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Colistin (COL) is a cationic cyclic peptide that disrupts negatively-charged bacterial cell membranes and frequently serves as an antibiotic of last resort to combat multidrug-resistant Gram-negative bacterial infections. Emergence of the horizontally transferable plasmid-borne mobilized colistin resistance (mcr) determinant and its spread to Gram-negative strains harboring extended-spectrum β-lactamase and carbapenemase resistance genes threatens futility of our chemotherapeutic arsenal. COL is widely regarded to have zero activity againstmcr+patients based on standard antimicrobial susceptibility testing (AST) performed in enriched bacteriological growth media; consequently, the drug is withheld from patients withmcr+infections. However, these standard testing media poorly mimic in vivo physiology and omit host immune factors. Here we report previously unrecognized bactericidal activities of COL againstmcr-1+isolates ofEscherichia coli(EC),Klebsiella pneumoniae(KP), andSalmonella enterica(SE) in standard tissue culture media containing the physiological buffer bicarbonate. Moreover, COL promoted serum complement deposition on themcr-1+Gram-negative bacterial surface and synergized potently with active human serum in pathogen killing. At COL concentrations readily achievable with standard dosing, the peptide antibiotic killedmcr-1+EC, KP, and SE in freshly isolated human blood proved effective as monotherapy in a murine model ofmcr-1+EC bacteremia. Our results suggest that COL, currently ignored as a treatment option based on traditional AST, may in fact benefit patients withmcr-1+Gram negative infections based on evaluations performed in a more physiologic context. These concepts warrant careful consideration in the clinical microbiology laboratory and for future clinical investigation of their merits in high risk patients with limited therapeutic options.

Recent understanding of antimicrobial chemotherapy has expanded to appreciate significant impacts on the host–pathogen relationship by antibiotics. Omadacycline statistically outperformed linezolid in treating acute bacterial skin and skin structure infections in patients with diabetes mellitus in a recent post-hoc analysis of the OASIS-1 and OASIS-2 clinical trials. This difference may speak directly or indirectly to neutrophil dysfunction in diabetes. Neutrophil dysfunction increases the likelihood of Gram-negative bacterial infection, whereby diabetics may benefit from the broader spectrum of omadacycline compared with linezolid. Indirectly, oxazolidinones like linezolid have been shown to be dependent on neutrophil function, potentially compromising the potency of this drug class in diabetics. Finally, tetracyclines like omadacycline have collateral anti-inflammatory properties that have not been seen in other antibiotic drug classes. These differences may impact clinical outcomes in the treatment of infections that are not predicted by their antimicrobial activities alone, as measured in standard susceptibility testing assays.

Background: Coronavirus disease 2019 (Covid-19) remains a pandemic with multiple challenges to confirm patient infectivity: lack of sufficient tests, accurate results, validated quality, and timeliness of results. We hypothesize that a rapid 15-minute Point-Of-Care serological test to evaluate past infection complements diagnostic testing for Covid-19 and significantly enhances testing availability. Method: A three arm observational study at Sharp Healthcare, San Diego, California was conducted using the Clungene® lateral flow immunoassay (LFI) and compared with the Cobas® Roche real-time polymerase chain reaction (RT-PCR) results. Arm 1: Thirty-five (35) subjects with confirmed Covid-19 using RT-PCR were tested twice: prior to 14 days following symptom onset and once between 12 and 70 days. Arm 2: Thirty (30) subjects with confirmed Covid-19 using RT-PCR were tested 12-70 days post symptom onset. Arm 3: Thirty (30) subjects with a negative RT-PCR for Covid-19 were tested 1–10 days following the RT-PCR test date. Results: Specificity of confirmed negative Covid-19 by RT-PCR was 100% (95% CI, 88.4%–100.0%); meaning there was 100% negative positive agreement between the RT-PCR and the Clungene® serological test results. Covid-19 subjects tested prior to day 7 of symptom onset were antibody negative. In subjects 7–12 days following symptom onset with a confirmed positive Covid-19 by RT-PCR, the combined sensitivity of IgM and IgG was 58.6% (95% CI, 38.9%–76.5%). In subjects 13–70 days following symptom onset with a confirmed positive Covid-19 by RT-PCR, the combined sensitivity of IgM and IgG was 90.5% (95% CI, 80.4%–96.4%). Conclusion: The Clungene® lateral flow immunoassay (LFI) is a useful tool to confirm individuals with an adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) indicating past infection. Providing Point-Of-Care results within 15 minutes without any laboratory instrumentation or specialized software has an added value of increasing test availability to patients who have been symptomatic for more than 1 week to confirm past infection. Performance characteristics are optimal after 13 days with a sensitivity and specificity of 90% and 100%, respectively. Statement of novelty: Formal controlled clinical studies of Covid-19 antibody tests have been limited. This study demonstrates the utility of the 15 minute rapid Clungene® test and the potential for expanded use where Covid-19 RT-PCR testing and vaccination is limited.

