At the beginning of the 21st century, antimicrobial resistance is common, has developed against every class of antimicrobial drug, and appears to be spreading into new clinical niches. We describe determinants likely to influence the future epidemiology and health impact of antimicrobial-resistant infections. Understanding these factors will ultimately optimize preventive strategies for an unpredictable future.

Community-acquired respiratory tract infections (RTIs) account for a substantial proportion of outpatient antimicrobial drug prescriptions worldwide. Concern over the emergence of multidrug resistance in pneumococci has largely been focused on penicillin-resistant Streptococcus pneumoniae. Macrolide antimicrobial drugs have been widely used to empirically treat community-acquired RTIs because of their efficacy in treating both common and atypical respiratory pathogens, including S. pneumoniae. However, increased macrolide use has been associated with a global increase in pneumococcal resistance, which is leading to concern over the continued clinical efficacy of the macrolides to treat community-acquired RTIs. We provide an overview of macrolide-resistant S. pneumoniae and assess the impact of this resistance on the empiric treatment of community-acquired RTIs.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has rarely been reported in the hospital setting. We report an outbreak of 7 cases of skin and soft tissue infections due to a strain of CA-MRSA. All patients were admitted to the labor and delivery, nursery, or maternity units during a 3-week period. Genetic fingerprinting showed that the outbreak strain was closely related to the USA 400 strain that includes the midwestern strain MW2. All isolates contained the staphylococcal chromosome cassette mec type IV. Genes for Panton-Valentine leukocidin and staphylococcal enterotoxin K were detected in all isolates, and most contained other enterotoxin genes. Testing of nearly 2,000 MRSA isolates collected during citywide surveillance studies from 1999 to 2003 showed that ≈1% were genetically related to MW2. CA-MRSA strain MW2 has been present in this region at least since 1999. This study documents the spread of this strain among healthy newborns at 1 hospital.

Fluoroquinolone resistance in Streptococcus pneumoniae is primarily mediated by point mutations in the quinolone resistance–determining regions of gyrA and parC. Antimicrobial resistance mutations in housekeeping genes often decrease fitness of microorganisms. To investigate the fitness of quinolone-resistant S. pneumoniae (QRSP), the relative growth efficiencies of 2 isogenic QRSP double mutants were compared with that of their fluoroquinolone-susceptible parent, EF3030, by using murine nasopharyngeal colonization and pneumonia models. Strains containing the GyrA: Ser81Phe, ParC: Ser79Phe double mutations, which are frequently seen in clinical QRSP, competed poorly with EF3030 in competitive colonization or competitive lung infections. However, they efficiently produced lung infection even in the absence of EF3030. The strain containing the GyrA: Ser81Phe, ParC: Ser79Tyr double mutations, which is seen more frequently in laboratory-derived QRSP than in clinical QRSP, demonstrated reduced nasal colonization in competitive or noncompetitive lung infections. However, the strain was equally able to cause competitive or noncompetitive lung infections as well as EF3030.

Vancomycin-resistant enterococci (VRE) have caused hospital outbreaks worldwide, and the vancomycin-resistance gene (vanA) has crossed genus boundaries to methicillin-resistant Staphylococcus aureus. Spread of VRE, therefore, represents an immediate threat for patient care and creates a reservoir of mobile resistance genes for other, more virulent pathogens. Evolutionary genetics, population structure, and geographic distribution of 411 VRE and vancomycin-susceptible Enterococcus faecium isolates, recovered from human and nonhuman sources and community and hospital reservoirs in 5 continents, identified a genetic lineage of E. faecium (complex-17) that has spread globally. This lineage is characterized by 1) ampicillin resistance, 2) a pathogenicity island, and 3) an association with hospital outbreaks. Complex-17 is an example of cumulative evolutionary processes that improved the relative fitness of bacteria in hospital environments. Preventing further spread of this epidemic E. faecium subpopulation is critical, and efforts should focus on the early disclosure of ampicillin-resistant complex-17 strains.

