Combination Antimicrobial Therapy Research Articles

Antimicrobial use and mortality among intensive care unit patients with bloodstream infections: implications for stewardship programs

BackgroundBloodstream infections (BSIs) are one of the most critical illnesses requiring intensive care unit (ICU) admission. Antimicrobial therapy (AMT) is one of the vital management strategies for the treatment of BSIs; it should be chosen appropriately to reduce mortality. ObjectivesThis is the first study to investigate the types of antimicrobial agents administered in the ICU setting and the predictor variables associated with mortality. MethodsThis retrospective study was conducted at King Abdullah University Hospital (KAUH). All hospitalized patients admitted to the ICU and received at least one antimicrobial agent over 3 years period (January 1, 2017, to December 31, 2019) were included in the study. Electronic patients' medical records were used to collect patients' demographic and clinical characteristics, patient general health status, events that occurred during hospitalization, and events after obtaining the blood culture. Descriptive analysis was done to identify the types of antimicrobials used and the distribution of the microorganisms among the study participants. The susceptibility test of the bloodstream culture was checked for each patient. Moreover, crude mortality and its associated factors were investigated. ResultsA total of 1051 patients were enrolled in the study, where 650 patients (61.84%) were treated with three or more antimicrobial agents. The most frequent antimicrobials used were piperacillin/tazobactam followed by teicoplanin, meropenem, and levofloxacin. About half of the patients died within 30-days of BSI, which was associated with several factors including advanced age, presence of co-morbidities, nosocomial infections or healthcare-associated infections, length of ICU stay, respiratory tract infections, receiving vasopressor during the hospital stay, concurrent positive culture other than blood with BSI, receiving combination antimicrobial therapy, those who were complicated with septic shock or renal failure, receiving total parenteral protein (TPN) nutrition, and inappropriate empiric antimicrobial therapy. ConclusionIn conclusion, the administration of the antimicrobials among ICU patients was highly based on a combination of three or more agents covering a broad spectrum of microorganisms. The mortality rate was high among patients which were associated with inappropriate empirical therapy. Therefore, the antimicrobial stewardship (ASP) protocol has to be evaluated in the hospital for ICU patients. Moreover, we suggest recommending that hospital policies should apply the ASP protocol, infection control, implement the antimicrobial de-escalation protocol, and do best controlling on the co-morbid conditions, especially for ages 65 years or more to reduce the mortality rate in the ICU.

Interactions between Medical Plant-Derived Bioactive Compounds: Focus on Antimicrobial Combination Effects.

It is accepted that the medicinal use of complex mixtures of plant-derived bioactive compounds is more effective than purified bioactive compounds due to beneficial combination interactions. However, synergy and antagonism are very difficult to study in a meticulous fashion since most established methods were designed to reduce the complexity of mixtures and identify single bioactive compounds. This study represents a critical review of the current scientific literature on the combined effects of plant-derived extracts/bioactive compounds. A particular emphasis is provided on the identification of antimicrobial synergistic or antagonistic combinations using recent metabolomics methods and elucidation of approaches identifying potential mechanisms that underlie their interactions. Proven examples of synergistic/antagonistic antimicrobial activity of bioactive compounds are also discussed. The focus is also put on the current challenges, difficulties, and problems that need to be overcome and future perspectives surrounding combination effects. The utilization of bioactive compounds from medicinal plant extracts as appropriate antimicrobials is important and needs to be facilitated by means of new metabolomics technologies to discover the most effective combinations among them. Understanding the nature of the interactions between medicinal plant-derived bioactive compounds will result in the development of new combination antimicrobial therapies.

Clinical Efficacy and Safety of Antimicrobial Photodynamic Therapy in Residual Periodontal Pockets during the Maintenance Phase.

