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Multidrug resistance in bacteria is an important issue and is increasing in frequency worldwide because of the limitations of therapeutic agents. From 2010 to 2019, 14 new systemic antibiotics received regulatory approval in the United States. However, few new antibiotics have been introduced in Republic of Korea to combat multidrug-resistant pathogens. Here, we introduce six novel antibiotics for Gram-positive bacteria and five for Gram-negative bacteria approved by the United States Food and Drug Administration and the European Medicines Agency from 2009 to October 2021, and recommend that they be approved for use in Republic of Korea at the earliest possible date.

Background: Escherichia coli is one of the most common causes of healthcare-associated infections (HAIs); multidrug resistance reduces available options for antibiotic treatment. We examined factors associated with the spread of multidrug-resistant E. coli phenotypes responsible for device- and procedure-related HAIs from acute care hospitals, long-term acute care hospitals, and inpatient rehabilitation facilities, using isolate and antimicrobial susceptibility data reported to the National Healthcare Safety Network during 2013-2017., Methods: We used multivariable logistic regression to examine associations between co-resistant phenotypes, patient and healthcare facility characteristics, and time. We also examined the geographic distribution of co-resistant phenotypes each year by state and by hospital referral region to identify hot spots., Results: A total of 96 672 E. coli isolates were included. Patient median age was 62 years, and 60% were female; more than half (54%) were reported from catheter-associated urinary tract infections. From 2013 to 2017, 35% of the isolates were nonsusceptible to fluoroquinolones (FQs), 17% to extended-spectrum cephalosporins (ESCs), and 13% to both ESCs and FQs. The proportion of isolates co-resistant to ESCs and FQs was higher in 2017 (14%) than in 2013 (11%) (P < .0001); overall prevalence and increases were heterogeneously distributed across healthcare referral regions. Co-resistance to FQs and ESCs was independently associated with male sex, central line-associated bloodstream infections, long-term acute care hospitals, and the 2016-2017 (vs 2013-2014) reporting period., Conclusions: Multidrug resistance among E. coli causing device- and procedure-related HAIs has increased in the United States. FQ and ESC co-resistant strains appear to be spreading heterogeneously across hospital referral regions., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Multi-drug resistance (MDR) is one of the leading causes of the anticancer failures. Besides the blockage of the MDR pathways, the development of more potent drugs is with urgent needs, but has been postponed mainly due to an imbalance between safety and efficacy. The recent development of the bioorthogonal prodrug activation strategy has shown immense potential to balance safety and efficacy, while recent studies only focused on few drug entities such as doxorubicin and monomethyl auristatin E, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from food and drug administration (FDA) approved drugs to a heated antibody drug conjugates (ADC) warhead and a trichothecene toxin to demonstrate that the bioorthogonal caging and specific activation could serve as a general design to increase the therapeutic index of bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution was regulated by the cancer cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. The prodrug activation not only enhanced the synergistic therapeutic effect within a broad range of dose ratios but also allowed the convenient switching of drug identities to successfully combat MDR tumor in vivo. In general, this strategy might serve as a general platform, which can be readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled bioorthogonal prodrug activation would facilitate the discovery of anticancer drugs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Apparent treatment-resistant hypertension (aTRH) is a common condition associated with risk of cardiovascular events. However, the risk of cardiovascular mortality associated with aTRH in the US population is unknown. We aimed to assess the risk of cardiovascular disease (CVD) mortality associated with aTRH in the US population., Methods: We analyzed data from 6357 adult hypertensive participants of the National Health and Nutrition Examination Survey (1988-1994 and 1999-2010) linked to the National Death Index. Based on presence of uncontrolled hypertension [blood pressure (BP) ≥140/90 mmHg] and the number of antihypertensives prescribed, we classified participants into the following groups: non-aTRH (BP < 140/90 mmHg and ≤ 3 antihypertensives); controlled aTRH (BP < 140/90 mmHg and ≥ 4 antihypertensives); and uncontrolled aTRH (BP ≥140/90 mmHg and ≥ 3 antihypertensives)., Results: Of the 6357 participants, 1522 had aTRH, representing a US prevalence of 7.6 million. Of the participants with aTRH, 432 had controlled aTRH and 1090 had uncontrolled aTRH. During follow-up (median 6 years), there were 550 CVD deaths. The cumulative incidence of CVD mortality was significantly higher in the aTRH group compared with non-aTRH group (log-rank p < 0.001). In fully adjusted models, aTRH was associated with a 47% higher risk of CVD mortality compared with the non-aTRH group [1.47 (1.1-1.96)]. Similar increase in risk of CVD mortality was noted across aTRH subgroups compared with the non-aTRH group: controlled aTRH [1.66 (1.03-2.68)] and uncontrolled aTRH [1.43 (1.05-1.94)]. Among non-aTRH subgroups, those on 3 antihypertensive medications had a 35% increased risk of CVD mortality than those on < 3 medications [1.35 (0.98-1.86)]., Conclusions: aTRH is a common condition, affecting approximately 7.6 million Americans. Regardless of BP control, people with aTRH remain at a higher risk of cardiovascular outcomes. The risk of cardiovascular disease mortality remains high among those with controlled BP on 3 medications (non-aTRH) or ≥ 4 medications (controlled aTRH), groups not generally considered at high risk. Future risk reduction interventions should consider focusing on these high-risk groups.

