¹. Simultaneous detection of all DPs and VEL was performed on UV detector at 305 nm. The performance parameters like precision, specificity and linearity of the method were validated using reference standards as prescribed by ICHQ2 (R1). Limits of quantification and limits of detection were determined from calibration curve using the expression 10δ/slope and 3δ/slope respectively. The proposed method is stability-indicating and effectively applied to the analysis of process impurities and DPs in VEL drug substance and VEL-CSD. Full article

Antibiotic resistance is increasing worldwide making it necessary to search for alternative antimicrobials. Sodium bituminosulfonate is a long-known substance, whose antimicrobial inhibitory activity has recently been re-evaluated. However, to the best of our knowledge, the bactericidal mode of action of this substance has not been systematically characterized. The aim of this study was to investigate the in vitro bactericidal activity of sodium bituminosulfonate by determining the minimal bactericidal concentrations (MBC), as well as the rapidity of bactericidal effect by time-kill curves. Clinical isolates of methicillin-susceptible (MSSA, n = 20) and methicillin-resistant (mecA/mecC-MRSA, n = 20) Staphylococcus aureus were used to determine MBC by a broth microdilution method. Sodium bituminosulfonate (Ichthyol^® light) was tested in double-dilution concentration steps ranging from 0.03 g/L to 256 g/L. For time-kill analysis, two reference and two clinical S. aureus strains were tested with different concentrations of sodium bituminosulfonate (1× minimal inhibitory concentration (MIC), 2× MIC, 4× MIC, 16× MIC and 256× MIC). For MSSA isolates, MBC₅₀, MBC₉₀ and the MBC range were 0.5 g/L, 1.0 g/L and 0.125–1.0 g/L; (MBC/MIC ratio)₅₀, (MBC/MIC ratio)₉₀ and the range of the MBC/MIC ratio were 4, 4 and 1–8, respectively. Among MRSA isolates, MBC₅₀, MBC₉₀ and the MBC range amounted to 0.5 g/L, 1.0 g/L and 0.06–1.0 g/L; (MBC/MIC ratio)₅₀, (MBC/MIC ratio)₉₀ and the range of the MBC/MIC ratio were 2, 4 and 1–8, respectively. Time-kill kinetics revealed a bactericidal effect after 30 min for sodium bituminosulfonate concentrations of 16× MIC and 256× MIC. The bactericidal activity against MSSA and MRSA was demonstrated for sodium bituminosulfonate. The killing was very rapid with the initial population reduced by 99.9% after only short incubation with concentrations of 16× MIC and higher. Full article

Mycobacterium tuberculosis is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target C_max concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment. Full article

The prevalence of patients hospitalized in ICUs with COVID-19 and co-infected by pathogenic bacteria is relevant in this study, considering the integrality of treatment. This systematic review assesses the prevalence of co-infection in patients admitted to ICUs with SARS-CoV-2 infection, using the PRISMA guidelines. We examined the results of the PubMed, Embase, and SciELO databases, searching for published English literature from December 2019 to December 2021. A total of 542 rec ords were identified, but only 38 were eligible and, and of these only 10 were included. The tabulated studies represented a sample group of 1394 co-infected patients. In total, 35%/138 of the patients were co-infected with Enterobacter spp., 27% (17/63) were co-infected with methicillin-sensitive Staphylococ cus aureus, 21% (84/404) were co-infected with Klebsiella spp., 16% (47/678) of patients were co-infected with coagulase-negative Staphylococcus, 13% (10/80) co-infected with Escherichia coli (ESBL), and 3% (30/1030) of patients were co-infected with Pseudomonas aeruginosa. The most common co-infections were related to blood flow; although in the urinary and respiratory tracts of patients Streptococcus pneumoniae was found in 57% (12/21) of patients, coagulase negative Staphylococcus in 44% (7/16) of patients, and Escherichia coli was found in 37% (11/29) of patients. The present research demonstrated that co-infections caused by bacteria in patients with COVID-19 are a concern. Full article

Mycoplasma hyopneumoniae is the primary agent of Swine Enzootic Pneumonia (SEP). Vaccines reduce the clinical manifestation of the disease but do not prevent infection. The present study aimed to evaluate the use of antimicrobial drugs to minimize the impact of M. hyopneumoniae. For this, 32 pregnant female pigs and their litters were selected and then followed from birth to slaughter. The study involved three experimental groups that received metaphylactic treatment with different protocols involving tilmicosin, valnemulin, tulathromycin, and a control group to compare the effect of treatments against M. hyopneumoniae infection throughout the phases. Performance data were recorded, and the piglets were evaluated for the occurrence of cough. Nasal swab and blood collection was conducted periodically to detect M. hyopneumoniae shedding and anti-M. hyopneumoniae IgG, respectively. At slaughter, the lungs of animals from all groups were evaluated, and samples were collected for histopathological examination and qPCR for M. hyopneumoniae detection. All protocols promoted a reduction in consolidation lung lesions when compared to the control group. Individuals treated with valnemulin showed increased performance results, lower mortality, and low bacterial load in the lung. The results are promising and may indicate an alternative in the strategic control of M. hyopneumoniae infection in pigs. Full article