Antimicrobial photodynamic therapy (a-PDT) in combination with scaling root planing (SRP) is more effective at improving periodontal status than SRP alone. However, the effectiveness of a-PDT in combination with irrigation for patients undergoing periodontal maintenance has not been clarified. This study evaluated the efficacy and safety of a-PDT in the maintenance phase. Patients who had multiple sites with bleeding on probing (BOP) and periodontal probing depth (PPD) of 4–6 mm in the maintenance phase were treated with a split-mouth design. These sites were randomly assigned to one of two groups: the a-PDT group and the irrigation group. In the a-PDT group, the periodontal pockets were treated with light-sensitive toluidine blue and a light irradiator. In the irrigation group, the periodontal pockets were simply irrigated using an ultrasonic scaler. After 7 days, the safety and efficacy of a-PDT were assessed. The mean PPD of the a-PDT group had reduced from 4.50 mm to 4.13 mm, whereas negligible change was observed in the irrigation group. BOP significantly improved from 100% to 33% in the PDT group, whereas it hardly changed in the irrigation group. No adverse events were observed in any patients. a-PDT may be useful as a noninvasive treatment in the maintenance phase, especially in patients with relatively deep periodontal pocket.

Nonmarinum, Nontuberculous Mycobacterial Infections of the Upper Extremity: A Multi-Institutional Descriptive Report

We analyzed patient demographic factors involved in the development of nonmarinum, nontuberculous mycobacterial infections (NTMI) involving the upper extremity, and assessed diagnostic and prognostic values of commonly used preoperative laboratory and imaging studies, as well as factors related to recurrence of disease and patient outcomes. Patients from 2 academic, tertiary facilities with culture-proven, nonmarinum NTMI involving the upper extremity were reviewed. Patient-related factors and clinical outcomes were extracted. The analysis was based on pathogen identification (rapid- vs slow-growing subspecies) and immune status. Our 76 patients had a mean age of 59 years, and 65% were male. Forty-eight percent reported an injury, and hands were frequently involved (58%). Forty-one percent were immunosuppressed (19% organ transplant recipients). The mean symptom duration prior to presentation was 203 days. The culture identification took a mean of 33 days, with 25 different species identified (subcategorized as rapid or slow growers). Seventy-seven percent had solitary lesions, with a cutaneous or subcutaneous location most common. Immunosuppressed patients were treated longer with antibiotics (243 vs 155 days in immunocompetent patients) and experienced higher rates of side effects, complications, and recurrence. All patients underwent debridement to control infection, including 4 individuals who required amputations. One-third experienced complications and/or recurrence, regardless of the organism type. Upper-extremity nonmarinum NTMI is often misdiagnosed, causing management delays. Early consideration in differential diagnoses of chronic, painful swelling, nodular or inflammatory lesions, or septic arthritis is crucial. Tissue biopsy with specimens for histopathology and microbiological analysis (mycobacterial smear, cultures, and broad range polymerase chain reaction) and early involvement with an infectious disease specialist are recommended. Empiric antibiotic therapy is not standard. Debridement and prolonged, directed combination antimicrobial therapy is required; however, adverse reactions are commonly encountered. Type of study/level of evidence Prognostic IV.

The Combination Antibiogram Evaluation for Antimicrobial Susceptibility of Carbapenem-Resistant Klebsiella pneumoniae and Carbapenem-Resistant Escherichia coli

