Real-Time Optimization of Pharmacodynamic Target Attainment at Infection Site during Treatment of Post-Neurosurgical Ventriculitis Caused by Carbapenem-Resistant Gram Negatives with Ceftazidime–Avibactam-Based Regimens: A Report of Two Cases

We present two cases of post-neurosurgical ventriculitis caused by carbapenem-resistant Gram-negative pathogens successfully treated with high-dose ceftazidime/avibactam. The existence of a real-time clinical pharmacological advice program, by enabling the optimization of the PK/PD targets over time at the infection site, turned out to be very helpful.

Multiclawed SiO2 Nano-Antibacterial Agent Based on Charge Inversed Ce6 Ionic Liquid Polymers for Combating Oral Biofilm Infection

Photodynamic antimicrobial chemotherapy (PACT) is a promising therapy against biofilm infection. However, due to the saliva clearance and obstacle of biofilm, the photosensitizer is difficult to concentrate in the infection site; then, the PACT is less effective on oral biofilm infection. In this article, we report a special nano-antibacterial agent (SiO2-PCe6-IL) to solve the bottleneck problem of PACT in treatment of oral biofilm infections. The SiO2-PCe6-IL was composed of SiO2 and poly ionic liquid photosensitizer (PCe6-IL) and had tri-fold features of eliminate biofilm infection: high binding ability, breaking biofilm barriers, and enrichment photosensitizer in infection site. In oral biofilm, the SiO2-PCe6-IL changed to SiO2-PIL+ like claws of octopus that could hold tightly with biofilm. Then, the poly-dodecyl on the SiO2-PIL+ broke down the barrier of biofilm. The results of HR-MS and zeta potential indicated that SiO2-PCe6-IL could change to positive (SiO2-PIL+) in acidic environment. The interaction forces and morphology results proved that the SiO2-PIL+ had a higher affinity to biofilm and could destroy the biofilm structure. Then, the photosensitizer was enriched in biofilm at sites of infection. The in vitro and in vivo experiments showed that SiO2-PCe6-IL could effectively eradicate oral biofilm infections and control of dental caries.

Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3+TCR+ Macrophages and Affects Their Phenotype, but Not Their Migration Ability

In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3+ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3+TCRαβ+) and the other does not (CD3+TCRαβ−). The role of Mycobacterium tuberculosis (Mtb) virulence in generating these subpopulations and the ability of these cells to migrate remains unclear. In this study, monocyte-derived macrophages (MDMs) infected in vitro with either a virulent (H37Rv) or an avirulent (H37Ra) Mtb strain were phenotypically characterized based on three MDM phenotypes (CD3−, CD3+TCRαβ+, and CD3+TCRαβ−); then, their migration ability upon Mtb infection was evaluated. We found no differences in the frequency of CD3+ MDMs at 24 h of infection with either Mtb strain. However, H37Rv infection increased the frequency of CD3+TCRαβ+ MDMs at a multiplicity of infection of 1 and altered the expression of CD1b, CD1c, and TNF on the surface of cells from both the CD3+ MDM subpopulations; it also modified the expression of CCR2, CXCR1, and CCR7, thus affecting CCL2 and IL-8 levels. Moreover, H37Rv infection decreased the migration ability of the CD3− MDMs, but not CD3+ MDMs. These results confirm that the CD3+ macrophage subpopulations express chemokine receptors that respond to chemoattractants, facilitating cell migration. Together, these data suggest that CD3+ MDMs are a functional subpopulation involved in the immune response against Mtb.

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.

Oleate Hydratase (OhyA) Is a Virulence Determinant in Staphylococcus aureus

The oleate hydratase protein family was discovered in commensal bacteria that utilize host unsaturated fatty acids as the substrates to produce a spectrum of hydroxylated products. These hydroxy fatty acids are thought to act as signaling molecules that suppress the inflammatory response to create a more tolerant environment for the microbiome. S. aureus is a significant human pathogen, and defining the mechanisms used to evade the immune response is critical to understanding pathogenesis. S. aureus expresses an OhyA that produces at least three 10-hydroxy fatty acids from host unsaturated fatty acids at the infection site, and an S. aureus strain lacking the ohyA gene has compromised virulence in an immunocompetent infection model.