In response to a rising concern for multidrug resistance and Clostridium difficile infections, the Centers for Medicare and Medicaid services (CMS) will require all long-term care (LTC) facilities to establish an antibiotic stewardship program by November 2017. Thus far, limited evidence describes implementation of antibiotic stewardship in LTC facilities, mostly in academic- or hospital-affiliated settings. To support compliance with CMS requirements and aid facilities in establishing a stewardship program, the Infection Advisory Committee at AMDA-The Society for Post-Acute and Long-Term Care Medicine, has developed an antibiotic stewardship policy template tailored to the LTC setting. The intent of this policy, which can be adapted by individual facilities, is to help LTC facilities implement an antibiotic stewardship policy that will meet or exceed CMS requirements. We also briefly discuss implementation of an antibiotic stewardship program in LTC settings, including a list of free resources to support those efforts., (Published by Elsevier Inc.)

Objectives: To examine factors associated with isolation precaution use in nursing home (NH) residents with multidrug-resistant organism (MDRO) infection., Design: Retrospective, cross-sectional analysis., Setting: Nursing homes with Centers for Medicare and Medicaid Services' certification from October 2010 to December 2013., Participants: Elderly, long-stay NH residents with positive MDRO infection assessments., Measurements: Data were obtained from the Minimum Data Set (MDS) 3.0, Certification and Survey Provider Enhanced Reporting, and Area Health Resource File. Multivariable regression with facility fixed effects was conducted., Results: The sample included 191,816 assessments of residents with MDRO infection, of which isolation use was recorded in 12.8%. Of the NHs reporting MDRO infection in the past year, 31% used isolation at least once among residents with MDRO infection. Resident characteristics positively associated with isolation use included locomotion (23.6%, P < .001) and eating (17.9%, P < .001) support. Isolation use was 14.3% lower in those with MDRO history (P < .001). Residents in NHs that had received an infection control-related citation in the past year had a greater probability of isolation use (3.4%, P = .02); those in NHs that had received a quality-of-care citation had lower probability of isolation use (-3.3%, P = .03)., Conclusion: This is the first study to examine the new MDS 3.0 isolation and MDRO items. Isolation was infrequently used, and the proportion of isolated MDRO infections varied between facilities. Inspection citations were related to isolation use in the following year. Further research is needed to determine whether and when isolation should be used to best decrease risk of MDRO transmission and improve quality of care., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Background: Broad-spectrum antimicrobials are given prophylactically post-transplant, although these agents are a risk factor for multidrug-resistant (MDR) infections and Clostridium difficile infection (CDI). This study aimed to determine whether an association exists between the duration of antimicrobials given early post-transplant and the development of MDR infections or CDI., Methods: A single-center retrospective analysis was performed on lung transplants from September 2009 to August 2014. Patients were excluded for cystic fibrosis (CF) or postoperative survival less than 30 d. Qualifying infections were defined as any new positive MDR bacterial culture or C. difficile assay from postoperative day 7-90 d after a broad-spectrum antimicrobial., Results: A total of 500 patients, 61% male, were identified, median age of 62 yr. MDR infections occurred in 169 (34%) and CDI in 31 (6%). Non-ICU days were associated with a decreased risk of MDR/CDI (OR 0.891, p = 0.0002), and duration of Gram-positive antimicrobials (OR 1.073, p = 0.0219) was associated with an increased risk., Conclusions: One-third (34%) of non-CF lung transplants develop MDR infections and 6% develop CDI within 90 d of postoperative antimicrobials. The duration of Gram-positive antimicrobials may increase the risk of MDR/CDI, while early transfer from the ICU may have a protective effect., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The importance of the commensal microbiota that colonizes the skin, gut, and mucosal surfaces of the human body is being increasingly recognized through a rapidly expanding body of science studying the human microbiome. Although, at first glance, these discoveries may seem esoteric, the clinical implications of the microbiome in human health and disease are becoming clear. As such, it will soon be important for practicing clinicians to have an understanding of the basic concepts of the human microbiome and its relation to human health and disease. In this Concise Review, we provide a brief introduction to clinicians of the concepts underlying this burgeoning scientific field and briefly explore specific disease states for which the potential role of the human microbiome is becoming increasingly evident, including Clostridium difficile infection, inflammatory bowel disease, colonization with multidrug-resistant organisms, obesity, allergic diseases, autoimmune diseases, and neuropsychiatric illnesses, and we also discuss current and future roles of microbiome restorative therapies., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Although gonorrhea has afflicted humans for centuries, and the causative bacterium, Neisseria gonorrhoeae, was identified more than a century ago, gonorrhea remains a public health problem in the United States. Gonorrhea is the second most commonly reported notifiable infection in the United States; >300,000 cases were reported in 2011. In the United States, health inequities persist; the incidence of reported gonorrhea among blacks is 17 times the rate among whites, likely because of structural socioeconomic factors.