Background: The incidence of carbapenem-resistant enterobacterales (CRE), Escherichia coli and Klebsiella pneumoniae increased twofold and tenfold within the past 20 years, respectively. CRE is resistant to most antibiotics and monotherapy cannot provide greater than 90% coverage. Combination antimicrobial regimen is introduced to increase the susceptibility rate and to recommend clinicians to make more informed decision in the selection of empirical therapy. Materials and Methods: Cross-sectional study on carbapenem-resistant E. coli and carbapenem-resistant K. pneumoniae isolated from blood, sputum, and urine of adult inpatients in Naresuan University Hospital were examined for 24 months, between January 1, 2018 and December 31, 2019. The susceptibility data were formulated in accordance with the Clinical and Laboratory Standards Institute M39 guidelines and the combination antibiogram was developed. Chi-square test and Fisher’s exact test were used to determine the differences in susceptibility rates. Results: Forty-three isolates of the carbapenem-resistant E. coli and 208 isolates of the carbapenem-resistant K. pneumoniae were included for the analysis. More CRE organisms were found in the Internal Medicine than in the non-Internal Medicine wards. Monotherapy regimen with amikacin was shown to cover 97.67% of the E. coli CRE in vitro and when used as an additional agent as meropenem plus amikacin, imipenem plus amikacin, piperacillin-tazobactam plus amikacin, or levofloxacin plus amikacin, which all the percent susceptible increased to 97.67% (p<0.001). The K. pneumoniae CRE data showed that only 1.92% was susceptible to meropenem. Meropenem plus gentamicin, imipenem plus gentamicin, piperacillin-tazobactam plus gentamicin and levofloxacin plus gentamicin could increase the percent susceptibility but to less than 90% with p<0.001. Conclusion: Aminoglycosides are the proposed addition for the empiric antimicrobial combination therapy to treat possible CRE infections. Meropenem plus amikacin, imipenem plus amikacin, piperacillin-tazobactam plus amikacin, or levofloxacin plus amikacin are proposed to use against E. coli CRE. No combination therapy is recommended for K. pneumoniae CRE. Keywords: Enterobacteriaceae; Carbapenem-resistant Klebsiella pneumoniae; Carbapenem-resistant Escherichia coli; CRE; Antimicrobial susceptibility; Combination antibiogram

Mutational Switch-Backs Can Accelerate Evolution of Francisella to a Combination of Ciprofloxacin and Doxycycline.

Combination antimicrobial therapy has been considered a promising strategy to combat the evolution of antimicrobial resistance. Francisella tularensis is the causative agent of tularemia and in addition to being found in the nature, is recognized as a threat agent that requires vigilance. We investigated the evolutionary outcome of adapting the Live Vaccine Strain (LVS) of F. tularensis subsp. holarctica to two non-interacting drugs, ciprofloxacin and doxycycline, individually, sequentially, and in combination. Despite their individual efficacies and independence of mechanisms, evolution to the combination arose on a shorter time scale than evolution to the two drugs sequentially. We conducted a longitudinal mutational analysis of the populations evolving to the drug combination, genetically reconstructed the identified evolutionary pathway, and carried out biochemical validation. We discovered that, after the appearance of an initial weak generalist mutation (FupA/B), each successive mutation alternated between adaptation to one drug or the other. In combination, these mutations allowed the population to more efficiently ascend the fitness peak through a series of evolutionary switch-backs. Clonal interference, weak pleiotropy, and positive epistasis also contributed to combinatorial evolution. This finding suggests that the use of this non-interacting drug pair against F. tularensis may render both drugs ineffective because of mutational switch-backs that accelerate evolution of dual resistance.

Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection

Mycobacterium chelonae is a rare cause of chronic disseminated cutaneous infections in immunocompromised patients. Multidrug-resistant M. chelonae infections present a challenge for treatment, and prolonged antimicrobial courses lead to significant toxicities and further antimicrobial resistance. We report a case of refractory cutaneous disseminated M. chelonae infection in a patient with seronegative arthritis on immunotherapy with tofacitinib that was treated with combination antimicrobial, surgical, and single bacteriophage therapy with excellent clinical response. The patient developed neutralizing antibodies against the bacteriophage but continues to have stable improvement of disease with negative biopsies and no evidence of bacterial resistance to the phage.

Microbial spectrum and drug resistance profile in solid malignancies in a large tertiary hospital from Palestine