Multidrug-resistant A. baumannii (MDRAB) VAP has high morbidity and mortality, and the rates are constantly increasing globally. Mono- and polybacterial MDRAB VAP might differ, including outcomes. We conducted a single-center, retrospective (January 2014–December 2016) study in the four ICUs (12–18–24 beds each) of a reference Lithuanian university hospital, aiming to compare the clinical features and the 30-day mortality of monobacterial and polybacterial MDRAB VAP episodes. A total of 156 MDRAB VAP episodes were analyzed: 105 (67.5%) were monomicrobial. The 30-day mortality was higher (p < 0.05) in monobacterial episodes: overall (57.1 vs. 37.3%), subgroup with appropriate antibiotic therapy (50.7 vs. 23.5%), and subgroup of XDR A. baumannii (57.3 vs. 36.4%). Monobacterial MDRAB VAP was associated (p < 0.05) with Charlson comorbidity index ≥3 (67.6 vs. 47.1%), respiratory comorbidities (19.0 vs. 5.9%), obesity (27.6 vs. 9.8%), prior hospitalization (58.1 vs. 31.4%), prior antibiotic therapy (99.0 vs. 92.2%), sepsis (88.6 vs. 76.5%), septic shock (51.9 vs. 34.6%), severe hypoxemia (23.8 vs. 7.8%), higher leukocyte count on VAP onset (median [IQR] 11.6 [8.4–16.6] vs. 10.9 [7.3–13.4]), and RRT need during ICU stay (37.1 vs. 17.6%). Patients with polybacterial VAP had a higher frequency of decreased level of consciousness (p < 0.05) on ICU admission (29.4 vs. 14.3%) and on VAP onset (29.4 vs. 11.4%). We concluded that monobacterial MDRAB VAP had different demographic/clinical characteristics compared to polybacterial and carried worse outcomes. These important findings need to be validated in a larger, prospective study, and the management implications to be further investigated. Full article

Kiwifruit bacterial canker caused by Pseudomonas syringae pv. actinidiae reduces kiwifruit crop yield and quality, leading to economic losses. Unfortunately, few agents for its control are available. We prepared three kinds of copper-based nanoparticles and applied them to control kiwifruit bacterial canker. The successful synthesis of Cu(OH)₂ nanowires, Cu₃(PO₄)₂ nanosheets, and Cu₄(OH)₆Cl₂ nanoparticles were confirmed by transmission and scanning electron microscopy, energy dispersive spectroscopy, X-ray diffraction analysis, and X-ray photoelectron spectroscopy. The minimum bactericidal concentrations (MBCs) of the three nanoparticles were 1.56 μg/mL, which exceeded that of the commercial agent thiodiazole copper (MBC > 100 μg/mL). The imaging results indicate that the nanoparticles could interact with bacterial surfaces and kill bacteria by inducing reactive oxygen species’ accumulation and disrupting cell walls. The protective activities of Cu(OH)₂ nanowires and Cu₃(PO₄)₂ nanosheets were 59.8% and 63.2%, respectively, similar to thiodiazole copper (64.4%) and better than the Cu₄(OH)₆Cl₂ nanoparticles (40.2%). The therapeutic activity of Cu₄(OH)₆Cl₂ nanoparticles (67.1%) bested that of Cu(OH)₂ nanowires (43.9%), Cu₃(PO₄)₂ nanosheets (56.1%), and thiodiazole copper (53.7%). Their therapeutic and protective activities for control of kiwifruit bacterial canker differed in vivo, which was related to their sizes and morphologies. This study suggests these copper-based nanoparticles as alternatives to conventional bactericides for controlling kiwifruit diseases. Full article

Hospital-acquired urinary tract infection (HAUTI) is one of the most common hospital-acquired infections, and over 80% of HAUTI are catheter-associated (CAUTI). Pseudomonas aeruginosa, as well as other non-glucose fermenting Gram negative organisms (NGFGN, e.g., Acinetobacter baumannii), are frequently covered empirically with “anti-Pseudomonals” being administered for every HAUTI (and CAUTI). However, this common practice was never trialed in controlled settings in order to quantify its efficacy and its potential impacts on hospitalization outcomes. There were 413 patients with HAUTI that were included in this retrospective cohort study (2017–2018), 239 (57.9%) had CAUTI. There were 75 NGFGN infections (18.2% of HAUTI, 22.3% of CAUTI). P. aeruginosa was the most common NGFGN (82%). Despite multiple associations per univariable analysis, recent (3 months) exposure to antibiotics was the only independent predictor for NGFGN HAUTI (OR = 2.4, CI-95% = 1.2–4.8). Patients who received empiric anti-Pseudomonals suffered from worse outcomes, but in multivariable models (one for each outcome), none were independently associated with the empiric administration of anti-Pseudomonals. To conclude, approximately one of every five HAUTI (and CAUTI) are due to NGFGN, which justifies the practice of empiric anti-Pseudomonals for patients with HAUTI (and CAUTI), particularly patients who recently received antibiotics. The practice is not associated with independent deleterious impacts on outcomes. Full article

The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT_>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT_>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity. Full article