We investigated the association between prescribing antimicrobial agents and antimicrobial resistance of Streptococcus pneumoniae among children with acute otitis media in southern Israel. During a 6-year period, all prescriptions of a sample of ≈20% of Jewish and Bedouin children <5 years of age were recorded and all pneumococcal isolates from middle ear fluid were collected. Although antimicrobial drug use was significantly higher in Bedouin children, the proportion of S. pneumoniae isolates with penicillin MIC ≥1.0 μg/mL was significantly higher in Jewish children. In both populations, antimicrobial prescriptions were markedly reduced over time, especially for penicillins and erythromycin. In contrast, azithromycin prescriptions increased from 1998 to 2001 with a parallel increase in macrolide and multidrug resistance. Penicillin resistance was associated with macrolide resistance. These findings strongly suggest that azithromycin affects increased antimicrobial resistance, including multidrug resistance, in S. pneumoniae.

The plasmid pVir may play a role in the virulence of Campylobacter jejuni, a leading cause of bacterial gastroenteritis. The pVir plasmid was identified in 17% of 104 C. jejuni clinical isolates studied and was significantly associated with the occurrence of blood in patient stool, a marker of invasive infection. The pVir plasmid was not associated with greater occurrence of diarrhea, fever, pain, vomiting, or need for patient hospitalization. Isolates containing pVir were also associated with the presence of a tetracycline-resistance plasmid, but pVir did not transfer with tetracycline-resistance plasmids to recipient strains of C. jejuni. The association of pVir and bloody stool suggests that pVir may be clinically relevant in C. jejuni infections.

A total of 184 methicillin-resistant Staphylococcus aureus (MRSA) strains were collected from patients who sought treatment primarily for skin and soft tissue infections from January 1, 1999, to March 31, 2002, in east-central Saskatchewan, Canada. Molecular subtyping analysis using pulsed-field gel electrophoresis showed 2 major clusters. Cluster A (n = 55) was composed of a multidrug-resistant MRSA strain associated with a long-term care facility and was similar to the previously reported nosocomial Canadian epidemic strain labeled CMRSA-2. Cluster B (n = 125) was associated with cases identified at community health centers and was indistinguishable from a community-associated (CA)-MRSA strain identified previously in the United States (USA400). Cluster B remained susceptible to a number of classes of antimicrobial agents and harbored the lukF-PV and lukS-PV toxin genes. Over 50% of both clonal groups displayed high-level resistance to mupirocin. This is the first report of the USA400 strain harboring the lukF-PV and lukS-PV toxin genes in Canada.

Streptococcus pneumoniae isolates (N = 31,001) were collected from patients with community-acquired respiratory tract infections during the PROTEKT US surveillance study (2000–2003). While the macrolide (erythromycin) resistance rate remained stable at ≈29%, the prevalence of resistant isolates containing both erm(B) and mef(A) increased from 9.7% in year 1 to 16.4% in year 3, with substantial regional variability. Almost all (99.2%) dual erm(B)+mef(A) macrolide-resistant isolates exhibited multidrug resistance, whereas 98.6% and 99.0% were levofloxacin- and telithromycin-susceptible, respectively. These strains were most commonly isolated from the ear or middle-ear fluid of children. Of 152 representative erm(B)+mef(A) isolates, >90% were clonally related to the multidrug-resistant international Taiwan^19F-14 clonal complex 271 (CC271). Of 366 erm(B)+mef(A) isolates from the PROTEKT global study (1999–2003), 83.3% were CC271, with the highest prevalence seen in South Africa, South Korea, and the United States. This study confirms the increasing global emergence and rapidly increasing US prevalence of this multidrug-resistant pneumococcal clone.

The incidence of multidrug-resistant (MDR) Salmonella Typhimurium infections in humans, and in particular MDR definitive phage type 104 (DT104), has increased substantially in many countries in the last 2 decades, often associated with increased illness. To examine the magnitude of this problem, a survey was conducted among countries with available antimicrobial resistance or phage typing surveillance data. A total of 29, primarily industrialized, countries participated in the survey, which covered the years 1992–2001. Overall, the incidence of MDR S. Typhimurium and DT104 increased continuously during this period, although the problem affected primarily Europe and North America. The increase appeared to have peaked in the United Kingdom but not in other countries. Also, the incidence of quinolone-resistant S. Typhimurium was increasing. This survey implies that MDR S. Typhimurium constitutes an increasing public health problem in large parts of the world and emphasizes the importance of surveillance and control programs.