Objective: To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) reported to the National Healthcare Safety Network (NHSN) during 2009-2010., Methods: Central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections were included. Pooled mean proportions of isolates interpreted as resistant (or, in some cases, nonsusceptible) to selected antimicrobial agents were calculated by type of HAI and compared to historical data., Results: Overall, 2,039 hospitals reported 1 or more HAIs; 1,749 (86%) were general acute care hospitals, and 1,143 (56%) had fewer than 200 beds. There were 69,475 HAIs and 81,139 pathogens reported. Eight pathogen groups accounted for about 80% of reported pathogens: Staphylococcus aureus (16%), Enterococcus spp. (14%), Escherichia coli (12%), coagulase-negative staphylococci (11%), Candida spp. (9%), Klebsiella pneumoniae (and Klebsiella oxytoca; 8%), Pseudomonas aeruginosa (8%), and Enterobacter spp. (5%). The percentage of resistance was similar to that reported in the previous 2-year period, with a slight decrease in the percentage of S. aureus resistant to oxacillins (MRSA). Nearly 20% of pathogens reported from all HAIs were the following multidrug-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (3%); extended-spectrum cephalosporin-resistant K. pneumoniae and K. oxytoca (2%), E. coli (2%), and Enterobacter spp. (2%); and carbapenem-resistant P. aeruginosa (2%), K. pneumoniae/oxytoca (<1%), E. coli (<1%), and Enterobacter spp. (<1%). Among facilities reporting HAIs with 1 of the above gram-negative bacteria, 20%-40% reported at least 1 with the resistant phenotype., Conclusion: While the proportion of resistant isolates did not substantially change from that in the previous 2 years, multidrug-resistant gram-negative phenotypes were reported from a moderate proportion of facilities.

Background: The effect of adherence, treatment failure, and comorbidities on the cost of HIV care is not well understood., Objective: To characterize the cost of HIV care including combination antiretroviral treatment (ART)., Research Design: Observational study of administrative data., Subjects: Total 1896 randomly selected HIV-infected patients and 288 trial participants with multidrug-resistant HIV seen at the US Veterans Health Administration (VHA)., Measures: Comorbidities, cost, pharmacy, and laboratory data., Results: Many HIV-infected patients (24.5%) of the random sample did not receive ART. Outpatient pharmacy accounted for 62.8% of the costs of patients highly adherent with ART, 32.2% of the cost of those with lower adherence, and 6.2% of the cost of those not receiving ART. Compared with patients not receiving ART, high adherence was associated with lower hospital cost, but no greater total cost. Individuals with a low CD4 count (<50 cells/mm) incurred 1.9 times the cost of patients with counts >500. Most patients had medical, psychiatric, or substance abuse comorbidities. These conditions were associated with greater cost. Trial participants were less likely to have psychiatric and substance abuse comorbidities than the random sample of VHA patients with HIV., Conclusions: Patients receiving combination ART had higher medication costs but lower acute hospital cost. Poor control of HIV was associated with higher cost. The cost of psychiatric, substance abuse, rehabilitation, and long-term care and medications other than ART, often overlooked in HIV studies, was substantial.

Gram&#x2010;negative bacilli are an important cause of infection in healthcare and community settings. Antimicrobial resistance, including resistance to multiple antimicrobial classes, is an ongoing problem among gram&#x2010;negative bacilli. This synopsis reviews the incidence of multidrug resistance among gram&#x2010;negative bacilli in the United States and describes emerging issues in their epidemiology.

USA300 methicillin-resistant Staphylococcus aureus (MRSA) isolates are usually resistant only to oxacillin, erythromycin, and, increasingly, levofloxacin. Of these, oxacillin and levofloxacin resistances are chromosomally encoded. Plasmid-mediated clindamycin, mupirocin, and/or tetracycline resistance has been observed among USA300 isolates, but these descriptions were limited to specific patient populations or isolated occurrences. We examined the antimicrobial susceptibilities of invasive MRSA isolates from a national surveillance population in order to identify USA300 isolates with unusual, possibly emerging, plasmid-mediated antimicrobial resistance. DNA from these isolates was assayed for the presence of resistance determinants and the presence of a pSK41-like conjugative plasmid. Of 823 USA300 isolates, 72 (9%) were tetracycline resistant; 69 of these were doxycycline susceptible and tetK positive, and 3 were doxycycline resistant and tetM positive. Fifty-one (6.2%) isolates were clindamycin resistant and ermC positive; 22 (2.7%) isolates were high-level mupirocin resistant (mupA positive); 5 (0.6%) isolates were trimethoprim-sulfamethoxazole (TMP-SMZ) resistant, of which 4 were dfrA positive; and 7 (0.9%) isolates were gentamicin resistant and aac6'-aph2'' positive. Isolates with pSK41-like plasmids (n = 24) were positive for mupA (n = 19), dfrA (n = 6), aac6'-aph2'' (n = 6), tetM (n = 2), and ermC (n = 8); 20 pSK41-positive isolates were positive for two or more resistance genes. Conjugative transfer of resistance was demonstrated between four gentamicin- and mupirocin-resistant and three gentamicin- and TMP-SMZ-resistant USA300 isolates; transconjugants harbored a single pSK41-like plasmid, which was PCR positive for aac6'-aph2'' and either mupA and/or dfrA. USA300 and USA100 isolates from the same state with identical resistance profiles contained pSK41-like plasmids with indistinguishable restriction and Southern blot profiles, suggesting horizontal plasmid transfer between USA100 and USA300 isolates.

Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings and are especially prevalent and problematic in intensive care units. Few antimicrobial treatment options remain for patients infected with the most resistant of these pathogens. Recent data shed light on the extent of the multidrug-resistant Gram-negative problem and suggest potential strategies to prevent transmission and improve clinical outcomes. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of healthcare-associated infections in critically ill patients, discusses issues regarding detection and recognition of these organisms, and reviews recommended methods to prevent patient-to-patient transmission of these formidable pathogens. Recent guidance from the Centers for Disease Control and Prevention for detection and control of carbapenemase-producing Enterobacteriaceae is discussed, along with potential strategies to optimize the existing antimicrobial treatment options for patients with multidrug-resistant Gram-negative infections.

Traditionally, pneumonia developing in patients who receive health care services in the outpatient environment, such as nursing homes, long-term care facilities, and dialysis centers, has been classified and treated as community-acquired pneumonia (CAP). Recent studies, however, have shown that this type of infection, known as health care-associated pneumonia (HCAP) is distinct from CAP in terms of its epidemiology and etiology, and increases the risk for infection with multidrug-resistant (MDR) pathogens. A review of available clinical data about HCAP was conducted to determine effective empiric treatment strategies and improve clinical outcomes. Analysis of multi-institutional clinical data showed that mortality associated with HCAP is higher than with CAP, suggesting that patients with HCAP may have been treated as hospitalized patients with CAP and received inappropriate initial empiric antibiotic treatment. All patients presenting to the hospital with suspected HCAP or CAP should be evaluated for their underlying risk of infection with MDR pathogens. Because HCAP may be similar to hospital-acquired pneumonia (HAP) both clinically and etiologically, it should be treated as HAP until culture data become available. A greater recognition of HCAP as a new class of pneumonia with a distinct epidemiologic, microbiologic, and clinical profile should lead physicians to initiate appropriate empiric antibiotic therapy more often, thereby improving the likelihood for optimal clinical outcomes and patient care.

Resistance to modern anthelmintics by ruminant nematode parasites is an increasing problem throughout the world. To date the problem has largely been reported in parasites of small ruminants, but there are increasing reports of such resistance in nematodes recovered from cattle. Until now there have been no published reports of drug resistant parasites from cattle in North America. In 2002 a producer in the upper Midwest who backgrounds young cattle acquired from the southeastern US experienced lower than expected weight gain as well as apparent parasitic gastroenteritis in his cattle during the fall. Fecal sample results supported the suspicion that decreased productivity and diarrhea were the result of GI nematode parasitism. The operation used intensive grazing management and practiced strategically timed deworming for >17 year. In 2003, all animals were dewormed the first week of May with Ivomec Plus, then with Dectomax Injectable on 4 June and 17 July. On 31 July, 10 randomly taken fecal samples showed EPG values from 0 to 55. To assess whether the apparent decreased drug efficacy was the result of drug resistance in the nematode population, on 18 August approximately 150 heads, previously strategic timed dewormed, of 9-11 month old cattle from one pasture were selected for study. The calves were randomly assigned to 1 of 6 treatment groups: untreated (U), ivermectin injectable (I), moxidectin pour-on (M), doramectin injectable (D), eprinomectin pour-on (E), albendazole oral (A). Cattle were weighed prior to treatment and the drug was dosed according to label directions. Seven days later, 3 calves from each group were slaughtered for worm recovery. Fecal samples taken from the remaining animals at 14 days after treatment showed that the reduction of mean fecal EPG value for each group was: U-46%, I-52%, M-72%, D-61%, E-8%, and A-68%. Worm recovery from the slaughter calves showed that all groups harbored significant numbers of Haemonchus placei and H. contortus. In addition, all avermectin-treated groups contained significant numbers of Cooperia punctata, and smaller numbers of C. oncophora and C. spatulata. These results imply that the pastures studied contain substantial numbers of H. contortus resistant to both avermectins and benzimidazoles, and H. placei and Cooperia sp. resistant to all the commonly used avermectin anthelmintics. This is the first report of anthelmintic resistance in American cattle parasites.

Toolkit created as "call to action to health care executives." Financial impact of MDROs should compel CEOs to get involved. Executives are "uniquely positioned" to contribute to the end of the era of antibiotic resistance.

As healthcare transitions to the home environment, there is an increasing need to prevent and control infections traced to telehealth equipment. Background information about infection control is presented, and the need for a survey of agency cleaning policies is described. Findings from 31 agencies using telehealth equipment are described followed by suggested Best Practice Guidelines for the cleaning of telehealth equipment.

