Carbapenem-resistant Organisms Research Articles

Non-carbapenem antimicrobial therapy in young infant with urinary tract infections caused by community-acquired extended-spectrum β-lactamase-producing Escherichia coli

The frequency of urinary tract infections (UTIs) caused by community-acquired extended-spectrum β-lactamase (CA-ESBL)-producing Enterobacteriaceae is increasing worldwide. Increased carbapenem use may lead to selection of carbapenem-resistant organisms, resulting in dire consequences for hospitals. We compared the outcomes of non-carbapenem antimicrobial therapy on UTIs caused by CA-ESBL-producing and non-producing Escherichia coli (E. coli) in infants younger than 6 months of age. We conducted a retrospective chart review, from January 2010 to December 2018, in infants (0-6 months old) with diagnosed UTIs caused by CA-ESBL-producing and non-producing E. coli at the Pusan National University Children's Hospital. Chart reviews were completed for patients whose urine sample had been collected using urinary catheterization. We treated all patients using non-carbapenem antimicrobials. Two weeks after therapy completion, clinical states were evaluated. There were 105 and 582 patients diagnosed with UTIs caused by CA-ESBL-producing and non-producing E. coli, respectively. The mean age at diagnosis in ESBL and non-ESBL groups was 2.7±1.6 and 2.8±1.1 months (P=0.711), respectively. There were no significant differences between ESBL and non-ESBL groups in the duration of fever (1.2±0.5 and 1.2±0.4 days, respectively, P=0.761) or clinical cure states post therapy (101/105 and 567/582, respectively, P=0.513). This study found no significant differences in treatment outcomes between ESBL and non-ESBL groups treated with non-carbapenem antimicrobials. Therefore, initially administered non-carbapenem antimicrobials can be continued in patients with UTIs caused by CA-ESBL-producing E. coli who show clinical improvement.

Epidemiology and Mechanisms of Ceftazidime–Avibactam Resistance in Gram-Negative Bacteria

Carbapenem resistance presents a major challenge for the global public health network, as clinical infections caused by carbapenem-resistant organisms (CRO) are frequently associated with significant morbidity and mortality. Ceftazidime–avibactam (CAZ–AVI) is a novel cephalosporin/β-lactamase inhibitor combination offering an important advance in the treatment of CRO infections. CAZ–AVI has been reported to inhibit the activities of Ambler classes A, C, and some class D enzymes. However, bacterial resistance has been emerging shortly after the introduction of this combination in clinical use, with an increasing trend. Understanding these resistance mechanisms is crucial for guiding the development of novel treatments and aiding in the prediction of underlying resistance mechanisms. This review aims to systematically summarize the epidemiology of CAZ–AVI-resistant strains and recently identified resistance mechanisms of CAZ–AVI, with a focus on the production of β-lactamase variants, the hyperexpression of β-lactamases, reduced permeability, and overexpressed efflux pumps. The various mechanisms of CAZ–AVI resistance that have emerged within a short timescale emphasize the need to optimize the use of current agents, as well as the necessity for the surveillance of CAZ–AVI-resistant pathogens.

CON: Carbapenems are NOT necessary for all infections caused by ceftriaxone-resistant Enterobacterales.

Carbapenems are considered the drugs of choice for the treatment of serious infections caused by ceftriaxone-resistant Enterobacterales. However, because of the dramatic increase in carbapenem-resistant organisms worldwide, finding alternatives to carbapenems is a must. The potential options include β-lactam/β-lactamase inhibitor combinations, temocillin, cephamycins and some non-β-lactam drugs. The most controversial is piperacillin/tazobactam; the results of the MERINO trial are challenged because the isolates of patients with worse outcomes were frequently not susceptible to piperacillin/tazobactam when studied by reference methods, and also because the drug was not administered in extended infusion. Other potential options are briefly discussed. We conclude that carbapenems are not necessary for all patients with infections caused by ceftriaxone-resistant Enterobacterales.

Healthcare resource use in hospitalized patients with carbapenem-resistant Gram-negative infections

Antimicrobial resistance (AMR) is a threat to global public health. Infections with resistant organisms are more challenging to treat, often delay patient recovery and can increase morbidity and mortality. Healthcare costs associated with treating patients with AMR organisms are poorly described. In particular, data for specific organisms, such as those harbouring carbapenem resistance, are lacking. This was a retrospective, matched (1:1), single-centre, cohort study at a Central London hospital, comparing costs and resource use of 442 adult inpatients infected with either carbapenem-sensitive (CSO) or carbapenem-resistant organisms (CRO) over a two-year period. Resource use and micro-costing data were obtained from the hospital Patient, Education and Research Costing System (PERCS), and included both direct and indirect costs. Overall, the median healthcare-related cost of treating a patient with a CRO was more than double (£49,537 vs £19,299) that of treating a patient with a CSO. There were statistically significant increases in expenditure across 21 of 44 measured parameters including critical care costs, which accounted for the greatest proportion of overall costs in both groups. Infections were predominantly of the respiratory tract (41%) and caused by Pseudomonas aeruginosa (76%). Infection with CROs increases healthcare expenditure significantly. Many of the costs, including patient support, portering and catering, have been underappreciated in previous work. We additionally note that patients infected with CROs have longer hospital stays, and increased theatre operating times compared with patients infected with CSOs.