BackgroundSince the available data for bloodstream infections in solid malignancy tumors are somewhat limited in Palestine, prevention of infection before the occurrence, controlling it when it occurs, and implementing stewardship programs are important ways in the whole therapy of solid tumor patients, which is becoming challenging recently with the evolution of more antimicrobial drug-resistant pathogens. Therefore, our study aims to assess the microbial spectrum and antimicrobial sensitivity and the overall outcome related to many clinical risk factors in patients with solid tumor patients seeking care in a referral hospital as an experience from a developing country.MethodsFrom the onset of 2018 to the end of 2020, a total of 116 episodes with positive blood cultures were retrospectively studied and analyzed in 96 patients who had solid tumors in a referral hospital in Palestine.ResultsWe identified 116 positive blood cultures in 96 patients with a male to female ratio of 1:1. The mean age was 58 years. Breast cancer was the tumor most frequently recorded (13.5%), followed by urinary tract tumors (10.4%). The most common source of episodes with positive blood culture was catheter-related. Gram-positive bacteria accounted for 52.6% of blood cultures with the predomination of Staphylococcus species. On the contrary, Gram-negative bacteria were documented in 39.7% of the cultures, with E. coli being the most frequent bacteria. Regarding fungi that were only Candida species, it was isolated in 15.5% of the cultures.28.4% of patients started on a single antimicrobial as an initial regimen, the remaining started combination antimicrobial therapy. The initial antimicrobials used most frequently were aminoglycosides in 29.3% of the episodes. All species of Staphylococcus were sensitive to vancomycin. Enterococcus species were fully resistant to ciprofloxacin. In the case of E. coli, the isolates were 100% sensitive to imipenem, meropenem, and amikacin and were mostly resistant to ampicillin, where the sensitivity was only about 19.5%. P.aeruginosa was sensitive in 83.3% of cultures to both piperacillin-tazobactam and gentamicin, but highly resistant to imipenem, in which sensitivity decreased to 50%. The isolates of Klebsiella species were 72.2% sensitive to gentamicin, meropenem, and imipenem and 100% resistant to ampicillin. A. baumannii was 50% sensitive to trimethoprim-sulfamethoxazole. Candida species showed high sensitivity to both caspofungin and flucytosine (83.3%), followed by 77.8% sensitivity to voriconazole. Death was reported in 27.6% of the episodes and there was a significant relationship between shock at presentation and death (p = 0.010).ConclusionsThe findings of this investigation confirm the prevalent BSI seen in patients with solid malignancies and demonstrate a significant percentage of antibiotic resistance. Therefore, stewardship programs that dig deep before using any type of antimicrobials will help reduce the risk of resistance to antibiotics. In addition, the implementation of infection control surveillance plays an important role in decreasing the risk of contamination.

A Fatal Case of Nocardia Bacteremia in a Lung Transplant Recipient

<h3>Introduction</h3> <i>Nocardia</i> bacteremia is an extremely rare disease. Although closely associated with immunocompromised states, only a few cases have been reported after lung transplant (LT). <h3>Case Report</h3> We present a case of <i>Nocardia</i> bacteremia in a 75-year-old man after bilateral LT (11/2017) for combined pulmonary fibrosis and emphysema. Nearing 3 years posttransplant, pulmonary function tests (PFTs) revealed an obstructive pattern with downtrending FEV₁ from baseline; work-up for acute cellular rejection, infection, and antibody-mediated rejection was unremarkable. Serial PFTs ultimately suggested CLAD-BOS phenotype, and he received photopheresis with some stabilization. However, over the next 2 months, he required 2 hospital admissions with need for high-dose intravenous steroids given hypercapnia in the setting of underlying rejection. At 38 months posttransplant, he developed lower extremity cellulitis and new-onset anorexia, generalized weakness, and rapid decline in mental status with need for a third hospitalization and mechanical ventilation with vasopressor support. Infectious work-up and empiric broad-spectrum antibiotic coverage were initiated. Within 12 hours, both blood cultures were positive for <i>Nocardia cyriacigeorgica</i> (Gram stain, <b>Figure A</b>). Meropenem and trimethoprim/sulfamethoxazole were substituted without clinical improvement over the next several days. Brain MRI ruled out cerebral nocardiosis; chest CT showed bibasilar consolidations with air space opacities. An echocardiogram estimated a left ventricular ejection fraction between 20-25% with severe diffuse hypokinesis, likely stress-induced cardiomyopathy, with no evidence of vegetations. Bronchoscopy revealed superinfection with pan-sensitive <i>Pseudomonas</i> spp, without isolation of <i>Nocardia</i> spp. The patient deteriorated and died 39 months after transplant. <h3>Summary</h3> <i>Nocardia</i> bacteremia, scarcely reported in LT recipients, portends a poor prognosis despite aggressive combination antimicrobial therapy.

A Review: Antimicrobial Therapy for Human Pythiosis.

