Ian M. Gould

Antibiotic resistance—the need for global solutions

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-Year Analysis of Susceptibilities of Noncandidal Yeast Species to Fluconazole and Voriconazole Determined by CLSI Standardized Disk Diffusion Testing

ABSTRACT Fluconazole in vitro susceptibility test results determined by the CLSI M44-A disk diffusion method for 11,240 isolates of noncandidal yeasts were collected from 134 study sites in 40 countries from June 1997 through December 2007. Data were collected for 8,717 yeast isolates tested with voriconazole from 2001 through 2007. A total of 22 different species/organism groups were isolated, of which Cryptococcus neoformans was the most common (31.2% of all isolates). Overall, Cryptococcus (32.9%), Saccharomyces (11.7%), Trichosporon (10.6%), and Rhodotorula (4.1%) were the most commonly identified genera. The overall percentages of isolates in each category (susceptible, susceptible dose dependent, and resistant) were 78.0%, 9.5%, and 12.5% and 92.7%, 2.3%, and 5.0% for fluconazole and voriconazole, respectively. Less than 30% of fluconazole-resistant isolates of Cryptococcus spp., Cryptococcus albidus, Cryptococcus laurentii, Trichosporon beigelii/Trichosporon cutaneum, Rhodotorula spp., Rhodotorula rubra/Rhodotorula mucilaginosa, and Rhodotorula glutinis remained susceptible to voriconazole. Emerging resistance to fluconazole was documented among isolates of C. neoformans from the Asia-Pacific, Africa/Middle East, and Latin American regions but not among isolates from Europe or North America. This survey documents the continuing broad spectrum of activity of voriconazole against opportunistic yeast pathogens but identifies several of the less common species with decreased azole susceptibility. These organisms may pose a future threat to optimal antifungal therapy and emphasize the importance of prompt and accurate species identification.

A genomic portrait of the emergence, evolution and global spread of a methicillin resistant Staphylococcus aureus pandemic

The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens.

New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance

Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.

Antimicrobial drug use and methicillin-resistant Staphylococcus aureus, Aberdeen, 1996-2000.

Relationships between antimicrobial use and MRSA prevalence are analyzed in Aberdeen, Scotland.

Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997-2005: An 8.5-Year Analysis of Susceptibilities of Candida and Other Yeast Species to Fluconazole and Voriconazole by CLSI Standardized Disk Diffusion Testing

ABSTRACT Fluconazole in vitro susceptibility test results for 205,329 yeasts were collected from 134 study sites in 40 countries from June 1997 through December 2005. Data were collected for 147,776 yeast isolates tested with voriconazole from 2001 through 2005. All investigators tested clinical yeast isolates by the CLSI M44-A disk diffusion method. Test plates were automatically read and results recorded with a BIOMIC image analysis system. Species, drug, zone diameter, susceptibility category, and quality control results were collected quarterly. Duplicate (same patient, same species, and same susceptible-resistant biotype profile during any 7-day period) and uncontrolled test results were not analyzed. Overall, 90.1% of all Candida isolates tested were susceptible (S) to fluconazole; however, 10 of the 22 species identified exhibited decreased susceptibility (<75% S) on the order of that seen with the resistant (R) species C. glabrata and C. krusei. Among 137,487 isolates of Candida spp. tested against voriconazole, 94.8% were S and 3.1% were R. Less than 30% of fluconazole-resistant isolates of C. albicans, C. glabrata, C. tropicalis, and C. rugosa remained S to voriconazole. The non-Candida yeasts (8,821 isolates) were generally less susceptible to fluconazole than Candida spp. but, aside from Rhodotorula spp., remained susceptible to voriconazole. This survey demonstrates the broad spectrum of these azoles against the most common opportunistic yeast pathogens but identifies several less common yeast species with decreased susceptibility to antifungal agents. These organisms may pose a future threat to optimal antifungal therapy and emphasize the importance of prompt and accurate species identification.

The epidemiology of antibiotic resistance

Antibiotic resistance has reached crisis point in many hospitals around the world. The majority are swamped with meticillin-resistant Staphylococcus aureus (MRSA), and many with multidrug-resistant (MDR) Gram-negatives. Whilst there are good treatment alternatives available for serious infections due to MRSA, mortality rates remain high. For MDR Gram-negatives the situation is more complex and worrying. There are few, if any, new agents in development that can be expected to benefit the situation in the next decade. Moreover, extreme (or extensive) drug-resistant and even pandrug-resistant Gram-negative infections are increasingly being described. Although definitions are confused in this area, reports suggest that patients in some intensive care units are dying from lack of availability of any antibiotic active against certain strains of Pseudomonas aeruginosa and Acinetobacter baumannii. A better understanding of the molecular basis of resistance is urgently needed if it is to be successfully overcome. Moreover, we urgently need better global early warning systems to detect new resistances and put mechanisms in place for their control.

Antibiotic resistance: the perfect storm

The worldwide epidemic of antibiotic resistance is in danger of ending the golden age of antibiotic therapy. Resistance impacts on all areas of medicine, and is making successful empirical therapy much more difficult to achieve. Antibiotic choices are often severely restricted, and the pipeline of new antibiotics is almost dry. Resistance cannot be prevented, but its development and spread can be slowed. One of the tools at our disposal is maximising diversity in our prescribing. The advent of tigecycline, the first in a new class of intravenous antibiotics, is important in this context, giving us a further monotherapy option for severe infections. Another strategy is seriously to curtail the large amount of unnecessary antibiotic use in many areas of life, not only medical practice. The various aspects of this strategy are briefly reviewed.

Systematic Review of Antimicrobial Drug Prescribing in Hospitals

Standardizing methods and reporting could improve interventions that reduce Clostridium difficile–associated diarrhea and antimicrobial drug resistance.

An outbreak of multiply-resistant Klebsiella pneumoniae in the Grampian region of Scotland

A predominantly hospital-based outbreak of multiply-resistant Klebsiella pneumoniae capsular type K2 (MRK) expressing expanded spectrum betalactamase (ESBL) activity and fully sensitive only to the carbapenems and amikacin is described. The organism was isolated from 283 patients between March 1992 and September 1995. The outbreak started in the intensive care unit (ICU) of a major acute hospital and spread through surgical wards, a medical ward, a geriatric unit in a separate hospital and various other local hospitals. Environmental screening revealed extensive ward contamination. The decline of the outbreak after the spring of 1995 coincided with the re-emphasis of standard infection control procedures and the launch of a works programme aimed at addressing underlying sites of environmental contamination. Of the 283 cases, 166 (59.0%) were detected through a specially instigated case finding programme. The MRK caused 11 cases of septicaemia, two postoperative intra-abdominal abscesses, one case of postoperative meningitis, 102 cases of urinary tract infection and 28 wound infections and was isolated from the respiratory tracts of five patients with ventilator associated pneumonia. The difficulty in controlling the outbreak is ascribed to heavy environmental contamination, frequent inter- and intra-hospital patient transfers and prolonged carriage of the outbreak strain.