Deep learning model for prediction of extended-spectrum beta-lactamase (ESBL) production in community-onset Enterobacteriaceae bacteraemia from a high ESBL prevalence multi-centre cohort.

Adequate empirical antimicrobial coverage is instrumental in clinical management of community-onset Enterobacteriaceae bacteraemia in areas with high ESBL prevalence, while balancing the risk of carbapenem overuse and emergence of carbapenem-resistant organisms. It is unknown whether machine learning offers additional advantages to conventional statistical methods in prediction of ESBL production. To develop a validated model to predict ESBL production in Enterobacteriaceae causing community-onset bacteraemia. 5625 patients with community-onset bacteraemia caused by Escherichia coli, Klebsiella species and Proteus mirabilis during 1 January 2015-31 December 2019 from three regional hospitals in Hong Kong were included in the analysis, after exclusion of blood cultures obtained beyond 48h of admission. The prevalence of ESBL-producing Enterobacteriaceae was 23.7% (1335/5625). Deep neural network and other machine learning algorithms were compared against conventional statistical model via multivariable logistic regression. Primary outcomes compared consisted of predictive model area under curve of receiver-operator characteristic curve (AUC), and macro-averaged F1 score. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Deep neural network yielded an AUC of 0.761 (95% CI 0.725-0.797) and F1 score of 0.661 (95% CI 0.633-0.689), which was superior to logistic regression (AUC 0.667 (95% CI 0.627-0.707), F1 score 0.596 (95% CI 0.567-0.625)). Deep neural network had a specificity of 91.5%, sensitivity of 37.5%, NPV of 82.5%, and PPV of 57.9%. Deep neural network is superior to logistic regression in predicting ESBL production in Enterobacteriaceae causing community-onset bacteraemia in high-ESBL prevalence area. Machine learning offers clinical utility in guiding judicious empirical antibiotics use.

Isolation and Molecular Characterization of Multi Drug Resistant Gram-Negative Bacteria from Clinical Samples in Tertiary Care Hospital, South India

Background and Aims Emergence of multi drug resistant MDR gram negative bacteria GNB is a serious threat and major challenge encountered by healthcare professionals. This study aimed to evaluate the distribution of antimicrobial resistance patterns in drug resistant GNB isolated at tertiary care hospital.Methods A total of 934 GNB strains were included in this study. Bacterial identification and disk diffusion testing were performed using standard microbiological techniques. Phenotypic detection of ESBL was assessed using double disk synergy test. Multiplex PCR assay was optimized to detect NDM-1 OXA-48 VIM IMP and KPC genes in carbapenem resistant GNB.Results The most common GNB identified were E. coli n46449.7 K. pneumoniae n13714.7 Acinetobacter Sp n13114 P. aeruginosa n11212 and Enterobacter Sp n313.3. Out of 934 isolates 808.6 were resistant to all tested antibiotics including carbapenems fluoroquinolones and aminoglycosides with high rate of resistant among Acinetobacter sp n454.8. On the other hand among 16818 carbapenem resistant isolates NDM-1 was most predominant in E. coli n2313.7 followed by K. pneumoniae n169.5 Acinetobacter Sp. n158.9 and P. aeruginosa n84.8. OXA-48 was most common in Acinetobacter Sp. n4124.4 followed by E. coli n74.2 and K. pneumoniae n63.6. Among 221 23.7 ESBL producing GNB E. coli n16717.9 was most common followed by K. pneumoniae n303.2 and Acinetobacter Sp n91.Conclusions The occurrence of bacterial infections caused by MDR-GNB and carbapenem resistant GNB infections is high. It is important for clinicians to evaluate and focus on the risk factors associated with the acquisition of MDR and carbapenem resistant organisms in hospital environment.