Platelets are a critical immune defense against Staphylococcus aureus bloodstream infections. Staphylococcus aureus α-toxin is a virulence factor that decreases platelet viability and accelerates platelet clearance. It has been shown that ticagrelor blocks α-toxin–mediated platelet injury and resulting thrombocytopenia, protecting mice in a lethal S. aureus sepsis model. We now present the use of ticagrelor as adjunctive therapy in a patient with a S. aureus endovascular infection and thrombocytopenia, associated with restoration of platelet count and bacteremia clearance. Ticagrelor enhanced platelet killing of the S. aureus bloodstream isolate from the treated patient in vitro.

BACKGROUND Despite unprecedented speed in the execution of the COVID-19 vaccine and therapeutic clinical trials, pregnant patients have been largely excluded from initial studies. In addition, pregnant patients who are unvaccinated against SARS-CoV-2 have greater morbidity risk with severe COVID-19 disease as compared to patients of similar age and comorbidity status. Intravenous immunoglobulin (IVIG) has been deemed safe in pregnancy in other diseases. Prior data demonstrate the possible benefit of utilizing IVIG for the treatment in hospitalized patients with severe respiratory symptoms associated with COVID-19 active infections when administered within 14 days of COVID symptom onset. CASE REPORT We administered IVIG (Privigen®, CSL Behring) 0.5 g/kg daily for 3 consecutive days to 4 pregnant patients (ages 24-34 years of age) who were hospitalized with moderate-to-severe COVID-19 and not vaccinated against SARS-CoV-2. All patients received concomitant glucocorticoid therapy. Gestational ages were 26, 17, 35, and 35 weeks. All patients were discharged home breathing room air after a mean hospital stay of 15 days. Two patients had uncomplicated cesarean section at 35 weeks during the hospitalization. The pre-term pregnancies at 17 and 26 weeks were intact at hospital discharge and resulted in normal vaginal deliveries at term. All 4 patients consented to participate in this case series report. CONCLUSIONS IVIG may be a safe treatment consideration in pregnant women with severe COVID-19 to avoid pregnancy complications. Its use warrants further study in pregnancy acute respiratory distress syndrome (ARDS) due to SARS-CoV-2, influenza, and other respiratory viruses to which pregnant patients are vulnerable.

Vancomycin was introduced nearly 65 years ago and remains the standard antibiotic for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Staphylococcus aureus remains highly susceptibility to vancomycin (>97%). Despite this, MRSA treatment failure with vancomycin is high in complicated bacteremia. Additionally, vancomycin can cause nephrotoxicity, leading to new therapeutic drug monitoring guidance. This demonstrates how difficult it is to dose vancomycin in a way that is both efficacious and safe, especially during long courses of therapy. Often underappreciated are the cost, resources, and complexity of vancomycin care at a time when alternative antibiotics are becoming cost comparable. This perspective highlights a bigger picture of how the treatment repertoires of many other diseases have changed and advanced since vancomycin’s introduction in the 1950s, yet the vancomycin MRSA treatment standard remains. While vancomycin can still have a role, 65 years may be a practical retirement age for vancomycin in highly complex endovascular infections.

