Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies.

BACKGROUND: The factors contributing to the accelerated convergent evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Unraveling the contribution of viral replication in immunocompromised patients is important for the early detection of novel mutations and developing approaches to limit COVID-19. METHODS: We deep sequenced SARS-CoV-2 RNA from 192 patients (64% hospitalized, 39% immunosuppressed) and compared the viral genetic diversity within the patient groups of different immunity and hospitalization status. Serial sampling of 14 patients was evaluated for viral evolution in response to antiviral treatments. RESULTS: We identified hospitalized and immunosuppressed patients with significantly higher levels of viral genetic diversity and variability. Further evaluation of serial samples revealed accumulated mutations associated with escape from neutralizing antibodies in a subset of the immunosuppressed patients treated with antiviral therapies. Interestingly, the accumulated viral mutations that arose in this early Omicron wave, which were not common in the patient viral lineages, represent convergent mutations that are prevalent in the later Omicron sublineages, including the XBB, BA.2.86.1 and its descendent JN sublineages. CONCLUSIONS: Our results illustrate the importance of identifying convergent mutations generated during antiviral therapy in immunosuppressed patients, as they may contribute to the future evolutionary landscape of SARS-CoV-2. Our study also provides evidence of a correlation between SARS-CoV-2 convergent mutations and specific antiviral treatments. Evaluating high-confidence genomes from distinct waves in the pandemic with detailed patient metadata allows for discerning of convergent mutations that contribute to the ongoing evolution of SARS-CoV-2.

Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.

BACKGROUND: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment. METHODS: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression. RESULTS: Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%). CONCLUSIONS: The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.

Reported HIV-related stigma according to race and ethnicity.

People living with HIV/AIDS (PLWHA) have long experienced structural, community, and personal stigma. We explored differences in experienced HIV-related stigma according to race/ethnicity using quantitative and qualitative measures. Sixty-four patients were enrolled in this study (22 White and 42 people of color [POC]). POC scored higher than White PLWHA on all 12 survey statements, with statistically significant differences in disclosure concerns and with one of the statements on public attitudes towards PLWHA. Common themes in the qualitative interview were HIV disclosure concerns and fear of rejection. These data demonstrate that stigma continues to be a significant concern for PLWHA, particularly POC, meaningfully impacting their lives. By acknowledging and working to reduce negative perceptions about PLWHA, physicians may improve care for their patients by developing more trusting relationships.

Disseminated Protothecosis Due to Prototheca zopfii and Literature Review.

ABSTRACT: Prototheca species are achlorophyllic algae that are a rare cause of infection in humans. It most commonly causes localized cutaneous disease and rarely disseminated infection. Immunocompromised patients have the highest risk of disseminated protothecosis, with a higher mortality rate than localized cutaneous infections. At the species level, infections caused by Prototheca zopfii are reported less frequently than those caused by Prototheca wickerhamii. The diagnosis can be made using histopathology, culture, and molecular testing. There is no definitive evidence for an effective treatment, which currently consists of antifungals (primarily amphotericin B). With only a handful of cases of disseminated protothecosis reported worldwide that are caused by P. zopfii , we herein present an additional case of a postbone marrow transplant patient in the Midwest of the United States.

Critical Time Windows for Air Pollution Exposure and Birth Weight in a Multicity Canadian Pregnancy Cohort.

BACKGROUND: Maternal prenatal exposure to air pollution has been associated with adverse birth outcomes. However, previous studies focused on a priori time intervals such as trimesters reported inconsistent associations. OBJECTIVES: We investigated time-varying vulnerability of birth weight to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) using flexible time intervals. METHODS: We analyzed 1,300 live, full-term births from Maternal-Infant Research on Environmental Chemicals, a Canadian prospective pregnancy cohort spanning 10 cities (2008-2011). Daily PM2.5 and NO2 concentrations were estimated from ground-level monitoring, satellite models, and land-use regression, and assigned to participants from pre-pregnancy through delivery. We developed a flexible two-stage modeling method-using a Bayesian Metropolis-Hastings algorithm and empirical density threshold-to identify time-dependent vulnerability to air pollution without specifying exposure periods a priori. This approach identified critical windows with varying lengths (2-363 days) and critical windows that fell within, or straddled, predetermined time periods (i.e., trimesters). We adjusted the models for detailed infant and maternal covariates. RESULTS: Critical windows associated with reduced birth weight were identified during mid- to late-pregnancy for both PM2.5 and NO2: -6 g (95% credible interval: -11, -1 g) and -5 g (-10, -0.1 g) per µg/m3 PM2.5 during gestational days 91-139 and 249-272, respectively; and -3 g (-5, -1 g) per ppb NO2 during days 55-145. DISCUSSION: We used a novel, flexible selection method to identify critical windows when maternal exposures to air pollution were associated with decrements in birth weight. Our results suggest that air pollution impacts on fetal development may not be adequately captured by trimester-based analyses.