Methicillin-resistant Staphylococcus aureus (MRSA) is increasingly a cause of nosocomial and community-onset infection with unknown national scope and magnitude. We used the National Hospital Discharge Survey to calculate the number of US hospital discharges listing S. aureus–specific diagnoses, defined as those having at least 1 International Classification of Diseases (ICD)-9 code specific for S. aureus infection. The number of hospital discharges listing S. aureus-specific diagnoses was multiplied by the proportion of methicillin resistance for each corresponding infection site to determine the number of MRSA infections. From 1999 to 2000, an estimated 125,969 hospitalizations with a diagnosis of MRSA infection occurred annually, including 31,440 for septicemia, 29,823 for pneumonia, and 64,706 for other infections, accounting for 3.95 per 1,000 hospital discharges. The method used in our analysis may provide a simple way to assess trends of the magnitude of MRSA infection nationally.

Collaboration between networks presents opportunities to increase analytical power and cross-validate findings. Multivariate analyses of 2 large, international datasets (MYSTIC and SENTRY) from the Global Advisory on Antibiotic Resistance Data program explored temporal, geographic, and demographic trends in Escherichia coli resistance from 1997 to 2001. Elevated rates of nonsusceptibility were seen in Latin America, southern Europe, and the western Pacific, and lower rates were seen in North America. For most antimicrobial drugs considered, nonsusceptibility was higher in isolates from men, older patients, and intensive care unit patients. Nonsusceptibility to ciprofloxacin was higher in younger patients, rose with time, and was not associated with intensive care unit status. In univariate analyses, estimates of nonsusceptibility from MYSTIC were consistently higher than those from SENTRY, but these differences disappeared in multivariate analyses, which supports the epidemiologic relevance of findings from the 2 programs, despite differences in surveillance strategies.

We investigated in a sample of Latinos the practices of antimicrobial drug importation and use of nonprescribed antimicrobial drugs. In interviews conducted with 219 adults, we assessed health beliefs and past and present behaviors consistent with acquiring antimicrobial drugs without a prescription in the United States. Many (30.6%) believed that antimicrobial drugs should be available in the United States without a prescription. Furthermore, 16.4% had transported nonprescribed antimicrobial drugs into the United States, and 19.2% had acquired antimicrobial agents in the United States without a prescription. A stepwise logistic regression analysis showed that the best predictors of having acquired nonprescribed antimicrobial drugs in the United States were beliefs and behavior consistent with limited regulations on such drugs. Many persons within the Latino community self-medicate with antimicrobial drugs obtained without a prescription both inside and outside the United States, which adds to the reservoir of antimicrobial drugs in the United States.

We conducted a cross-sectional study to determine the prevalence of, and risk factors for, colonization with fluoroquinolone (FQ)-resistant Escherichia coli in residents in a long-term care facility. FQ-resistant E. coli were identified from rectal swabs for 25 (51%) of 49 participants at study entry. On multivariable analyses, prior FQ use was the only independent risk factor for FQ-resistant E. coli carriage and was consistent for FQ exposures in the previous 3, 6, 9, or 12 months. Pulsed-field gel electrophoresis of FQ-resistant E. coli identified clonal spread of 1 strain among 16 residents. Loss (6 residents) or acquisition (7 residents) of FQ-resistant E. coli was documented and was associated with de novo colonization with genetically distinct strains. Unlike the case in the hospital setting, FQ-resistant E. coli carriage in long-term care facilities is associated with clonal spread.