Background Besides antistaphylococcal beta-lactams and source control, there are limited validated antimicrobial salvage options in patients with prolonged methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including infective endocarditis (IE). Methods MSSA IE cases treated with ertapenem (ETP) plus cefazolin (CZ) were compared with matched IE cases treated with standard beta-lactam monotherapy. The bactericidal activity of ETP plus CZ was also compared with nafcillin (NAF), CZ, and ETP alone using an in vitro MSSA biofilm model. Results The median duration of bacteremia experienced by patients (n = 12) while on CZ or NAF was 4 days (range 1–16 days) compared with 1 day (range 1–3 days) for patients (n = 5) treated with ETP + CZ (P = .01, Mann-Whitney U test). Cefazolin and NAF alone or in combination did not achieve biofilm eradication at clinically relevant concentrations. However, the addition of ETP to CZ led to bactericidal eradication within biofilms at standard dosing. Conclusions Ertapenem reduces CZ concentrations required to eradicate MSSA biofilms to those achievable in vivo by standard dosing, translating into shorter bacteremia duration in patients with MSSA endocarditis. Larger studies are needed to investigate ETP plus CZ therapy in the treatment of biofilm-related MSSA infections such as endocarditis.

Background Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). Methods We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan–Meir analysis to assess the time to nephrotoxicity between the 2 groups. Results We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560–6.993). Results of the stratified Kaplan–Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). Conclusions Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis has been reported after SARS-CoV-2 infection, but not after SARS-CoV-2 vaccination. We report the first known case of anti-NMDAR encephalitis after SARS-CoV-2 immunization in a young female presenting with acute psychosis, highlighting a rare potential immunological complication of vaccination against SARS-CoV-2 that is currently being distributed worldwide. The patient presented initially with anxiety and hypochondriacal delusions which progressed to psychosis and catatonia but returned to baseline with aggressive immunomodulatory therapy consisting of intravenous immunoglobulin, high-dose glucocorticoids, and rituximab. This study highlights that the workup of acute psychosis should include establishing a history of recent vaccination followed by a thorough neurological assessment, including for anti-NMDAR antibodies in blood and cerebrospinal fluid.

Treatment with immunomodulators, such as intravenous immunoglobulin (IVIG), may attenuate inflammatory responses observed in the severe stages of acute respiratory distress syndrome (ARDS) caused by coronavirus disease 19 (COVID-19). We retrospectively evaluated the clinical courses of 12 COVID-19 patients who received IVIG at various stages of their illness, including within the first 72 h of clinical presentation, after initiation of mechanical ventilation, and after prolonged ventilation and ICU stay. The patients included 9 men and 3 women with a median age of 50 years (range 23–74), median Charlson Comorbidity Score of 2 (range 0–7), and median Acute Physiology and Chronic Health Evaluation Score of 13 (range 5–33) at the time of IVIG. The IVIG total dose ranged from 0.5 to 2.0 g/kg (median 1.25 g/kg) distributed over 1–4 daily doses. The most common regimen received was 0.5 g/kg daily for 3 days. The median time to IVIG administration was 9 days (range 0–48 days) after admission. The median time from first IVIG dose administration to hospital discharge was 14 days (range 3–48). The 5 patients who received IVIG ≤4 days of admission demonstrated a significantly shorter length of hospital stay after treatment (median 7 days, range 3–14 days) than the 7 patients who received it >7 days after admission (median 33 days, range 8–48 days, p = 0.03, Mann-Whitney U test). These cases demonstrate that IVIG may improve the clinical state of patients with moderate to severe COVID-19 infection. Despite very high illness severity scores, all patients survived hospital discharge. No thrombotic events occurred and IVIG was well tolerated, despite most cases demonstrating very elevated D-dimer suggestive of active intravascular fibrinolysis. We believe that IVIG warrants immediate clinical trial evaluation in COVID-19 to confirm its role as a mainstay treatment of moderate to severe COVID-19 infection as a means to reduce hospital stay and utilization of ICU resources, including mechanical ventilation, and potentially reduce mortality.