Background: The World Health Organization (WHO) recommends that tuberculosis (TB) patients receive directly observed therapy (DOT). Randomized controlled trials have not consistently shown that this practice improves TB treatment success rates. In Thailand, one of 22 WHO-designated high burden TB countries, patients may have TB treatment observed by a health care worker (HCW), family member, or no one. We studied whether DOT improved TB treatment outcomes in a prospective, observational cohort., Methods and Findings: We prospectively collected epidemiologic data about TB patients treated at public and private facilities in four provinces in Thailand and the national infectious diseases hospital from 2004-2006. Public health staff recorded the type of observed therapy that patients received during the first two months of TB treatment. We limited our analysis to pulmonary TB patients never previously treated for TB and not known to have multidrug-resistant TB. We analyzed the proportion of patients still on treatment at the end of two months and with treatment success at the end of treatment according to DOT type. We used propensity score analysis to control for factors associated with DOT and treatment outcome. Of 8,031 patients eligible for analysis, 24% received HCW DOT, 59% family DOT, and 18% self-administered therapy (SAT). Smear-positive TB was diagnosed in 63%, and 21% were HIV-infected. Of patients either on treatment or that defaulted at two months, 1601/1636 (98%) patients that received HCW DOT remained on treatment at two months compared with 1096/1268 (86%) patients that received SAT (adjusted OR [aOR] 3.8; 95% confidence interval [CI] 2.4-6.0) and 3782/3987 (95%) patients that received family DOT (aOR 2.1; CI, 1.4-3.1). Of patients that had treatment success or that defaulted at the end of treatment, 1369/1477 (93%) patients that received HCW DOT completed treatment compared with 744/1074 (69%) patients that received SAT (aOR 3.3; CI, 2.4-4.5) and 3130/3529 (89%) patients that received family DOT (aOR 1.5; 1.2-1.9). The benefit of HCW DOT compared with SAT was similar, but smaller, when comparing patients with treatment success to those with death, default, or failure., Conclusions: In Thailand, two months of DOT was associated with lower odds of default during treatment. The magnitude of benefit was greater for DOT provided by a HCW compared with a family member. Thailand should consider increasing its use of HCW DOT during TB treatment.

(1) The choice of treatment for HIV-infected patients in whom several lines of antiretroviral therapy have failed is particularly difficult. Some antiretroviral drugs (enfuvirtide and some HIV protease inhibitors) remain effective, at least in the short term. (2) Maraviroc is the first CCR5 antagonist to be licensed for use in this setting. It acts by blocking one of the two coreceptors, CCR5, needed for HIV entry into CD4+ lymphocytes. It is approved for use in HIV-infected patients with multiple antiretroviral failure. (3) Two double-blind placebo-controlled trials including 1076 patients infected by HIV strains using only the CCR5 coreceptor tested the effect of adding maraviroc at a dose of 300 mg twice a day to an optimised treatment. After 8 weeks, maraviroc was more effective than placebo in reducing viral load (undetectable in 45.5% versus 16.7% of patients) and in increasing the CD4+ cell count (+124 cells/mm3 versus +61 cells/mm3); both of these differences are statistically significant. (4) After treatment with maraviroc, 50% to 60% of patients harboured viruses that did not exclusively rely on CCR5 for host cell entry. The possible clinical consequences of this change in tropism are unclear. (5) A double-blind trial of maraviroc included 190 patients with multiple antiretroviral failure who were infected by HIV variants not requiring CCR5 for host cell entry; maraviroc was not shown to be effective. (6) Data obtained with other CCR5 antagonists, and preclinical data obtained with maraviroc, point to a possible increase in the risk of hepatitis, infections, cancer, and QT prolongation. More data are also needed concerning the risk of muscle toxicity and ischaemic cardiovascular events. (7) Maraviroc is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of interactions with CYP 3A4 inducers and inhibitors. (8) In practice, given the absence of long-term evaluation, clinical assessment of maraviroc is too limited to recommend the use of this drug outside the clinical trial setting.

Mortality from battlefield wounds has historically declined, thanks to better surgical management, faster transport of casualties, and improved antibiotics. Today, one of the major challenges facing U.S. military caregivers is the presence of multidrug-resistant organisms in orthopaedic extremity wounds. The most frequently identified resistant strains of bacteria are Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter calcoaceticus-baumannii complex. Overuse of broad-spectrum antibiotics may be an important factor in building resistant strains. Acinetobacter infections appear to hospital-acquired and not from an initial colonization of the injury. More research is required to give military physicians the tools they require to reduce the infection rate and defeat multidrug-resistant organisms.

A strategy to combat multidrug-resistant (MDR) Salmonella in ground beef is urgently needed. A national multi-disciplinary meeting reviewed the epidemiology of MDR Salmonella infection and contamination in humans, animals, and retail meat. In spite of a recent overall decrease in human MDR Salmonella isolates, certain types, such as Salmonella enterica serotype Newport multidrug-resistant-AmpC strain and Salmonella enterica serotype Typhimurium definitive type (DT) 104, have persisted, and several recent large outbreaks of human infection have occurred. Key agencies that contribute to a safe ground beef supply were represented at the meeting and contributed to the discussion of possible control strategies from the farm to the table. Several of the control strategies suggested are unpopular to some, including restricting the use of antimicrobial agents in food animals, designation of multidrug-resistant Salmonella as an adulterant in ground beef, and improving the mechanisms for product trace-back investigations. Nevertheless, enhanced farm-based animal infection control, judicious veterinary and human antibiotic use, regulatory controls, and consumer practices will lead to important industry, veterinary, and public health outcomes.