Human pythiosis is associated with poor prognosis with significant mortality caused by Pythium insidiosum. Antimicrobials’ in vitro and in vivo results against P. insidiosum are inconsistent. Although antimicrobials are clinically useful, they are not likely to achieve therapeutic success alone without surgery and immunotherapy. New therapeutic options are therefore needed. This non-exhaustive review discusses the rationale antimicrobial therapy, minimum inhibitory concentrations, and efficacy of antibacterial and antifungal agents against P. insidiosum. This review further provides insight into the immunomodulating effects of antimicrobials that can enhance the immune response to infections. Current data support using antimicrobial combination therapy for the pharmacotherapeutic management of human pythiosis. Also, the success or failure of antimicrobial treatment in human pythiosis might depend on the immunomodulatory effects of drugs. The repurposing of existing drugs is a safe strategy for anti-P. insidiosum drug discovery. To improve patient outcomes in pythiosis, we suggest further research and a deeper understanding of P. insidiosum virulence factors, host immune response, and host immune system modification by antimicrobials.

Applications of Antimicrobial Photodynamic Therapy against Bacterial Biofilms.

Antimicrobial photodynamic therapy and allied photodynamic antimicrobial chemotherapy have shown remarkable activity against bacterial pathogens in both planktonic and biofilm forms. There has been little or no resistance development against antimicrobial photodynamic therapy. Furthermore, recent developments in therapies that involve antimicrobial photodynamic therapy in combination with photothermal hyperthermia therapy, magnetic hyperthermia therapy, antibiotic chemotherapy and cold atmospheric pressure plasma therapy have shown additive and synergistic enhancement of its efficacy. This paper reviews applications of antimicrobial photodynamic therapy and non-invasive combination therapies often used with it, including sonodynamic therapy and nanozyme enhanced photodynamic therapy. The antimicrobial and antibiofilm mechanisms are discussed. This review proposes that these technologies have a great potential to overcome the bacterial resistance associated with bacterial biofilm formation.

Investigational agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: progress in clinical trials

ABSTRACT Introduction Bacteremia caused by Staphylococcus aureus is common. Cases caused by methicillin-resistant S. aureus (MRSA) are particularly formidable and often lethal. The mortality associated with MRSA bacteremia has not significantly decreased over the past couple of decades and concerns regarding efficacy and toxicity of standard therapy highlight the need for novel agents and new therapeutic approaches. Areas covered This paper explores clinical trials investigating novel therapeutic approaches to S. aureus bacteremia. There is a special focus on MRSA bacteremia. Monotherapy and combination therapies and novel antimicrobials and adjunctive therapies that are only recently being established for therapeutic use are discussed. Expert opinion The unfavorable safety profile of combination antimicrobial therapy in clinical trials has outweighed its benefits. Therefore, future investigation should focus on optimizing duration and de-escalation protocols. Antibody and bacteriophage lysin-based candidates have mostly been limited to safety trials, but progress with these agents is demonstrated through a lysin-based agent receiving a phase III trial. Antibiotics indicated for use in treating MRSA skin infections see continued investigation as treatments for MRSA bacteremia despite the difficulty of completing trials in this patient population. Promising agents include dalbavancin, ceftobiprole, ceftaroline, and exebacase.

A practical laboratory method to determine ceftazidime-avibactam-aztreonam synergy in patients with New Delhi metallo-beta-lactamase (NDM)–producing Enterobacterales infection

In response to infection with New Delhi metallo-beta-lactamase (NDM)-producing Enterobacterales, combination antimicrobial therapy with ceftazidime/avibactam (CAZ/AVI) plus aztreonam (ATM) has been explored. This study evaluated a practical laboratory method of testing for clinically significant synergy between CAZ/AVI+ATM in NDM-producing Enterobacterales. Minimum inhibitory concentrations (MICs) of clinical NDM-producing isolates were determined for ATM alone and CAZ/AVI+ATM using broth dilution. Restoration of the ATM breakpoint after the addition of CAZ/AVI was explored. A CAZ/AVI Etest/ATM disc method was compared with broth dilution. Of 43 isolates, 33 (77%) were ATM resistant (median [range] MIC=56 [16-512] mg/L). Addition of CAZ/AVI restored the ATM breakpoint (MIC <4 mg/L) in 29 of 33 resistant isolates (89%). Overall, the Etest/disc method correlated with the findings from broth dilution in 35 of 43 cases (81%). Etest/disc sensitivity was 77% and specificity 85%. Positive predictive value was 92% and negative predictive value 61%. CAZ/AVI+ATM demonstrated significant synergy in most ATM-resistant NDM-producing Enterobacterales. The Etest/disc method is a quick, reproducible, and reliable method of testing for clinically relevant synergy in the microbiology laboratory.