Azithromycin (AZM), the most commonly prescribed antibiotic in the United States, is thought to have no activity against multidrug-resistant Gram-negative pathogens such as Achromobacter xylosoxidans (AX) per standard minimum inhibitory concentration testing in cation-adjusted Mueller Hinton Broth. Here we provide the first report of AZM bactericidal activity against carbapenem-resistant isolates of AX, with a multifold decrease in minimum inhibitory concentration across 12 clinical isolates when examined under physiologic testing conditions that better recapitulate the in vivo human environment. This pharmaceutical activity, evident in eukaryotic tissue culture media, is associated with enhanced AZM intracellular penetration and synergistic killing with human whole blood, serum, and neutrophils. Additionally, AZM monotherapy inhibited preformed AX biofilm growth in a dose-dependent manner together with a reduction in viable bacteria. In an illustrative case, AZM in combination with piperacillin-tazobactam exerted clear therapeutic effects in a patient with carbapenem-resistant AX mediastinitis, sternal osteomyelitis, and aortic graft infection. Our study reinforces how current antimicrobial testing practices fail to recapitulate the host environment or host-pathogen interactions and may misleadingly declare complete resistance to useful agents, adversely affecting patient outcomes. We conclude that AZM merits further exploration in the treatment of drug-resistant AX infections. Novel approaches to antimicrobial susceptibility testing that better recapitulate the host environment should be considered, especially as infections caused by multidrug-resistant Gram-negative bacterial pathogens are expanding globally with high morbidity and mortality.

Background Within the last decade, methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a frequent cause of purulent skin and soft tissue infections. New therapeutic options are being investigated for these infections. Methods We report an integrated analysis of 2 randomized, controlled studies involving omadacycline, a novel aminomethylcycline, and linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Omadacycline in Acute Skin and Skin Structure Infections Study 1 (OASIS-1) initiated patients on intravenous omadacycline or linezolid, with the option to transition to an oral formulation after day 3. OASIS-2 was an oral-only study of omadacycline versus linezolid. Results In total, 691 patients received omadacycline and 689 patients received linezolid. Infection types included wound infection in 46.8% of patients, cellulitis/erysipelas in 30.5%, and major abscess in 22.7%. Pathogens were identified in 73.2% of patients. S. aureus was detected in 74.7% and MRSA in 32.4% of patients in whom a pathogen was identified. Omadacycline was noninferior to linezolid using the Food and Drug Administration primary endpoint of early clinical response (86.2% vs 83.9%; difference 2.3, 95% confidence interval –1.5 to 6.2) and using the European Medicines Agency primary endpoint of investigator-assessed clinical response at the posttreatment evaluation. Clinical responses were similar across different infection types and infections caused by different pathogens. Treatment-emergent adverse events, mostly described as mild or moderate, were reported by 51.1% of patients receiving omadacycline and 41.2% of those receiving linezolid. Conclusions Omadacycline was effective and safe in ABSSSI. Clinical Trials Registration NCT02378480 and NCT02877927.

Background Multidrug-resistant (MDR) Acinetobacter baumannii infections have high mortality rates and few treatment options. Synergistic drug combinations may improve clinical outcome and reduce further emergence of resistance in MDR pathogens. Here we show an unexpected potent synergy of two translation inhibitors against the pathogen: commonly prescribed macrolide antibiotic azithromycin (AZM), widely ignored as a treatment alternative for invasive Gram-negative pathogens, and minocycline, among the current standard-of-care agents used for A. baumannii. Methods Media-dependent activities of AZM and MIN were evaluated in minimum inhibitory concentration assays and kinetic killing curves, alone or in combination, both in standard bacteriologic media (cation-adjusted Mueller-Hinton Broth) and more physiologic tissue culture media (RPMI), with variations of bicarbonate as a physiologic buffer. Synergy was calculated by fractional inhibitory concentration index (FICI). Therapeutic benefit of combining AZM and MIN was tested in a murine model of A. baumannii pneumonia. AZM + MIN synergism was probed mechanistically by bacterial cytological profiling (BCP), a quantitative fluorescence microscopy technique that identifies disrupted bacterial cellular pathways on a single cell level, and real-time kinetic measurement of translation inhibition via quantitative luminescence. AZM + MIN synergism was further evaluated vs. other contemporary high priority MDR bacterial pathogens. Findings Although two translation inhibitors are not expected to synergize, each drug complemented kinetic deficiencies of the other, speeding the initiation and extending the duration of translation inhibition as verified by FICI, BCP and kinetic luminescence markers. In an MDR A. baumannii pneumonia model, AZM + MIN combination therapy decreased lung bacterial burden and enhanced survival rates. Synergy between AZM and MIN was also detected vs. MDR strains of Gram-negative Klebsiella pneumoniae and Pseudomonas aeruginosa, and the leading Gram-positive pathogen methicillin-resistant Staphylococcus aureus. Interpretation As both agents are FDA approved with excellent safety profiles, clinical investigation of AZM and MIN combination regimens may immediately be contemplated for optimal treatment of A. baumannii and other MDR bacterial infections in humans. Fund National Institutes of Health U01 AI124326 (JP, GS, VN) and U54 HD090259 (GS, VN). IC was supported by the UCSD Research Training Program for Veterinarians T32 OD017863.