Shigella spp. infect approximately 450,000 persons annually in the United States, resulting in over 6,000 hospitalizations. Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th Shigella isolate from 16 state or local public health laboratories for susceptibility to 15 antimicrobial agents. From 1999 to 2002, NARMS tested 1,604 isolates. Among 1,598 isolates identified to species level, 1,278 (80%) were Shigella sonnei, 295 (18%) were Shigella flexneri, 18 (1%) were Shigella boydii, and 7 (0.4%) were Shigella dysenteriae. Overall, 1,251 (78%) were resistant to ampicillin and 744 (46%) were resistant to trimethoprim-sulfamethoxazole (TMP-SMX). Prevalence of TMP-SMX- or ampicillin- and TMP-SMX-resistant Shigella sonnei isolates varied by geographic region, with lower rates in the South and Midwest regions (TMP-SMX resistance, 27% and 30%, respectively; ampicillin and TMP-SMX resistance, 25% and 22%, respectively) and higher rates in the East and West regions (TMP-SMX resistance, 66% and 80%, respectively; ampicillin and TMP-SMX resistance, 54% and 65%, respectively). Nineteen isolates (1%) were resistant to nalidixic acid (1% of S. sonnei and 2% of S. flexneri isolates); 12 (63%) of these isolates had decreased susceptibility to ciprofloxacin. One S. flexneri isolate was resistant to ciprofloxacin. All isolates were susceptible to ceftriaxone. Since 1986, resistance to ampicillin and TMP-SMX has dramatically increased. Shigella isolates in the United States remain susceptible to ciprofloxacin and ceftriaxone.

Treatment of uncomplicated urinary tract infections (UTIs) has changed in the past few years with researchers advocating empiric treatment for shorter periods of time without the use of cultures. Researchers report that antibiotic resistance of Escherichia coli (E. coli) to commonly prescribed antibiotics in uncomplicated UTIs has been increasing. Trimethoprim/sulfamethoxazole (TMP/SMX) is 1 of these antibiotics. Researchers also report that resistance patterns may differ depending on the geographic area of the United States. In this study, the authors present the results of a 7-month retrospective chart analysis of 98 E. coli sensitivities to commonly prescribed antibiotics in the treatment of uncomplicated UTIs at a college health service. They examined the more common antibiotic choices and analyzed their in vitro responses. Of these antibiotics, ciprofloxacin, nitrofurantoin, amoxicillin/clavulanate, and TMP/SMX had the highest sensitivity rates. The authors compared the results with a previous study that they performed at the same institution in 1993. The results of this study show a sensitivity rate of 86% for TMP/SMX. When compared with the previous result of 87%, this represented a 1% change. Because of this slight decrease in sensitivity and the increasing concern over resistance, the authors suggest that they will continue to reevaluate the resistance pattern in their population on a regular basis. This will help determine if there is a need for modifying choices of empiric therapy for UTIs.

The need for new antimicrobial agents is greater than ever because of the emergence of multidrug resistance in common pathogens, the rapid emergence of new infections, and the potential for use of multidrug-resistant agents in bioweapons. Paradoxically, some pharmaceutical companies have indicated that they are curtailing anti-infective research programs. We evaluated the United States Food and Drug Administration (FDA) databases of approved drugs and the research and development programs of the world's largest pharmaceutical and biotechnology companies to document trends in the development of new antimicrobial agents. FDA approval of new antibacterial agents decreased by 56% over the past 20 years (1998-2002 vs. 1983-1987). Projecting future development, new antibacterial agents constitute 6 of 506 drugs disclosed in the developmental programs of the largest pharmaceutical and biotechnology companies. Despite the critical need for new antimicrobial agents, the development of these agents is declining. Solutions encouraging and facilitating the development of new antimicrobial agents are needed.

Background: Pediatric infections caused by resistant Gram-positive infections are an increasing concern with limited treatment options. Linezolid, a new oxazolidinone, is active against staphylococci, streptococci and enterococci., Objective: To assess clinical efficacy and safety of linezolid vs.vancomycin in antibiotic-resistant Gram-positive infections in children. DESIGN Hospitalized children (birth to 12 years of age) with nosocomial pneumonia, complicated skin/skin structure infections, catheter-related bacteremia, bacteremia of unknown source or other infections caused by Gram-positive bacteria were randomized 2:1 to receive linezolid intravenously followed by oral linezolid or vancomycin and then by an appropriate oral agent. Treatment duration was 10 to 28 days., Results: There were 321 patients enrolled (linezolid 219, vancomycin 102). Clinical cure rates were 79% vs.74% (P = 0.36) and 89% vs.85% (P = 0.31) for linezolid and vancomycin in intent-to-treat and clinically evaluable patients, respectively. Cure rates were similar by age and infection diagnosis. Pathogen eradication rates in microbiologically evaluable patients were high for linezolid and vancomycin, respectively, for methicillin-susceptible S. aureus (95% vs.94%; P = 0.82), methicillin-resistant S. aureus (88% vs.90%; P = 0.89) and methicillin-resistant coagulase-negative staphylococci (85% vs.83%, P = 0.87). In clinically evaluable patients, linezolid-treated patients required significantly fewer days of intravenous therapy compared with vancomycin-treated patients (8.0 +/- 4.8; 10.9 +/- 5.8 days, respectively; P < 0.001). In addition significantly fewer linezolid-treated patients had drug-related adverse events than did vancomycin-treated patients (19% vs.34%, respectively; P = 0.003). Hematologic events were uncommon and similar between treatment groups., Conclusions: Linezolid was well-tolerated and as effective as vancomycin in treating serious Gram-positive infections in children.