Infections Due to Acinetobacter baumannii-calcoaceticus Complex: Escalation of Antimicrobial Resistance and Evolving Treatment Options.

Bacteria within the genus Acinetobacter (principally A. baumannii-calcoaceticus complex [ABC]) are gram-negative coccobacilli that most often cause infections in nosocomial settings. Community-acquired infections are rare, but may occur in patients with comorbidities, advanced age, diabetes mellitus, chronic lung or renal disease, malignancy, or impaired immunity. Most common sites of infections include blood stream, skin/soft-tissue/surgical wounds, ventilator-associated pneumonia, orthopaedic or neurosurgical procedures, and urinary tract. Acinetobacter species are intrinsically resistant to multiple antimicrobials, and have a remarkable ability to acquire new resistance determinants via plasmids, transposons, integrons, and resistance islands. Since the 1990s, antimicrobial resistance (AMR) has escalated dramatically among ABC. Global spread of multidrug-resistant (MDR)-ABC strains reflects dissemination of a few clones between hospitals, geographic regions, and continents; excessive antibiotic use amplifies this spread. Many isolates are resistant to all antimicrobials except colistimethate sodium and tetracyclines (minocycline or tigecycline); some infections are untreatable with existing antimicrobial agents. AMR poses a serious threat to effectively treat or prevent ABC infections. Strategies to curtail environmental colonization with MDR-ABC require aggressive infection-control efforts and cohorting of infected patients. Thoughtful antibiotic strategies are essential to limit the spread of MDR-ABC. Optimal therapy will likely require combination antimicrobial therapy with existing antibiotics as well as development of novel antibiotic classes.

Cardiovascular device infections due to rapidly growing Mycobacteria: A review of cases at a tertiary care hospital

Cardiovascular device infection due to rapidly growing mycobacteria (RGM) is rarely encountered in clinical practice. Due to the increasing number of indications and use of cardiovascular devices in an aging population, optimized management of these infections is of great importance. We report seven cases of RGM cardiovascular device infection. Three patients had left-ventricular assist device (LVAD) infections; two patients had cardiovascular implantable device (CIED) infections; and one had an aortic vascular stent infection. Specific cardiac valvular infection was not detected among any of the patients. All patients had a high number of comorbidities which limited some patients from receiving optimal combination antimicrobial therapy. The prognosis of cardiovascular device infections with RGM is guarded with only four patients still alive; however, the treatment approach for each patient varied considerably and often based on concurrent medical conditions, overall adjustments to goals of care, and specific patient preferences. Further analysis of cardiovascular device infections with RGM is warranted to establish a more systematic approach in successful management.

Combination Therapy for Mycoplasma genitalium, and New Insights Into the Utility of parC Mutant Detection to Improve Cure.