157. patient to Environment Transmission of Multidrug-resistant Bacteria Within Intensive Care Units

BackgroundIdentifying risk factors for environmental contamination with multidrug-resistant organisms (MDROs) is essential to prioritize methods for prevention of hospital transmission.MethodsPatients admitted to an ICU with an MDRO detected on clinical culture in the prior 30 days were enrolled. Patients (4 body sites) and high-touch objects (HTO) (3 composite sites) in ICU rooms were sampled. Environmental transmission was defined by shared MDRO species cultured on patient and HTO cultures obtained on multiple time points during the patient’s stay. Risk factors for environmental transmission were identified with logistic regression.ResultsForty-five patients were included (median 2 days of longitudinal sampling [IQR 1–4 days]). Enrollment anatomic cultures included extended-spectrum beta-lactamase-producing Enterobacterales (ESBLE) (n=12, 27%), carbapenem-resistant organisms (CRO) (n=4, 9%), methicillin-resistant S.aureus (MRSA) (n=11, 24%), vancomycin-resistant Enterococci (VRE) (n=4, 9%), and C.difficile (CDIFF) (n=14, 31%). Patient colonization during serial sampling was common with CRO (n=21, 47%), ESBLE (n=16, 36%), and VRE (n=16, 36%) and less so with MRSA (n=7, 16%) and CDIFF (n=5, 11%). Detection of MDROs on environmental surfaces was also common with identification of CRO in 47% of patient rooms (n=21) and ESBLE in 29% (n=13); MRSA (n=2, 4%), VRE (n=9, 20%), and CDIFF (n=3, 7%) were rarer. Patient to environment transmission was observed in 40% of rooms (n=18). Thirteen (29%) rooms had foreign MDRO contamination (i.e., one not detected on a body culture), most (n=10) with CRO. Environmental MDROs were most common in bathroom/sinks (n=22), followed by surfaces near the patient (n=10), and least common surfaces often touched by staff within the room (n=6).On multivariable logistic regression, naïve to clustering by patient, recent receipt of a proton pump inhibitor (OR 2.35, 95% CI 1.00 – 5.52, P=0.049) and presence of one or more wounds (OR 2.56, 95% CI 1.05 – 6.26, P=0.038) were significantly associated with environmental transmission (OR 1.56, 95% CI 1.01 – 2.43, P=0.046) (Table 1). ConclusionMDRO contamination of patient rooms is common with detection of organisms attributed to, and foreign to, the occupant.DisclosuresMichael Z. David, MD PhD, GSK (Consultant)

1378. Reservoirs of Transmission of Resistant Gram-negative Pathogens Responsible for Neonatal Sepsis among Hospitalized Neonates in Pune, India

BackgroundNeonatal infections with resistant Gram-negative (GN) organisms are associated with high rates of mortality, with limited antibiotic treatment options. The role of maternal colonization and environmental GN organisms as reservoirs for transmission to neonates has not been well described.MethodsWe performed a prospective cohort study from October 12, 2018, until October 31, 2019, to describe the role of maternal and environmental GN colonization in BSI among neonates admitted to the neonatal intensive care unit (NICU) at a tertiary care center in Pune, India. Women admitted to Labor & Delivery with risk factors for neonatal sepsis who provided consent were enrolled and their neonates were followed until hospital discharge. For neonates who developed bloodstream infection (BSI), colonization with resistant GN organisms was assessed in their mothers from frozen vaginal and rectal swabs collected at enrollment and at delivery and in the neonates from frozen skin swabs and peri-rectal swabs collected at day of life (DOL) 0, 3, 7, and weekly until discharge. Environmental colonization was assessed with weekly sampling of unit sinks and the immediate neonatal care environment. Colonization samples were processed to identify organisms that matched neonatal blood culture isolates.Results953 women were enrolled, of whom 741 (78%) received antepartum antibiotics. Among 987 live born neonates, 12 (1%) died in the delivery room and 257 (26%) required NICU admission. Among neonates admitted to the NICU, 143 (56%) had at least one blood culture, of which 28 (20%) were positive; 21 (75%) had a GN BSI. The most common cause of neonatal BSI was Klebsiella pneumoniae, and 8 (38%) GN BSI were due to a carbapenem-resistant organism. No organism isolated from maternal samples matched organism and resistance pattern from neonatal blood culture. Matching strains were found in unit sinks and neonatal rectal and skin samples (Figure 1).Organism recovery from swabs and match to bloodstream isolate by sample source and time of collection from birth ConclusionAmong neonates born to mothers with risk factors for neonatal sepsis, GN organisms were the most common cause of neonatal BSI. Environmental and neonatal colonization may represent important reservoirs of transmission for these pathogens among neonates hospitalized in a tertiary care NICU in Pune, India.Disclosures All Authors: No reported disclosures

Cost-Effectiveness Analysis of New Beta-Lactam Beta-Lactamase Inhibitor Antibiotics Versus Colistin for the Treatment of Carbapenem-Resistant Infections.