Background: Increasing macrolide resistance among middle ear isolates complicates treatment of otitis media in children. When macrolide resistance is mediated via an efflux pump (M phenotype), the MICs of erythromycin, clarithromycin and azithromycin are usually below 32 microg/ml, and the pneumococcus remains susceptible to clindamycin. The association of prior specific macrolide therapy with the isolation of a macrolide resistant strain has not been reported., Objectives: To determine the mechanism of macrolide resistance in Streptococcus pneumoniae recovered from the middle ears of children with otitis media and their association, if any, with ethnicity, age, serogroup/serotype and prior antibiotic therapy., Methods: Middle ear isolates collected by members of the United States Pediatric Multicenter Pneumococcal Surveillance Group during a 6-year period from September 1994 through August 2000 were studied. Antibiotic susceptibility to penicillin and ceftriaxone was determined by microbroth dilution. Disc diffusion susceptibility to erythromycin and clindamycin was performed to categorize macrolide resistance mechanisms. The medical record was reviewed to determine demographics and history of previous antibiotic therapy. Isolates were serogrouped or serotyped by the capsular swelling method., Results: Of the 1088 isolates available for testing, 51% were nonsusceptible to penicillin and 37% were nonsusceptible to erythromycin. Erythromycin resistance increased form 15% in 1994 through 1995 to 56% in 1999 through 2000. Seventy-five percent of macrolide-resistant strains were M phenotype. Macrolide resistance was less likely in isolates recovered from African-Americans and more likely in isolates obtained from children <3 years of age and from isolates obtained at time of tympanostomy tube placement. Neither erythromycin, nor clarithromycin nor azithromycin prescribed in the 30 days before infection was more likely than another to be associated with increased macrolide resistance. However, any macrolide alone or in combination with another antimicrobial taken before infection was associated with increased macrolide resistance among the S. pneumoniae organisms isolated from the middle ear., Conclusions: Macrolide resistance among middle ear isolates of S. pneumoniae increased during the 6-year study. The proportion of M phenotype remained constant at 75%, meaning that these isolates remain susceptible to clindamycin. Continued surveillance to document potential changes is essential.

Along with the successes in improving the survival of preterm neonates have come changes in the epidemiology of pathogens that cause healthcare-associated infections. Although gram-negative bacilli and group B streptococci predominated in past years, gram-positive organisms such as staphylococci and enterococci have since taken on greater roles. This shift has been accompanied by difficulties in defining optimal treatments for these pathogens because of emerging resistance patterns.

Klebsiella pneumoniae is medically the most important organism of the Klebsiella species. It is responsible for a significant proportion of hospital-acquired infections including septicemias, urinary tract infections, pneumonia, and soft tissue infections especially in the immunocompromised hosts such as the neonate. The hands of healthcare workers and the gastrointestinal tract of hospitalized infants serve as reservoirs for the transmission of the organism and are responsible for multiple hospital outbreaks. In recent years, there has been an increase in the incidence of outbreaks caused by multidrug resistance K. pneumoniae organisms or the extended spectrum beta-lactamase (ESBL)-producing K. pneumoniae. The problems associated with extended spectrum beta-lactamase-producing organisms include difficulties in accurate antimicrobial susceptibility testing, limited treatment options and increased morbidity and perhaps mortality. Hence, prevention through implementation of strict infection control guidelines, effective hand washing and judicious use of antimicrobials such as third generation cephalosporins is important to effectively reduce the morbidity associated with this infection.

Change in the susceptibility of bacterial pathogens to antimicrobial agents is constant. The efficacy of a new drug may change as it is used in clinical settings, and resistant bacterial clones result from the encounter of drug and organism. Soon after the introduction of the sulfonamides in the mid-1930s, the first effective agents of the antimicrobial era, resistance of pneumococci and group A streptococci was evident. In each of the following decades, a different problem in multidrug resistance occurred among common bacterial pathogens: beta-lactamase-producing staphylococci in the 1950s; highly resistant gram-negative enteric bacteria in the 1960s; beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis in the 1970s; and multidrug-resistant pneumococci in the 1980s. Antimicrobial resistance among respiratory pathogens is now a common clinical problem throughout the world, and its management is a part of routine office practice. Currently in the United States, about 25% of pneumococci are resistant to penicillin, and 25% of H influenzae and 90% of M catarrhalis produce beta-lactamase and would be inactivated by organisms producing the enzyme. The emergence of penicillin and multidrug-resistant pneumococci and beta-lactamase-producing strains of H influenzae and M catarrhalis have special importance for the management of infections of the middle ear. The widespread use of oral and parenteral antimicrobial drugs for appropriate and inappropriate uses has driven the emergence and spread of resistant organisms. This article discusses current susceptibility patterns of organisms involved in middle ear infections, risk factors associated with development of resistant strains, strategies for limiting the incidence and spread of resistant organisms and, as part of the strategy, use of ototopical rather than systemic antimicrobial drugs for chronic suppurative otitis media (CSOM) and acute otitis media (AOM) in children with tympanostomy tubes. Although many ototopical agents are approved by the Food and Drug Administration for the indication of otitis externa, only ofloxacin otic is approved for treatment of CSOM in patients older than 12 years of age and AOM in children with tympanostomy tubes who are 1 year of age or older.