Mycoplasma genitalium (MG) infection is challenging to cure because of rising antimicrobial resistance and limited treatment options. This was a prospective evaluation of the efficacy and tolerability of resistance-guided combination antimicrobial therapy for MG treatment at Melbourne Sexual Health Centre (August 2019-December 2020). All patients received 7 days of doxycycline before combination therapy based on the macrolide-resistant profile. Macrolide-susceptible infections received combination doxycycline + azithromycin (1g, day 1; 500mg, days 2-4) and macrolide-resistant infections combination doxycycline + moxifloxacin (400mg daily for 7 days). Adherence and adverse effects were recorded at test-of-cure, recommended 14-28 days after antimicrobial completion. Sequencing was performed to determine the prevalence of single nucleotide polymorphisms (SNPs) in the parC gene and their association with moxifloxacin treatment outcomes in macrolide-resistant infections. Of 100 patients with macrolide-susceptible MG treated with doxycycline + azithromycin, 93 were cured (93.0%; 95% confidence interval [CI], 86.1-97.1). Of 247 patients with macrolide-resistant MG receiving doxycycline + moxifloxacin, 210 were cured (85.0%; 95% CI, 80.0-89.2). parC sequencing was available for 164 (66%) macrolide-resistant infections; 29% had SNPs at parC S83 or D87 (23% S83I). The absence of SNPs at parC S83/D87 was associated with 98.3% cure (95% CI, 93.9-99.8) following doxycycline + moxifloxacin. The presence of the parC S83I-SNP was associated with failure in 62.5% (95% CI, 45.8-77.3). Side effects were common (40%-46%) and predominantly mild and gastrointestinal. Combination doxycycline + azithromycin achieved high cure for macrolide-susceptible infections. However, in the context of a high prevalence of the parC S83I mutation (23%) in macrolide-resistant infections, doxycycline + moxifloxacin cured only 85%. Infections that were wild-type for S83/D87 experienced high cure following doxycycline + moxifloxacin, supporting the use of a parC-resistance/susceptibility testing strategy in clinical care.

Hydrogen peroxide potentiates antimicrobial photodynamic therapy in eliminating Candida albicans and Streptococcus mutans dual-species biofilm from denture base

BackgroundCandida albicans (C.albicans) is the primary pathogen of denture biofilm. Moreover, it could establish a cross-kingdom relationship with bacteria to enhance its virulence and resistance to antifungal drugs. This study aimed to investigate the efficacy of antimicrobial photodynamic therapy (aPDT) in combination with hydrogen peroxide (H2O2) against C.albicans and Streptococcus mutans (S.mutans) dual-species biofilm formed on polymethyl methacrylate (PMMA) disk, and explore its involved mechanisms. MethodsC.albicans and S.mutans were grown on PMMA disk for 48 h to form biofilm and received different treatments. The treatments included:1) phosphate-buffered saline (PBS) group,2) 100 mM H2O2 group,3) aPDT group,4) aPDT+ H2O2 and 5) H2O2+aPDT group. Colony forming units (CFU), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and scanning electron microscope (SEM) were used to evaluate the antimicrobial effects. Extracellular polysaccharide substance (EPS) production and observation, cell permeability of biofilm, and uptake of toluidine blue O (TBO) by biofilm were assessed to investigate the involved mechanism. ResultsThere was no significant difference between PBS group and H2O2 group in viable microorganisms and metabolic activity of biofilm. The treatment protocols containing aPDT group reduced microorganism numbers and metabolic activity when compared to PBS group or H2O2 group (P<0.05). H2O2+aPDT treatment showed the highest antimicrobial efficacy in comparison with other treatments (P<0.05). Pretreatment with H2O2 could decrease EPS production and enhance cell permeability, leading to increased TBO uptake in biofilm. ConclusionPretreatment with H2O2 improved aPDT efficiency in eliminating dual-species biofilm from PMMA disk by reducing EPS amount, enhancing cell permeability, and increasing TBO uptake.

1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation

BackgroundNontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections.MethodsThis was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed. ResultsA total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%).ConclusionOMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings. Disclosures Julie V. Philley, MD, Paratek Pharmaceuticals (Advisor or Review Panel member)Paratek Pharmaceuticals, Inc. (Consultant) Michael P. Veve, Pharm.D., Cumberland (Grant/Research Support)Paratek Pharmaceuticals (Research Grant or Support) Michael J. Rybak, PharmD, MPH, PhD, Paratek Pharmaceuticals (Research Grant or Support)