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.

Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.

BACKGROUND: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. OBJECTIVES: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). PATIENTS AND METHODS: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. RESULTS: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths. CONCLUSIONS: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients.

BACKGROUND: Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients. METHODS: Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected. RESULTS: Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event. CONCLUSIONS: Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.

Mucormycosis.

Mucormycosis is an infection caused by a group of filamentous molds within the order Mucorales. Infections may result from ingestion of contaminated food, inhalation of spores into the nares or lungs, or inoculation into disrupted skin or wounds. In developed countries, mucormycosis occurs primarily in severely immunocompromised hosts (e.g., those with hematological malignancies, organ transplantation, neutropenia, autoimmune disorders, or other impairments in immunity). Only 6 to 10% of cases occur in subjects with no underlying disease. In contrast, in developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or in immunocompetent subjects following trauma. Mucormycosis exhibits a marked propensity to invade blood vessels, leading to thrombosis, necrosis, and infarction of tissue. Mortality associated with invasive mucormycosis is high (> 30-50%), with 90% mortality associated with disseminated disease. Mortality rates are much lower, though still significant (10-30%), among patients with localized cutaneous disease.The diagnosis of mucormycosis relies upon histopathology and culture. Blood tests are of limited diagnostic value. Even with disseminated disease, blood cultures are usually negative. Mucorales have a distinct histological appearance, with irregular, nonseptate hyphae that branch at right angles. Cultures and/or polymerase chain reaction (PCR) are important to identify the genera.Based on anatomic localization, mucormycosis can be classified as one of six forms: (1) rhino-orbital-cerebral mucormycosis (ROCM), (2) pulmonary, (3) cutaneous, (4) gastrointestinal (GI), (5) disseminated, and (6) mucormycosis of uncommon sites. Among diabetics, ROCM is the most common clinical presentation, whereas lung involvement is uncommon. In contrast, among organ transplant recipients or patients with hematological malignancies (HemeM), pulmonary and disseminated diseases are most common. Mucormycosis can progress rapidly, and delay in initiation of treatment by even a few days markedly worsens outcomes.Due to the rarity of mucormycosis, randomized controlled therapeutic trials have not been performed. Lipid formulations of amphotericin B (LFAB) are the mainstay of therapy, but the newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug isavuconazonium sulfate), may be effective in patients refractory to or intolerant of LFAB. Early surgical debridement or excision plays an important adjunctive role. Additional studies are required to assess the optimal duration of therapy as well as the specific roles of LFAB and the triazoles in the treatment of mucormycosis.

Nocardia spp.: A Rare Cause of Pneumonia Globally.

Members of the Nocardia genus are ubiquitous in the environment. These aerobic, gram-positive organisms can lead to life-threatening infection, typically in immunocompromised hosts such as solid organ transplant recipients or those receiving immunosuppressive medications for other reasons. This current review discusses the microbiology of nocardiosis, risk factors for infection, clinical manifestations, methods for diagnosis, and treatment. Nocardiosis primarily affects the lung but may also cause skin and soft tissue infection, cerebral abscess, bloodstream infection, or infection involving other organs. Although rare as a cause of community-acquired pneumonia, Nocardia can have severe morbidity and mortality, particularly in patients with comorbidities or compromised immunity. Early diagnosis and timely initiation of therapy are critical to optimizing patient outcomes. Species identification is important in determining treatment, as is in vitro susceptibility testing. Sulfonamide therapy is usually indicated, although a variety of other antimicrobials may be useful, depending on the species and susceptibility testing. Prolonged therapy is usually indicated, for 6 to 12 months, and in some cases surgical debridement may be required to resolve infection.

Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD Study.

BACKGROUND: Studies of out-of-hospital cardiac arrest and sudden cardiac death (SCD) use emergency medical services records, death certificates, or definitions that infer cause of death; thus, the true incidence of SCD is unknown. Over 90% of SCDs occur out-of-hospital; nonforensic autopsies are rarely performed, and therefore causes of death are presumed. We conducted a medical examiner-based investigation to determine the precise incidence and autopsy-defined causes of all SCDs in an entire metropolitan area. We hypothesized that postmortem investigation would identify actual sudden arrhythmic deaths among presumed SCDs. METHODS: Between February 1, 2011, and March 1, 2014, we prospectively identified all incident deaths attributed to out-of-hospital cardiac arrest (emergency medical services primary impression, cardiac arrest) between 18 to 90 years of age in San Francisco County for autopsy, toxicology, and histology via medical examiner surveillance of consecutive out-of-hospital deaths, all reported by law. We obtained comprehensive records to determine whether out-of-hospital cardiac arrest deaths met World Health Organization (WHO) criteria for SCD. We reviewed death certificates filed quarterly for missed SCDs. Autopsy-defined sudden arrhythmic deaths had no extracardiac cause of death or acute heart failure. A multidisciplinary committee adjudicated final cause. RESULTS: All 20 440 deaths were reviewed; 12 671 were unattended and reported to the medical examiner. From these, we identified 912 out-of-hospital cardiac arrest deaths; 541 (59%) met WHO SCD criteria (mean 62.8 years, 69% male) and 525 (97%) were autopsied. Eighty-nine additional WHO-defined SCDs occurred within 3 weeks of active medical care with the death certificate signed by the attending physician, ineligible for autopsy but included in the countywide WHO-defined SCD incidence of 29.6/100 000 person-years, highest in black men (P<0.0001). Of 525 WHO-defined SCDs, 301 (57%) had no cardiac history. Leading causes of death were coronary disease (32%), occult overdose (13.5%), cardiomyopathy (10%), cardiac hypertrophy (8%), and neurological (5.5%). Autopsy-defined sudden arrhythmic deaths were 55.8% (293/525) of overall, 65% (78/120) of witnessed, and 53% (215/405) of unwitnessed WHO-defined SCDs (P=0.024); 286 of 293 (98%) had structural cardiac disease. CONCLUSIONS: Forty percent of deaths attributed to stated cardiac arrest were not sudden or unexpected, and nearly half of presumed SCDs were not arrhythmic. These findings have implications for the accuracy of SCDs as defined by WHO criteria or emergency medical services records in aggregate mortality data, clinical trials, and cohort studies.

Nocardia infections in solid organ transplantation: Guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation.

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Nocardia infections after solid organ transplantation (SOT). Nocardia infections have increased in the last two decades, likely due to improved detection and identification methods and an expanding immunocompromised population. The risk of developing nocardiosis after transplantation varies with the type of organ transplanted and the immunosuppression regimen used. Nocardia infection most commonly involves the lung. Disseminated infection can occur, with spread to the bloodstream, skin, or central nervous system. Early recognition of the infection and initial appropriate treatment is important to achieve good outcomes. Species identification and antimicrobial susceptibility testing are strongly recommended, as inter- and intraspecies susceptibility patterns can vary. Sulfonamide is the first-line treatment of Nocardia infections, and combination therapy with at least two antimicrobial agents should be used initially for disseminated or severe nocardiosis. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis may be helpful in preventing Nocardia infection after SOT.

Fungal Infections Complicating Lung Transplantation.

Lung transplantation is an increasingly utilized modality for treating advanced lung disease. However, lung transplant recipients (LTRs) experience high rates of infection-related mortality and, compared with other solid organ transplant recipients, are at increased risk of infectious complications given the intensity of immunosuppression employed, the presence of airway abnormalities after surgery and exposure of the allograft to the environment. Fungal infections, particularly mold infections, are problematic after transplantation as they are often associated with limited treatment options and poor outcomes. We describe the non-Candida fungal infections occurring in LTRs, including their epidemiology, clinical features, and treatment.