Infections caused by New Delhi metallo-β-lactamase (NDM)–producing strains of multidrug-resistant Klebsiella pneumoniae are a global public health threat lacking reliable therapies. NDM is impervious to all existing β-lactamase inhibitor (BLI) drugs, including the non–β-lactam BLI avibactam (AVI). Though lacking direct activity against NDMs, AVI can interact with penicillin-binding protein 2 in a manner that may influence cell wall dynamics. We found that exposure of NDM-1–producing K. pneumoniae to AVI led to striking bactericidal interactions with human cathelicidin antimicrobial peptide LL-37, a frontline component of host innate immunity. Moreover, AVI markedly sensitized NDM-1–producing K. pneumoniae to killing by freshly isolated human neutrophils, platelets, and serum when complement was active. Finally, AVI monotherapy reduced lung counts of NDM-1–producing K. pneumoniae in a murine pulmonary challenge model. AVI sensitizes NDM-1–producing K. pneumoniae to innate immune clearance in ways that are not appreciated by standard antibiotic testing and that merit further study.

A 5-question telephone survey was administered to compare satisfaction between patients receiving vancomycin vs daptomycin outpatient parenteral antimicrobial therapy (OPAT). Twenty-seven patients completed the survey (40%). Vancomycin had higher daily interference score than daptomycin (P = .03). All patients receiving daptomycin reported a satisfaction score ≥8/10, as compared to 67% of patients who received vancomycin (P < .03). OPAT antibiotics with less cumbersome administration regimens may translate into higher patient satisfaction and quicker return to life normalcy.

While microbiological resistance to vancomycin in Staphylococcus aureus is rare, clinical vancomycin treatment failures are common, and methicillin-resistant S. aureus (MRSA) strains isolated from patients after prolonged vancomycin treatment failure remain susceptible. Adaptive laboratory evolution was utilized to uncover mutational mechanisms associated with MRSA vancomycin resistance in a physiological medium as well as a bacteriological medium used in clinical susceptibility testing. Sequencing of resistant clones revealed shared and media-specific mutational outcomes, with an overlap in cell wall regulons (walKRyycHI, vraSRT). Evolved strains displayed similar properties to resistant clinical isolates in their genetic and phenotypic traits. Importantly, resistant phenotypes that developed in physiological media did not translate into resistance in bacteriological media. Further, a bacteriological media-specific mechanism for vancomycin resistance associated with a mutated mprF was confirmed. This study bridges the gap between the understanding of clinical and microbiological vancomycin resistance in S. aureus and expands the number of allelic variants (18 ± 4 mutations for the top 5 mutated genes) that result in vancomycin resistance phenotypes., Henrique Machado et al. describe mutational mechanisms associated with MRSA vancomycin resistance in Staphylococcus aureus using adaptive laboratory evolution experiments focused on tolerance. Their results reveal environment-dependent mutational strategies to vancomycin tolerization and the impact of mutations in regulatory genes, providing insight into the development of antibiotic resistance under multiple conditions.

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thereby providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a "toxin-platelet-AMR" regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof of concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.

The last several years have seen an emergence of literature documenting the utility of combination antimicrobial therapy, particularly in the salvage of refractory methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Recent clinical data are shaping conundrums of which regimens may be more beneficial, which can be potentially harmful, and which subset of patients stand to benefit from more aggressive treatment regimens than called for by current standards. In addition, the incorporation of combination therapy for MRSA bacteremia should be accompanied by the reminder that antimicrobial therapy does not need to be uniform for the entire duration, with an early intensive phase in high inoculum infections (eg, with combination therapy), followed by a consolidation phase (ie, monotherapy). This review and perspective consolidates the recent data on this subject and directs future goals in filling the knowledge gaps to methodically move forward towards improving patient outcomes.