1389. Nontuberculous Mycobacterial Infections of the Upper Extremity

BackgroundAlthough uncommon, nontuberculous mycobacterial infections (NTMI) of the upper extremity cause significant morbidity based on their natural history, delay in diagnosis, prolonged duration of antimicrobial therapy often combined with surgical debridement, and functional loss. Herein we describe our experience with such infections.MethodsRecords for adult patients from two academic, tertiary facilities with culture-proven NTMI involving the upper extremity were retrospectively reviewed. Demographic information, co-morbidities, laboratory and microbiological evaluation, management, and outcomes were extracted. Patients were analyzed based on pathogen identified and immune suppression.Results77 patients were identified. The mean age was 59 years and 65% of patients were male. 48% reported a preceding injury, with the hand being most frequently involved (58%). 41% were considered immune compromised; 19% of them were organ transplant recipients. Mean symptom duration prior to presentation was 203 days. Mean time to culture identification was 33 days, and 25 different species of NTM were identified (subcategorized as rapid or slow growers). 77% had solitary lesions, with cutaneous/subcutaneous location as the most common site. All patients underwent surgical debridement with four undergoing amputation to control infection. 69% received combination antimicrobial therapy for a mean duration of 184 days. Immunosuppressed patients were treated with antimicrobial therapy for a longer duration (mean 243 vs 155 days). One-third of patients experienced complications and/or recurrence regardless of organism type.ConclusionNTMI of the upper extremity is often misdiagnosed leading to significant delays in appropriate management. Knowledge of its protean manifestations and early consideration in the differential diagnosis of chronic, painful swelling of the hand or wrist, nodular or inflammatory lesions, or septic arthritis is crucial. A low threshold for surgical or biopsy with specimens sent for histopathology as well as microbiologic analysis is warranted. A combined approach with surgical debridement and prolonged combination antimicrobial therapy is necessary for optimal outcomes; however, adverse reactions from such therapy are commonly encountered.Disclosures All Authors: No reported disclosures

1237. Characterization and crystallization of OXA-935, a novel class D OXA-10-like beta-lactamase, found in Pseudomonas aeruginosa

BackgroundRecently, we described a collection of ST298 Pseudomonas aeruginosa (PA) isolates that caused a prolonged epidemic of XDR infections. Many of these contain derivatives of a new plasmid, pPABL048, that harbors an MDR integron, in1697. In1697 contains a series of antimicrobial resistance (AMR) genes, one of which is the class D β-lactamase blaOXA-10. Variants of blaOXA-10 have been described that confer both extended-spectrum β-lactamase (ESBL) and carbapenemase activity.MethodsOf all ST298 isolates, three were resistant to ceftazidime (CTZ). Genomic comparison of in1697 in CTZ-resistant and CTZ-sensitive strains revealed that all three strains harbored a blaOXA-10 allele with two single nucleotide variations resulting in amino acid changes at positions 153 (F153S) and 157 (G157D). Using the NCBI database, we identified this allele as unique and defined this β-lactamase as OXA-935. OXA-935 shares the G157D variation with OXA-14 which is known to confer resistance to ceftazidime. We sought to characterize the function of OXA-935 and to determine the crystal structures of OXA-14 and OXA-935. ResultsDeletion of blaOXA-935 phenotypically converted all three strains to CTZ-susceptible. Expression of blaOXA-14 and blaOXA-935 conferred CTZ-resistance to laboratory PA strains PA01 and PA14. Determination of the crystal structures of OXA-14 (PDB code 7L5R) and OXA-935 (PDB code 7L5V) revealed that the F153S variant resulted in increased flexibility in the enzyme’s Ω loop. Conformational changes in the Ω loop likely contributed to the lack of carbamylation at lysine-70 (K70) observed in OXA-935. Carbamylation of K70 is known to be critical for enzymatic activity of class D β-lactamases. ConclusionOXA-935 is very similar to OXA-14; however, comparison revealed that the F153S variant has unique structural features and is functionally distinct. Despite these differences, both enzymes confer high-level CTZ resistance. As we increasingly rely on β-lactam antimicrobial therapy (e.g. ceftazidime, cefepime) and combination (e.g. ceftazidime-avibactam) therapy to treat MDR PA infections, it is critical that we continue to explore the mechanistic basis of β-lactam AMR in an effort to preserve existing treatments and design novel ones. Disclosures All Authors: No reported disclosures