Aspergillus calidoustus case series and review of the literature.

Aspergillus calidoustus, previously classified as Aspergillus ustus, is an emerging pathogen in immunocompromised persons. We describe four recent cases of A. calidoustus and review 37 additional cases of A. calidoustus (n = 8) or A. ustus (n = 29) published through June 2016. Twenty (49%) cases occurred in patients with hematologic malignancy and/or receipt of hematopoietic cell transplantation, and 13 (32%) occurred in solid organ transplant recipients. Antifungal susceptibility was reported in 49% of cases and in 42% treatment failed. Overall mortality was 66% and, where reported, attributable mortality was 30%. A. calidoustus infection is associated with a high mortality rate and frequently displays in vitro antifungal resistance.

Infections Due to Acinetobacter baumannii in the ICU: Treatment Options.

Bacteria within the genus Acinetobacter (principally A. baumannii-calcoaceticus complex [ABC]) are gram-negative coccobacilli that may cause nosocomial infections in critically ill or debilitated patients (particularly ventilator-associated pneumonia and infections of the bloodstream, urinary tract, and wounds). Treatment of Acinetobacter infections is difficult, as Acinetobacter spp. are intrinsically resistant to multiple antimicrobial agents, and have a remarkable ability to acquire new resistance determinants via mechanisms that include plasmids, transposons, integrons, and resistance islands. Since the 1990s, global resistance to antimicrobials has escalated dramatically among ABC. Global spread of multidrug-resistant (MDR)-A. baumannii strains reflects dissemination of a few clones between hospitals, geographic regions, and continents; excessive use of antibiotics amplifies this spread. Many isolates are resistant to all antimicrobials except colistin (polymyxin E) and tigecycline, and some infections are untreatable with existing antimicrobial agents. Antimicrobial resistance poses a serious threat to treat or prevent infections due to ABC. Strategies to curtail environmental colonization with MDR-ABD will 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 of existing antibiotics as well as development of novel antibiotic classes.

Emergence of Antimicrobial Resistance among Pseudomonas aeruginosa: Implications for Therapy.

Pseudomonas aeruginosa (PA), a nonlactose fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of bloodstream, urinary tract, intra-abdominal, wounds/skin/soft tissue. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance among PA has escalated globally, via dissemination of several international multidrug-resistant "epidemic" clones. We review the emergence of antimicrobial resistance to this pathogen, and discuss approaches to therapy (both empirical and definitive).

Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis.

OBJECTIVES: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. PATIENTS AND METHODS: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September 2014. Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. RESULTS: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR = 3.56, 95% CI = 1.02-12.40, P = 0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. CONCLUSIONS: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure.

Emergence of antimicrobial resistance among Acinetobacter species: a global threat.

PURPOSE OF REVIEW: Bacteria within the genus Acinetobacter [principally Acinetobacter baumannii-calcoaceticus complex (ABC)] are Gram-negative coccobacilli that may cause serious nosocomial infections (particularly ventilator-associated pneumonia and infections of the bloodstream, urinary tract, and wounds) as well as community-acquired infections (often skin/soft tissue infections in the context of trauma). Within the past two decades, Acinetobacter spp. have been responsible for an increasing number of infections in intensive care units (ICUs) globally. Treatment of Acinetobacter infections is difficult, as Acinetobacter spp. are intrinsically resistant to multiple antimicrobial agents, and have a remarkable ability to acquire new resistance determinants via multiple mechanisms. RECENT FINDINGS: Since the 1990s, global resistance to antimicrobials has escalated dramatically among ABC. Global spread of multidrug-resistant (MDR) A. baumannii strains reflects dissemination of a few clones between hospitals, geographic regions, and continents; this spread is amplified by excessive use of antibiotics. Many isolates are resistant to all antimicrobials except colistin (polymyxin E), and some infections are untreatable with existing antimicrobial agents. SUMMARY: Antimicrobial resistance poses a serious threat to control infections due to ABC. Strategies to curtail environmental colonization with MDR-ABD will require aggressive infection control efforts and cohorting of infected patients. Thoughtful antibiotic strategies are essential to limit the consequences and spread of MDR-ABC. Optimal therapy will likely require combination antimicrobial therapy of existing antibiotics as well as development of novel antibiotic classes.