Introduction: Carbapenem-resistant organisms (CROs) present a serious public health problem. Limited treatment options has led to increased use of colistin and polymyxin. Since 2014, the US Food and Drug Administration approved 4 new beta-lactam beta-lactamase inhibitor (BLBLI) combination antibiotics with activity against CROs. These new antibiotics have been shown to be more effective and less toxic than colistin and polymyxin but are considerably more expensive. This study evaluated the cost-effectiveness of the new BLBLIs versus colistin-based therapy for the treatment of CROs. Methods: A decision-tree microsimulation model was used to evaluate the cost effectiveness of the new BLBLIs versus colistin-based therapy for the treatment of CROs. Treatment groups differed in risk of mortality and risk of an acute kidney injury (AKI). The relative risk of mortality was determined by creating a meta-analysis comparing new BLBLIs to colistin. Cost inputs included medication costs and the cost to treat an AKI. The primary outcomes include quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). Model inputs included: clinical outcomes and adverse events (30-day mortality and AKI); cost of treatment and adverse drug events; and health utilities. A 3% discount was applied for outcomes. A lifetime horizon was used from the perspective of the US healthcare system with a willingness-to-pay (WTP) threshold of $100 000. A sensitivity analysis was done to incorporate uncertainty. Results: The meta-analysis found the treatment with a new BLBLI was associated with a 50% decrease in the relative risk of 30-day mortality compared to colistin (RR 0.47, 95% CI 0.25-0.88). Treatment with a new BLBLI cost $16 200 and produced 11.5 QALYs, on average. The average colistin based regimen cost $3500 and produced 8.3 QALYs. The new BLBLIs were determined to be cost-effective with an ICER of $3900 per QALY gained. Treatment with a BLBLI remained cost-effective under all uncertainty scenarios tested. Conclusion: New BLBLIs are cost-effective compared to colistin for the treatment of CROs and are associated with improved mortality and fewer AKI events. The use of colistin should be reserved for cases where new BLBLIs are not available or there is documented resistance to these new antibiotics.

Molecular Characterization of New Delhi Metallo-ß-Lactamases-Producing Bacteria in the Gastrointestinal Tract of Intensive Care Unit Patients.

Background: The emergence of carbapenem-resistance in the gut flora of patients in the intensive care unit (ICU) poses a significant risk for infection with these types of pathogens.Materials and methods: New Delhi metallo-ß-lactamase 1 (NDM-1) in the gut flora of ICU patients was detected in cultures of a single rectal swab from each patient admitted to the ICU for a minimum period of 48 hrs. Samples were processed in the microbiology laboratory using blood agar and MacConkey agar. Identification of pathogens, carbapenem resistance, and metallo-ß-lactamase production was made using standard laboratory procedures. Bacterial isolates were also used for the determination of the NDM-1 gene by molecular methods.Results: One hundred twenty-two patients with different clinical presentations were recruited in the study. Two hundred nine bacteria were isolated, with Escherichia coli being the most common isolate. A total of 54/122 (44.3%) patients harbored carbapenem-resistant organisms (CRO), 36/122 (29.5%) carried metallo-β-lactamase-producing organisms (MBLO), and 30/122 (24.6%) carried bacteria with the NDM-1 gene. Patients who harbored CRO and MBLO had longer mean duration of stay in the ICU and hospital than those not harboring CRO and MBLO. All the metallo-β-lactamases were simultaneously resistant to other groups of antibiotics also. Use of invasive devices, three or more classes of antibiotics, hospitalization during the previous six months, comorbidities, and hospital stay for ≥48 hours before ICU admission had a significant association with colonization with CRO.Conclusion: Patients admitted in ICU or with serious diseases should be screened for gastrointestinal carriage of carbapenem-resistant organisms. Irrational use of antibiotics must be stopped to prevent the emergence and spread of such organisms.

Early identification and optimal management of carbapenem-resistant Gram-negative infection