The impact and prevalence of antimicrobial drug resistance in rural community healthcare settings is uncertain. Prospective surveillance in 51 rural hospitals in Idaho and Utah examined the epidemiologic features of clinical cases of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Thirty-two cases of VRE were reported; for 6, the patient had no prior healthcare exposure or coexisting condition. Among the 724 MRSA cases available for evaluation, 405 (56%) were healthcare-associated (HA-MRSA), and 319 (44%) were community-associated (CA-MRSA). The characteristics of HA-MRSA and CA-MRSA patients with coexisting factors were similar, which suggests community transmission of healthcare strains. CA-MRSA cases without coexisting factors, however, demonstrated features previously reported for community strains. MRSA infections were substantially more frequent than VRE in rural communities in the western United States. Based on epidemiologic criteria, a large proportion of MRSA cases were community-associated. CA-MRSA rates were predictive of institutional MRSA rates.

In 1999, Wisconsin initiated an educational campaign for primary care clinicians and the public to promote judicious antimicrobial drug use. We evaluated its impact on clinician knowledge and beliefs; Minnesota served as a control state. Results of pre- (1999) and post- (2002) campaign questionnaires indicated that Wisconsin clinicians perceived a significant decline in the proportion of patients requesting antimicrobial drugs (50% in 1999 to 30% in 2002; p<0.001) and in antimicrobial drug requests from parents for children (25% in 1999 to 20% in 2002; p = 0.004). Wisconsin clinicians were less influenced by nonpredictive clinical findings (purulent nasal discharge [p = 0.044], productive cough [p = 0.010]) in terms of antimicrobial drug prescribing. In 2002, clinicians from both states were less likely to recommend antimicrobial agent treatment for the adult case scenarios of viral respiratory illness. For the comparable pediatric case scenarios, only Wisconsin clinicians improved significantly from 1999 to 2002. Although clinicians in both states improved on several survey responses, greater overall improvement occurred in Wisconsin.

The Wisconsin Antibiotic Resistance Network (WARN) was launched in 1999 to educate physicians and the public about judicious antimicrobial drug use. Public education included radio and television advertisements, posters, pamphlets, and presentations at childcare centers. Physician education included mailings, susceptibility reports, practice guidelines, satellite conferences, and presentations. We analyzed antimicrobial prescribing data for primary care physicians in Wisconsin and Minnesota (control state). Antimicrobial prescribing declined 19.8% in Minnesota and 20.4% in Wisconsin from 1998 to 2003. Prescribing by internists declined significantly more in Wisconsin than Minnesota, but the opposite was true for pediatricians. We conclude that the secular trend of declining antimicrobial drug use continued through 2003, but a large-scale educational program did not generate greater reductions in Wisconsin despite improved knowledge. State and local organizations should consider a balanced approach that includes limited statewide educational activities with increasing emphasis on local, provider-level interventions and policy development to promote careful antimicrobial drug use.

Recently, a high proportion of patients with late-stage Trypanosoma brucei gambiense trypanosomiasis, who had been treated with melarsoprol in some disease-endemic areas, subsequently relapsed. To determine whether the frequency of postmelarsoprol relapses increased over time, we reviewed data from 2,221 trypanosomiasis patients treated with melarsoprol during this period in Nioki, Democratic Republic of Congo, from 1982 to 2001. The frequency of relapses was 5.6%(31/553), 6.8%(35/512), 4.5%(18/398), 11.4%(34/299), and 5.0%(17/343) for those treated from 1982 to 1985, 1986 to 1989, 1990 to 1993, 1994 to 1997, and 1998 to 2001, respectively. The higher frequency of relapses in 1994 to 1997 was associated with an incremental dosage regimen of melarsoprol. In multivariate analysis, after adjustment for treatment regimen, sex, residence, and trypanosomes in cerebrospinal fluid, postmelarsoprol relapses did not increase in Nioki, perhaps because 1) little drug pressure exists; 2) subtherapeutic doses have rarely been administered; 3) little potential exists for the preferential transmission of melarsoprol-resistant strains.

Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is the most common pathogen among patients with skin and soft tissue infections seeking treatment at a Los Angeles (USA) area emergency department. The proportion caused by MRSA increased from 29% in 2001 to 2002 to 64% in 2003 to 2004. No clinical or historical features reliably predict MRSA etiology.

Mycobacterium tuberculosis isolates cultured from 6 patients associated with an isoniazid-resistant M. tuberculosis outbreak acquired rifampicin resistance. The rpoB gene sequence showed that resistance was associated with rare mutations in each isolate. Three isolates had a mutation outside the rifampicin resistance–determining region.