Encapsulation of Photothermal Nanoparticles in Stealth and pH-Responsive Micelles for Eradication of Infectious Biofilms In Vitro and In Vivo

Photothermal nanoparticles can be used for non-antibiotic-based eradication of infectious biofilms, but this may cause collateral damage to tissue surrounding an infection site. In order to prevent collateral tissue damage, we encapsulated photothermal polydopamine-nanoparticles (PDA-NPs) in mixed shell polymeric micelles, composed of stealth polyethylene glycol (PEG) and pH-sensitive poly(β-amino ester) (PAE). To achieve encapsulation, PDA-NPs were made hydrophobic by electrostatic binding of indocyanine green (ICG). Coupling of ICG enhanced the photothermal conversion efficacy of PDA-NPs from 33% to 47%. Photothermal conversion was not affected by micellar encapsulation. No cytotoxicity or hemolytic effects of PEG-PAE encapsulated PDA-ICG-NPs were observed. PEG-PAE encapsulated PDA-ICG-NPs showed good penetration and accumulation in a Staphylococcus aureus biofilm. Penetration and accumulation were absent when nanoparticles were encapsulated in PEG-micelles without a pH-responsive moiety. PDA-ICG-NPs encapsulated in PEG-PAE-micelles found their way through the blood circulation to a sub-cutaneous infection site after tail-vein injection in mice, yielding faster eradication of infections upon near-infrared (NIR) irradiation than could be achieved after encapsulation in PEG-micelles. Moreover, staphylococcal counts in surrounding tissue were reduced facilitating faster wound healing. Thus, the combined effect of targeting and localized NIR irradiation prevented collateral tissue damage while eradicating an infectious biofilm.

The impact of lactate clearance on outcomes according to infection sites in patients with sepsis: a retrospective observational study

Whether lactate clearance (LC) influences outcomes differently depending on the infection site in sepsis cases is not fully elucidated. Herein, we analyzed LC’s clinical utility as a predictor of patient outcomes according to infection site. This retrospective study, conducted at two tertiary emergency critical care medical centers in Japan, included patients with sepsis or septic shock. The associations between infection site (lungs vs. other organs) and in-hospital mortality and ventilator-free days (VFDs) were evaluated using univariable and multivariate analyses. We assessed LC’s ability to predict in-hospital mortality using the area under the receiver operating characteristic curve. Among 369 patients with sepsis, infection sites were as follows: lungs, 186 (50.4%); urinary tract, 45 (12.2%); abdomen, 102 (27.6%); and other, 36 (9.8%). Patients were divided into a pneumonia group or non-pneumonia group depending on their infection site. The pneumonia group displayed a higher in-hospital mortality than the non-pneumonia group (24.2% vs. 15.8%, p = 0.051). In the multivariate analysis, lower LC was associated with higher in-hospital mortality [adjusted odds ratio (AOR), 0.97; 95% confidence interval (CI) 0.96–0.98; p < 0.001] and fewer VFD [adjusted difference p value (AD), − 1.23; 95% CI − 2.42 to − 0.09; p = 0.025] in the non-pneumonia group. Conversely, LC did not affect in-hospital mortality (AOR 0.99; 95% CI 0.99–1.00; p = 0.134) and VFD (AD − 0.08; 95% CI − 2.06 to 1.91; p = 0.854) in the pneumonia group. Given the differences in the impact of LC on outcomes between the pneumonia and non-pneumonia groups, this study suggests that optimal treatment strategies might improve outcomes. Further studies are warranted to validate our results and develop optimal therapeutic strategies for sepsis patients.

Autonomous treatment of bacterial infections in vivo using antimicrobial micro- and nanomachines

The increasing resistance of bacteria to existing antibiotics constitutes a major public health threat globally. Most current antibiotic treatments are hindered by poor delivery to the infection site, leading to undesired off-target effects and drug resistance development and spread. Here, we describe micro- and nanomachines that effectively and autonomously deliver antibiotic payloads to the target area. The active motion and antimicrobial activity of the silica-based robots are driven by catalysis of the enzyme urease and antimicrobial peptides, respectively. These antimicrobial machines show micromolar bactericidal activity in vitro against different Gram-positive and Gram-negative pathogenic bacterial strains and act by rapidly depolarizing their membrane. Finally, they demonstrated autonomous anti-infective efficacy in vivo in a clinically relevant abscess infection mouse model. In summary, our machines combine navigation, catalytic conversion, and bactericidal capacity to deliver antimicrobial payloads to specific infection sites. This technology represents a much-needed tool to direct therapeutics to their target to help combat drug-resistant infections.

Smart Polymeric Delivery System for Antitumor and Antimicrobial Photodynamic Therapy

Photodynamic therapy (PDT) has attracted tremendous attention in the antitumor and antimicrobial areas. To enhance the water solubility of photosensitizers and facilitate their accumulation in the tumor/infection site, polymeric materials are frequently explored as delivery systems, which are expected to show target and controllable activation of photosensitizers. This review introduces the smart polymeric delivery systems for the PDT of tumor and bacterial infections. In particular, strategies that are tumor/bacteria targeted or activatable by the tumor/bacteria microenvironment such as enzyme/pH/reactive oxygen species (ROS) are summarized. The similarities and differences of polymeric delivery systems in antitumor and antimicrobial PDT are compared. Finally, the potential challenges and perspectives of those polymeric delivery systems are discussed.