Carbapenem resistance in Gram-negative bacteria is associated with severe infections in the hospital setting. No uniform screening policy or agreed set of criteria exists within the EU to inform treatment decisions for infections caused by carbapenem-resistant Gram-negative bacteria. To develop a range of consensus statements to survey experts in carbapenem resistance, to identify potential similarities and differences across the EU and across specialties. The survey contained 43 statements, covering six key topics relating to carbapenem-resistant organisms: microbiological screening; diagnosis; infection control implementation; antibiotic stewardship; use of resources; and influencing policy. In total, 136 survey responses were received (66% infectious disease specialists, 18% microbiologists, 11% intensive care specialists, 4% other/unknown) from France, Germany, Greece, Italy, Spain, and the UK. High, or very high, levels of agreement were seen for all 43 consensus statements, indicating good alignment concerning early identification and optimal management of infection due to carbapenem-resistant organisms. We offer the following recommendations: (1) screening is required when a patient may have been exposed to the healthcare system in countries/hospitals where carbapenem-resistant organisms are endemic; (2) rapid diagnostic tools should be available in every institution; (3) all institutions should have a specific policy for the control of carbapenem-resistant organisms, which is routinely audited; (4) clear strategies are required to define both appropriate and inappropriate use of carbapenems; (5) priority funding should be allocated to the management of infections due to carbapenem-resistant organisms; and (6) international co-operation is required to reduce country-to-country transmission of carbapenem-resistant organisms.

Gram negative chronic osteomyelitis

Background: To assess the demographic profile, clinical and microbiological characteristics, management and treatment outcome in chronic osteomyelitis caused by gram negative organisms. Methods and materials: A chart review of inpatients admitted with chronic osteomyelitis due to gram negative organisms was done over one year from August 2017 to August 2018 in a tertiary care centre in Mumbai. Following data was recorded: demographic profile, clinical presentation, type and site of fracture, intraoperative cultures, management and clinical outcomes. Results: The study cohort comprised of 23 patients [14(61%) males]. Mean age was 54 years (range, 21–83 years). Most common site of fracture was tibia [n = 8 (34%)]. Most common clinical presentation was discharging sinus/wound [n = 20(86%)]. The mean duration of symptoms was 6 months (range, 6weeks–2years). A total of 25 gram negative organisms were isolated from 23 intraoperative samples. 12/25(48%) of these organisms were multi-drug resistant [4/12(33%) were carbapenem resistant and 8/12(66%) were extended spectrum beta-lactamase resistant]. 3/23 (13%) patients had simultaneous Staphylococcus aureus infection. 20/23 (86%) underwent combined surgical and medical management, [9/20(45%) surgical debridement (no implants), 6/20(30%) implant removal and debridement, 3/20(15%) implant retention and debridement, 2/20(10%) underwent amputation]. 3/23(14%) were treated with only antibiotics. Antibiotic impregnated beads were inserted in 8/23 patients. 18/23 (78%) patients had good clinical outcome and 5/23(22%) required repeated debridement (2 had implant retention, 2 had carbapenem resistant organism). Conclusion: Gram negative orthopaedic infections with resistant organisms are especially difficult to manage due to limited antibiotic options, poor penetration at the site of infection, need for prolonged duration of treatment and repeated surgical interventions. Synergistic combination of susceptible antibiotics with extensive debridement and antibiotic impregnated cement/beads at the local site may yield good results.

Epidemiological analysis of pathogens causing bloodstream infections in department of hematology in Guangdong Province

目的分析广东省50家医院血液内科血标本来源细菌的构成和耐药性，了解血液内科血流感染（BSI）的流行病学特征。方法基于国家细菌耐药监测网（CARSS）平台，对2019年广东省50家医院血液内科、呼吸内科和ICU由血标本分离的病原菌分布和碳青霉烯类耐药革兰阴性菌（CRO）检出率进行分析，同时对大肠埃希菌、肺炎克雷伯菌和铜绿假单胞菌药敏特征分儿童组（≤14岁）和成人组（>14岁）进行分析。参考CLSI 2019年M100文件标准判断结果。结果共收集广东省50家医疗机构（三级医院48家）血液内科、呼吸内科、重症监护治疗病房（ICU）三个科室各1618、1026、3626株血标本分离菌完整微生物信息资料。其中血液内科革兰阴性杆菌占71.8％，革兰阳性球菌占28.2％。血液内科分离前5位细菌是：大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、凝固酶阴性葡萄球菌和草绿色链球菌群。葡萄球菌属中耐甲氧西林金黄色葡萄球菌（MRSA）、耐甲氧西林的凝固酶阴性葡萄球菌（MRSCN）的检出率分别为19.7％和80.6％，未发现对万古霉素、利奈唑胺、替考拉宁耐药的菌株，无利奈唑胺耐药的肠球菌。草绿色链球菌群对青霉素G的耐药率为6.9％，对头孢曲松和头孢噻肟耐药率均超过25.0％。肠杆菌科细菌中大肠埃希菌和肺炎克雷伯菌儿童组耐药率普遍高于成人组。成人组肺炎克雷伯菌对美罗培南耐药率为14.1％，阴沟肠杆菌对碳青霉烯类耐药率超过25.0％，非发酵菌中铜绿假单胞菌对大部分抗菌药物敏感性超过80.0％，但儿童组对美罗培南的耐药率高于成人组（11.8％对6.5％）。鲍曼不动杆菌无对替加环素耐药菌株。科室之间比较，ICU和呼吸内科血标本革兰阳性球菌比例高于血液内科。呼吸内科碳青霉烯类耐药大肠埃希菌（CREC）和碳青霉烯类耐药肺炎克雷伯菌（CRKP）检出率最低，分别为0.3％和3.7％。血液内科碳青霉烯类耐药铜绿假单胞菌（CRPA）和碳青霉烯类耐药鲍曼不动杆菌（CRAB）检出率最低，分别为8.3％和25.8％。ICU整体碳青霉烯类耐药的革兰阴性杆菌检出率都最高。结论血液内科血标本来源细菌构成比与重要细菌耐药性与呼吸内科、ICU存在差异，广东地区血液内科肺炎克雷伯菌、铜绿假单胞菌、阴沟肠杆菌及以草绿色链球菌群为主的链球菌属比例明显高于ICU和呼吸内科。