Given that it is unlikely that randomized clinical trials will yield answers for treating the most challenging bacteremic infections caused by methicillin-resistant Staphylococcus aureus , clinicians, microbiologists, and pharmacists will have to cooperate to discover novel ways to select successful individualized antimicrobial therapy for these patients. An example of such a strategy was demonstrated in the identification and utilization of imipenem/cilastatin plus fosfomycin to treat a particularly recalcitrant MRSA bacteremia and spinal abscess.

BackgroundInterventions mitigating progression to mechanical ventilation in COVID-19 would markedly improve outcome and reduce healthcare utilization. We hypothesized that immunomodulation with IVIG would improve oxygenation and reduce length of hospital stay and progression to mechanical ventilation in COVID-19 pneumonia.MethodsPatients with COVID-19 were randomized 1:1 to prospectively receive standard of care (SOC) plus IVIG 0.5 g/kg/day × 3 days with methylprednisolone 40 mg 30 minutes before infusion versus SOC alone.Results16 subjects received IVIG plus SOC and 17 SOC alone. The median age was 51 years for SOC and 58 years for IVIG. APACHE II scores and Charlson comorbidity indices were similar for IVIG and SOC (median 7.5 vs 7 and 2 for both, respectively). Seven SOC versus 2 IVIG subjects required mechanical ventilation (p=0.12, Fisher exact test). Among subjects with A-a gradient of >200 mm Hg at enrollment, the IVIG group showed i) a lower rate of progression to requiring mechanical ventilation (2/14 vs 7/12, p=0.038 Fisher exact test), ii) shorter median hospital length of stay (11 vs 19 days, p=0.01 Mann Whitney U), iii) shorter median ICU stay (2.5 vs 12.5 days, p=0.006 Mann Whitey U), and iv) greater improvement in PaO2/FiO2 at 7 days (median [range] change from time of enrollment +131 [+35 to +330] vs +44·5 [-115 to +157], p=0.01, Mann Whitney-U test) than SOC.ConclusionThis pilot prospective randomized study comprising largely of Latino patients showed that IVIG significantly improved hypoxia and reduced hospital length of stay and progression to mechanical ventilation in COVID-19 patients with A-a gradient >200 mm Hg.

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20–30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two commonly prescribed drugs as adjunctive therapies to improve patient outcomes.

While microbiological resistance to vancomycin in Staphylococcus aureus is rare, clinical vancomycin treatment failures are common, and methicillin-resistant S. aureus (MRSA) strains isolated from patients after prolonged vancomycin treatment failure remain susceptible. Adaptive laboratory evolution was utilized to uncover mutational mechanisms associated with MRSA vancomycin resistance in a bacteriological medium used in clinical susceptibility testing and a physiological medium. Sequencing of resistant clones revealed shared and media-specific mutational outcomes, with an overlap in cell wall regulons (walKRyycHI, vraSRT). Evolved strains displayed similar genetic and phenotypic traits to resistant clinical isolates. Importantly, resistant phenotypes that developed in physiological media did not translate into resistance in bacteriological media. Further, a bacteriological media-specific mechanism for vancomycin resistance enabled by a mutated mprF was confirmed. This study bridges the gap of understanding between clinical and microbiological vancomycin resistance in S. aureus and expands the number of allelic variants that result in vancomycin resistance phenotypes.

Staphylococcus aureus strain TX0117 is a methicillin-susceptible bacterium with type A beta-lactamase exhibiting a high cefazolin inoculum effect. TX0117 was cured of blaZ, yielding TX0117c with increased antimicrobial peptide resistance. The sequencing and genome assembly of TX0117 elucidate six mutations between TX0117 and TX0117c, including relA truncation and mnA_1 substitution.

Despite the common ancestry of antimicrobial and immunological science, a divergence driven by artificially construed paradigms in microbiology has placed limits on how we understand the mechanisms of antibiotics in vivo. We summarize recent updates on data that shed light on how antibiotics interact with components of innate immunity.