We describe antimicrobial resistance among Escherichia coli isolated from free-living Canada Geese in Georgia and North Carolina (USA). Resistance patterns are compared to those reported by the National Antimicrobial Resistance Monitoring System. Canada Geese may be vectors of antimicrobial resistance and resistance genes in agricultural environments.

We found a 13% macrolide resistance in 3,866 Streptococcus pyogenes isolated from tonsillopharyngitis patients; 59% macrolide-resistant isolates were distributed in 5 clones, suggesting the importance of both resistance gene transfer and clonal dissemination in the spread of these organisms. We also report one of the largest collections of telithromycin-resistant isolates.

Few studies have evaluated the health consequences of antimicrobial-resistant Salmonella strains associated with outbreaks. Among 32 outbreaks occurring in the United States from 1984 to 2002, 22% of 13,286 persons in 10 Salmonella-resistant outbreaks were hospitalized, compared with 8% of 2,194 persons in 22 outbreaks caused by pansusceptible Salmonella strains (p<0.01).

We report the prevalence and characteristics of Salmonella strains resistant to ciprofloxacin and extended-spectrum cephalosporins in Taiwan from January to May 2004. All isolates resistant to extended-spectrum cephalosporins carried bla_CMY-2, and all ciprofloxacin-resistant Salmonella enterica serotype Choleraesuis isolates were genetically related.

Emergence of the newly identified 16S rRNA methylases RmtA, RmtB, and ArmA in pathogenic gram-negative bacilli has been a growing concern. ArmA, which had been identified exclusively in Europe, was also found in several gram-negative pathogenic bacilli isolated in Japan, suggesting global dissemination of hazardous multiple aminoglycoside resistance genes.

We report armA in an Escherichia coli pig isolate from Spain. The resistance gene was borne by self-transferable IncN plasmid pMUR050. Molecular analysis of the plasmid and of the armA locus confirmed the spread of this resistance determinant.

Multidrug-resistant tuberculosis was diagnosed in 21 HIV-negative, nonhospitalized male patients residing in northern Tunisia. A detailed investigation showed accelerated transmission of a Mycobacterium tuberculosis clone of the Haarlem type in 90% of all patients. This finding highlights the epidemic potential of this prevalent genotype.

Two case-control studies evaluated the prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carriage at hospital admission and characteristics of patients with CA-MRSA. Among 14,253 patients, CA-MRSA prevalence was 0.9/1,000 admissions. Although 5 CA-MRSA isolates contained Panton-Valentine leukocidin, only 1 patient had a previous skin infection. No easily modifiable risk factor for CA-MRSA was identified.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections increased from 2000 to 2003 in hospitalized pediatric patients in Houston. CA-MRSA was associated with greater illness than was infection with methicillin-susceptible strains. Children with CA-MRSA were younger and mostly African American. Of MRSA isolates, 4.5% had the inducible macrolide-lincosamide-streptogramin B phenotype.

After increasing from 1995 to 1999, invasive erythromycin-nonsusceptible Streptococcus pneumoniae rates per 100,000 decreased 53.6% in children from Baltimore, Maryland (US), from 1999 to 2001, which was partially attributed to strains related to the mefE-carrying England¹⁴-9 clone. The decline in infection rates was likely due to the pneumococcal 7-valent conjugate vaccine.

A novel, methicillin-resistant Staphylococcus aureus clone (Uruguay clone) with a non–multidrug-resistant phenotype caused a large outbreak, including 7 deaths, in Montevideo, Uruguay. The clone was distinct from the highly virulent community clone represented by strain MW2, although both clones carried Panton-Valentine leukocidin gene and cna gene.

Rifampin-resistant meningococcal disease occurred in a child who had completed rifampin chemoprophylaxis for exposure to a sibling with meningococcemia. Susceptibility testing of 331 case isolates found only 1 other case of rifampin-resistant disease in Minnesota, USA, during 11 years of statewide surveillance. Point mutations in the RNA polymerase β subunit (rpoB) gene were found in isolates from each rifampin-resistant case-patient.