An evaluation of meropenem/vaborbactam for the treatment of nosocomial pneumonia

ABSTRACT Introduction: Nosocomial pneumonias are the second most common healthcare-associated infections (HCAIs), often associated with the presence of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter species, and Enterobacter species. Increasing use of carbapenems has led to an increase in the prevalence of carbapenem-resistant gram-negative organisms, such as carbapenem-resistant Enterobacterales (CRE), P. aeruginosa (CRPA), and Acinetobacter baumannii (CRAB), limiting treatment options for patients at high-risk of multi-drug resistant (MDR) gram-negative pathogens. Areas covered: The purpose of this review is to discuss the role of meropenem/vaborbactam, a beta-lactam combined with a novel non-beta-lactam cyclic boronic acid beta-lactamase inhibitor (BLI), for the treatment of nosocomial pneumonia based on its chemistry, pharmacokinetics/dynamics, microbiological spectrum of activity, mechanisms of resistance, safety, and clinical efficacy. Expert opinion: Currently, any utilization of meropenem/vaborbactam beyond its FDA-approved indication for complicated urinary tract infections is considered off-label use; however, based on the pulmonary penetration of meropenem/vaborbactam, it is highly likely to be a safe and effective alternative to more toxic agents, like aminoglycosides and polymixins, for targeted therapy in pulmonary infections due to CRE. Unfortunately, the multifactorial resistance pattern of CRPA and other non-lactose-fermenting gram-negative bacteria restricts activity against these organisms which are common pathogens implicated in nosocomial pneumonia.

Surveillance and Control Efforts for Carbapenemase-Producing Gram-Negatives at a High Burden Vietnam University Hospital

Background: Carbapenem-resistant gram-negative bacteria are an urgent threat to healthcare safety around the world. In Vietnam, Although surveillance and control of multidrug-resistant organisms is a national priority, information on the burden of these resistant pathogens is still scarce. At University Medical Center Ho Chi Minh City, Vietnam, we aimed to better understand carbapenem-resistance through 2 phases: (1) assess proportion of carbapenem-resistant gram-negative organisms that are carbapanemase-producing (CP-CRO) and (2) assess transmission burden of carbapenemase-producing carbapenem-resistant Enterobacterieacea (CP-CRE) in the general intensive care unit (ICU). Methods: In the first phase, all gram-negative clinical isolates collected between November 2018 and April 2019 were tested for carbapenem-resistance using the disc-diffusion method and were defined as meropenem resistant using the Clinical and Laboratory Standards Institute 2018 break point (M100-Performance Standards for Antimicrobial Susceptibility Testing, 28th Edition). Carbapenem-resistant bacteria were tested for phenotypic carbapenemase-production using the Becton Dickinson Phoenix CPO Detect assay. In the second phase, we instituted CP-CRE rectal screening using CHROMagar mSuperCARBA media for all ICU patients from July through September 2019. Patients were screened on admission, and negative patients were rescreened every 2 days until discharge, death, or CRE-positive screening or culture. Admission prevalence and incidence of CP-CRE transmission was calculated among CP-CRE infected or colonized patients. Results: From November 2018 through April 2019, 599 gram-negative clinical isolates from 543 patient samples were identified. Of these, 108 were carbapenem-resistant; 107 (99%) of carbapenem-resistant isolates were carbapenemase-producing by phenotypic method. Most CP-CRO were Acinetobacter baumannii (45 of 107, 42%) or Klebsiella pneumoniae (39 of 107, 36%). During ICU CP-CRE colonization screening, the July positivity rate on admission was 40% (32 of 81), the August positivity rate on admission was 30% (21 of 71), and the September positivity rate on admission was 40% (30 of 75). Of those with negative admission screen, the proportion of new CP-CRE colonization in July was 45% (22 of 49), the proportion of new CP-CRE colonization in August was 64% (32 of 50), and the proportion of new CP-CRE colonization in September was 44% (20 of 45). Across all 3 months of screening, the proportions of CP-CRE that were Klebsiella, Citrobacter, or Enterobacter were 68% (118 of 174) and the proportion of CP-CRE that were Eschericia coli was 37% (56 of 174). The average number of days to turn from negative to positive screening result was 4.1. Conclusions: Our analysis demonstrates that nearly all carbapenem-resistant organisms at our hospital are carbapenemase producing. In the ICU, we identified a high burden of CP-CRE, attributable to high presence on admission and new acquisition in the ICU. An intervention package based on CDC-recommended enhanced infection control measures is being implemented to decrease CP-CRE transmission in the ICU.Funding: NoneDisclosures: None