Staphylococcus aureus bacteremia (SaB) causes significant disease in humans, carrying mortality rates of ~25%. The ability to rapidly predict SaB patient responses and guide personalized treatment regimens could reduce mortality. Here, we present a resource of SaB prognostic biomarkers. Integrating proteomic and metabolomic techniques enabled the identification of >10,000 features from >200 serum samples collected upon clinical presentation. We interrogated the complexity of serum using multiple computational strategies, which provided a comprehensive view of the early host response to infection. Our biomarkers exceed the predictive capabilities of those previously reported, particularly when used in combination. Lastly, we validated the biological contribution of mortality-associated pathways using a murine model of SaB. Our findings represent a starting point for the development of a prognostic test for identifying high-risk patients at a time early enough to trigger intensive monitoring and interventions.

Objective Development of antimicrobial resistance during monotherapy of complicated methicillin-resistant Staphylococcus aureus bacteremia is problematic due to cross-resistance between vancomycin (VAN) and daptomycin, the only approved agents for this condition. Our objective was to demonstrate that development of resistance under conditions of suboptimal VAN (200 mg q 12 h) exposure in S. aureus can be attenuated by addition of cefazolin (CFZ). Methods Two strains of S. aureus, 1 methicillin-susceptible Staphylococcus aureus (MSSA) (RN9120) and 1 methicillin-resistant S. aureus (MRSA) (JH1), were evaluated. The organisms were exposed to subtherapeutic VAN concentrations in a 1-compartment pharmacokinetic/pharmacodynamic model combined with recycling in the presence and absence of CFZ. Changes in MIC to glyco/lipopeptides and β-lactams along with susceptibility to human cathelicidin LL-37 killing were studied. Population analysis profiles (PAPs) were performed to detect changes in VAN heteroresistance. Results VAN MIC of both organisms increased from 1 to 4 mg/L within 144 h under subtherapeutic VAN exposure. Increase in VAN MIC was associated with increased glyco/lipopeptides MICs. Additionally, increased survival in LL-37 killing assays from 40% to >90% accompanied the increase in VAN MIC. Addition of CFZ prevented the emergence of VAN-intermediate S. aureus. PAPs demonstrated an attenuation of VAN area under the curve shift (reduced organism selection with higher MICs values) when suboptimal VAN exposure was accompanied with CFZ compared to VAN alone (MSSA 17.81 versus 36.027, MRSA −0.35 versus 17.92, respectively). Given the emerging data on the clinical benefits of β-lactam adjunctive therapy in refractory MRSA bacteremia, additional studies on a larger collection of clinical isolates are needed to establish the utility of VAN plus CFZ for treatment of MRSA bacteremia.

β-lactam-β-lactamase inhibitors (BLIs) have previously demonstrated antimicrobial activity against Acinetobacter baumannii (AB). Colistin retains the highest susceptibility rate against A. baumannii, and has demonstrated synergy with other antimicrobials, including β-lactam-BLIs. Therefore, we assessed the potential individual activity and synergistic combinations in vivo against carbapenem-susceptible (CS) and multidrug-resistant (MDR) A. baumannii isolates in neutropenic thigh and lung infection models. In vitro, colistin and tazobactam MICs were 1 and 16 µg/mL against AB 25–49 (CS) and 1 and 128 µg/mL against AB 5075 (MDR) respectively. In the lung model, tazobactam alone and in combination with colistin achieved a 1-log reduction in CFU, while colistin alone was not active against AB 25–49. No activity was observed against AB 5075. In the thigh model, tazobactam with and without colistin was bacteriostatic against AB 25–49 but did not demonstrate any activity against AB 5075. Avibactam and colistin alone and in combination were not active against either isolate. No synergy was observed; however, we found tazobactam activity against A. baumannii. This activity was not observed for the non-β-lactam-BLI, avibactam. This suggests that binding to penicillin-binding proteins of the β-lactam molecule is required for tazobactam activity against A. baumannii. These data point to an added role of β-lactam-BLIs beyond their primary purpose of β-lactamase inhibition in the treatment of MDR A. baumannii infections by enhancing the activity of peptide antibiotics, a property that is not shared by the novel non-β-lactam-BLIs. Future studies are needed to define tazobactam and colistin activity in an A. baumannii infection model.