Infants in the neonatal intensive care unit (NICU) have many risk factors for infection. Compared with older children and adults, infants, particularly premature infants, are relatively immunocompromised. Patients in the NICU have intrinsic risk factors for infections due to immunological "deficiencies" or inadequate development of mechanical barriers such as skin and gastrointestinal tract mucosa. Like other ICU populations, NICU patients have extrinsic risk factors for infection such as prolonged hospitalization, invasive procedures, instrumentation, medical treatments and concomitant medical conditions. Compared with healthy full-term infants, patients in the NICU develop abnormal flora, which is generally acquired in the NICU from patient-to-patient transmission via hand carriage of healthcare workers. This flora is frequently multidrug-resistant as it has developed under the selective pressure of antibiotics and can cause invasive disease. An understanding of the risk factors that are associated with hospital-acquired infections is essential to design preventive strategies.

A total of 1,531 recent clinical isolates of Streptococcus pneumoniae were collected from 33 medical centers nationwide during the winter of 1999--2000 and characterized at a central laboratory. Of these isolates, 34.2% were penicillin nonsusceptible (MIC > or = 0.12 microg/ml) and 21.5% were high-level resistant (MIC > or = 2 microg/ml). MICs to all beta-lactam antimicrobials increased as penicillin MICs increased. Resistance rates among non-beta-lactam agents were the following: macrolides, 25.2 to 25.7%; clindamycin, 8.9%; tetracycline, 16.3%; chloramphenicol, 8.3%; and trimethoprim-sulfamethoxazole (TMP-SMX), 30.3%. Resistance to non-beta-lactam agents was higher among penicillin-resistant strains than penicillin-susceptible strains; 22.4% of S. pneumoniae were multiresistant. Resistance to vancomycin and quinupristin-dalfopristin was not detected. Resistance to rifampin was 0.1%. Testing of seven fluoroquinolones resulted in the following rank order of in vitro activity: gemifloxacin > sitafloxacin > moxifloxacin > gatifloxacin > levofloxacin = ciprofloxacin > ofloxacin. For 1.4% of strains, ciprofloxacin MICs were > or = 4 microg/ml. The MIC(90)s (MICs at which 90% of isolates were inhibited) of two ketolides were 0.06 microg/ml (ABT773) and 0.12 microg/ml (telithromycin). The MIC(90) of linezolid was 2 microg/ml. Overall, antimicrobial resistance was highest among middle ear fluid and sinus isolates of S. pneumoniae; lowest resistance rates were noted with isolates from cerebrospinal fluid and blood. Resistant isolates were most often recovered from children 0 to 5 years of age and from patients in the southeastern United States. This study represents a continuation of two previous national studies, one in 1994--1995 and the other in 1997--1998. Resistance rates with S. pneumoniae have increased markedly in the United States during the past 5 years. Increases in resistance from 1994--1995 to 1999--2000 for selected antimicrobial agents were as follows: penicillin, 10.6%; erythromycin, 16.1%; tetracycline, 9.0%; TMP-SMX, 9.1%; and chloramphenicol, 4.0%, the increase in multiresistance was 13.3%. Despite awareness and prevention efforts, antimicrobial resistance with S. pneumoniae continues to increase in the United States.

As part of the SENTRY Antimicrobial Surveillance Program, a total of 1078 Acinetobacter species and 842 Stenotrophomonas maltophilia isolates were collected between January 1997 and December 1999 from 5 geographic regions (Canada, the United States, Latin America, Europe, and the Asia-Pacific). The frequency of infections (by geographic region and body site), including those due to imipenem-resistant Acinetobacter species and trimethoprim-sulfamethoxazole (TMP-SMZ)-resistant S. maltophilia, was evaluated. The possibility of seasonal variations in bloodstream infections caused by Acinetobacter species was studied, as was the activity of several therapeutic antimicrobials against all strains. Acinetobacter species and S. maltophilia were most frequently associated with pulmonary infections, independent of the region evaluated. In contrast, patterns of antimicrobial resistance markedly varied among distinct geographic regions, especially for nosocomial isolates. Although the carbapenems were the most active antimicrobials against Acinetobacter species, nearly 11.0% of the nosocomial isolates were resistant to this drug group in both regions. TMP-SMZ, ticarcillin-clavulanic acid, gatifloxacin, and trovafloxacin were the only agents with consistent therapeutic activity against S. maltophilia isolates. Rates of resistance to TMP-SMZ ranged from 2% in Canada and Latin America to 10% in Europe. The geographic differences in resistance patterns among Acinetobacter species and S. maltophilia isolates observed in this study emphasize the importance of local surveillance in determining the most adequate therapy for acinetobacter and S. maltophilia infections and the possible clonal, epidemic nature of occurrence.