New Approaches to Colonization Screening in Response to Emerging Antimicrobial Resistance

Background: The capacity to monitor the emergence of carbapenemase-producing organisms (CPO) is critical in limiting transmission. CPO-colonized patients can be identified by screening rectal specimens for carbapenemase genes and the Cepheid GeneXpert Carba-R (XCR), the only FDA-approved test, is limited to 5 carbapenemase genes and cannot identify the bacterial species. Objective: We describe the development and validation of culture-based methods for the detection of CPO in rectal cultures (RCs) and nonrectal cultures (NRCs) of tracheal aspirate and axilla-groin swabs. Methods: Colonization screening was performed at 3 US healthcare facilities; specimens of RC swabs and NRC ESwabs were collected. Each specimen was inoculated to a MacConkey broth enrichment tube for overnight incubation then were subcultured to MacConkey agar with meropenem and ertapenem 10 µg disks (BEMA) and CHROMagar KPC (KCHR) or CHROMagar Acinetobacter (ACHR). All media were evaluated for the presence of carbapenem-resistant organisms; suspect colonies were screened by real-time PCR for the most common carbapenemase genes. MALDI-TOF was performed for species identification. BEMA, a previously validated method, was the comparator for 52 RCs; clinical culture (CC) served as the comparator method for 66 NRCs. Select CPO-positive and -negative specimens underwent reproducibility testing. Results: Among 56 patients undergoing colonization screening, 12 (21%) carried a CPO. Only 1 patient had CPO solely from RC. Also, 6 patients had both CPO-positive RC and NRC, and 5 patients only had a CPO-positive NRC. Of the latter, 4 had a CPO-positive tracheal specimen, and 1 had a positive culture from both tracheal and axilla-groin specimens. Sensitivity of BEMA (70%) for NRC was lower than for KCHR (96%) and ACHR (88 %) for all specimens. All methods showed a specificity of 100% and reproducibility of 92%. The detected CPO included OXA-23–positive Acinetobacter baumannii, NDM-positive Escherichia coli, KPC-positive Pseudomonas aeruginosa and 4 genera of KPC-positive Enterobacteriaceae. Conclusions:The addition of nonrectal specimens and use of selective media contributed to increased sensitivity and enhanced identification of CPO-colonized patients. Positive cultures were equally distributed among the 3 specimen types. The addition of the nonrectal specimens resulted in the identification of more colonized patients. The culture-based method was successful in detecting an array of different CPOs and target genes, including genes not detected by the Carba-R assay (eg, blaOXA-23-like). Enhanced isolation and characterization of CPOs will be key in aiding epidemiologic investigations and strengthening targeted guidance for containment strategies.Funding: NoneDisclosures: We discuss the drug combination aztreonam-avibactam and acknowledge that this drug combination is not currently FDA approved.

Unresolved issues in the identification and treatment of carbapenem-resistant Gram-negative organisms.

Carbapenem-resistant organisms (CROs), including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, are a threat worldwide. This review will cover mechanisms of resistance within CROs and challenges with identification and treatment of these organisms while pointing out unresolved issues and ongoing challenges. The treatment of CROs has expanded through newer therapeutic options. Guided utilization through genotypic and phenotypic testing is necessary in order for these drugs to target the appropriate mechanisms of resistance and select optimal antibiotic therapy. Identification methods and treatment options need to be precisely understood in order to limit the spread and maximize outcomes of CRO infections.

The Effect of Host Immunity on Predicting the Mortality of Carbapenem-Resistant Organism Infection.

Carbapenem-resistant organisms (CROs) are associated with considerable mortality clinically. There is a lack of effective tool to predict individual prognosis. We aim to determine if host immunity can be utilized to predict the prognosis of patients infected with CRO. From December 2018 to August 2019, we recruited CRO-infected patients to evaluate risk factors for 30-day mortality. Clinical, routine laboratory, immune and microbiological features were investigated and subjected to univariate and multivariate analyses. The final predictive models were established based on the regression coefficients of multivariate logistic regression. A total of 127 CRO-infected patients were enrolled in our study, including 85 survivors and 42 non-survivors. The number and IFN-γ producing ability of lymphocytes were remarkably decreased in non-survivors. The number of IFN-γ+CD4+ T cells could effectively predict 30-day mortality of CRO infection. Its area under the receiver operating characteristic (ROC) curve, sensitivity, specificity and accuracy, were 0.889 (95% confidence interval [CI], 0.834–0.945), 81.0, 80.0, and 80.3%, respectively. In multivariate analysis of laboratory parameters, IFN-γ+CD4+ T cell number and creatinine concentration were selected for the 2-marker model to predict prognosis fleetly. Its area under the ROC curve, sensitivity, specificity and accuracy were 0.894 (95% CI, 0.841–0.947), 83.3, 82.4, and 82.7%, respectively. Impaired lymphocyte function was an important factor to affect the outcome of CRO-infected patients. A 2-marker model based on the combination of IFN-γ+CD4+ T cell number and creatinine showed good performance in predicting the prognosis of CRO infection.

Metagenomic next-generation sequencing of rectal swabs for the surveillance of antimicrobial-resistant organisms on the Illumina Miseq and Oxford MinION platforms.

Antimicrobial resistance (AMR) is a public health threat where efficient surveillance is needed to prevent outbreaks. Existing methods for detection of gastrointestinal colonization of multidrug-resistant organisms (MDRO) are limited to specific organisms or resistance mechanisms. Metagenomic next-generation sequencing (mNGS) is a more rapid and agnostic diagnostic approach for microbiome and resistome investigations. We determined if mNGS can detect MDRO from rectal swabs in concordance with standard microbiology results. We performed and compared mNGS performance on short-read Illumina MiSeq (N = 10) and long-read Nanopore MinION (N = 5) platforms directly from rectal swabs to detect vancomycin-resistant enterococci (VRE) and carbapenem-resistant Gram-negative organisms (CRO). We detected Enterococcus faecium (N = 8) and Enterococcus faecalis (N = 2) with associated van genes (9/10) in concordance with VRE culture-based results. We studied the microbiome and identified CRO, Pseudomonas aeruginosa (N = 1), Enterobacter cloacae (N = 1), and KPC-producing Klebsiella pneumoniae (N = 1). Nanopore real-time analysis detected the blaKPC gene in 2.3min and provided genetic context (blaKPC harbored on pKPC_Kp46 IncF plasmid). Illumina sequencing provided accurate allelic variant determination (i.e., blaKPC-2) and strain typing of the K. pneumoniae (ST-15). We demonstrated an agnostic approach for surveillance of MDRO, examining advantages of both short- and long-read mNGS methods for AMR detection.

Implementation of an antimicrobial stewardship programme and reduction in carbapenemase-producing Enterobacterales in an Australian local health district.

BackgroundCarbapenemase-producing Enterobacterales (CPE) are increasingly seen in Australian hospitals. Antimicrobial stewardship (AMS) interventions have been shown to reduce rates of carbapenem-resistant organisms; data on their effect on CPE rates are limited.ObjectivesTo explore the effect of a multi-site computer-supported AMS programme on the rates of CPE in an Australian local health district.MethodsAll laboratory CPE isolates between 2008 and 2018 were identified. Microbiological and demographic data, CPE risk factors and outcomes were collected. Monthly carbapenem use was expressed as DDD per 1000 occupied bed days (OBD). Hand hygiene compliance rates among healthcare workers were analysed. A computer-supported AMS programme was implemented district-wide in 2012. Bivariate relationships were examined using Pearson’s r and predictors of CPE isolates using time series linear regression.ResultsWe identified 120 isolates from 110 patients. Numbers of CPE isolates and carbapenem use both showed a strong downward trend during the study period; the decreases were strongly correlated (r = 0.80, P = 0.006). The positive relationship between carbapenem use and CPE isolation was maintained while adjusting for time (b = 0.05, P < 0.001). Average yearly consumption of carbapenems fell by 20%, from 18.4 to 14.7 DDD/1000 OBD following implementation of the AMS programme. Hand hygiene compliance rates remained high throughout.ConclusionsWe demonstrated a reduction of CPE isolates in conjunction with reduced carbapenem use, longitudinally consolidated by a formal AMS programme. Prospective studies are needed to validate the effect of AMS on carbapenem resistance, especially in high-prevalence settings.