The oxazolidinones

The need for effective antibiotics to manage the ever increasing frequency of antibiotic-resistant gram-positive infections in much of the developed world has led to the clinical development of the first oxazolidinone antibiotic, linezolid. Linezolid possesses bacteriostatic activity against both antibiotic-susceptible and resistant strains of staphylococci, enterococci, and streptococci of relevance to human infection. Clinical trials have confirmed its effectiveness in the treatment of serious infections of skin and soft tissue and the lower respiratory tract. Linezolid has also provided improved outcomes in the treatment of serious vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus infections in a compassionate use program. Emergence of linezolid-resistant gram-positive cocci during clinical use has recently been described, suggesting that its present role in therapy should be reserved for the treatment of antibiotic-resistant gram-positive infections.     

Increasing antimicrobial resistance: Therapeutic implications for enterococcal infections

Enterococcus was designated a genus distinct from the streptococci in 1984. Enterococci cause a variety of monomicrobial and polymicrobial infections, mainly in compromised patients. These infections include bacteremia, urinary and biliary tract infections, intra-abdominal sepsis, and decubitus and diabetic foot ulcers. Enterococcal infections may be acquired from the patient’s endogenous intestinal flora or exogenously from a fecally contaminated environment. Enterococci are inherently resistant to many antimicrobial agents and readily acquire additional resistances, which is likely the reason that enterococci have become prominent nosocomial pathogens. Only the combination of a cell wall-active antibiotic to which the Enterococcus is susceptible (ie, certain β-lactams or vancomycin) plus an aminoglycoside (ie, gentamicin or streptomycin) is bactericidal, and is required for cure of endocarditis, meningitis and probably infection in neutropenic patients; bacteriostatic activity is sufficient to treat most other infections. Treatment of infections caused by strains resistant to b-lactams, glycopeptides and aminoglycosides has become problematic due the limited number of therapeutic options. No medical therapy is reliably effective for endocarditis caused by strains resistant to all cell wall-active antibiotics and all aminoglycosides. New antimicrobial agents, such as linezolid and quinupristin/dalfopristin, have recently become available, but their activity against enterococci is mainly bacterostatic.     

Harnessing bacteriocin biology as targeted therapy in the GI tract

Recently, our laboratory demonstrated that bacteriocins produced by commensal enterococci provide an advantage in niche maintenance in the highly competitive environment of the gastrointestinal (GI) tract. Bacterial production of bacteriocins is a conserved defense strategy to help establish an ecological niche. Bacteriocin-encoding genes in enterococci are often carried on mobile genetic elements, including conjugative plasmids, enabling the transfer of such traits to other community members in a shared niche. Use of a novel mouse model for enterococcal colonization of the GI tract allowed us to investigate enterococcal dynamics and the role of enterococcal bacteriocins in the mouse GI tract. We examined the role of bacteriocin-21, carried on the pPD1 plasmid, in enterococcal colonization of the gut. We discovered that Enterococcus faecalis (EF) harboring pPD1 effectively colonizes the GI tract by using Bac-21 to eliminate its competition. In our study, we also present evidence for active conjugation in the GI tract, a strategy EF uses to enhance the number of bacteriocin producers in a given niche and eliminate bacteriocin-susceptible populations. Using an engineered strain of EF that is capable of producing Bac-21 but impaired in its conjugation ability, we were able to reduce pre-existing colonization by vancomycin-resistant enterococci in the mouse gut. Thus, our results suggest a novel therapeutic strategy to de-colonize antibiotic-resistant enterococci from the GI tract of patients and thereby prevent the emergence of resistant enterococcal infections that are otherwise difficult, or impossible, to treat.     

Epidemiology and mechanisms of glycopeptide resistance in enterococci

PURPOSE OF REVIEW: This review updates epidemiologic trends and our understanding of glycopeptide resistance in enterococci. RECENT FINDINGS: Colonization and infection rates with vancomycin resistant enterococci continue to increase throughout the world while factors contributing to this rise continue to be defined. While no interventions exist to eradicate colonization, infection control procedures are cost effective and decrease the prevalence of vancomycin resistant enterococcal colonization and infection. New molecular methods show great promise in strengthening our ability to detect colonization with these bacteria. Furthermore, our understanding of the origin of vancomycin resistant enterococci continues to grow. Paenibacillus species found in soil have been found to carry homologues of vanA-associated glycopeptide resistance genes found in enterococci. Also, additional evidence supports previous data that VanB-associated resistance may have been horizontally transferred from gastrointestinal tract bacteria to enterococci. Finally, glycopeptide resistance has been transferred to methicillin-resistant Staphylococcus aureus in clinical practice on several occasions. SUMMARY: The prevalence of vancomycin resistant enterococci will likely continue to increase. Implementation of infection control strategies, in conjunction with deployment of advanced technologies for detection of vancomycin resistant enterococci, may curb this rise. The emergence of vancomycin resistant S. aureus is of concern.     

The respiratory threat posed by multidrug resistant Gram‐negative bacteria

Respiratory infections are a major cause of global mortality and morbidity. In recent years, an increased incidence of multidrug‐resistant (MDR) Gram‐negative bacteria (GNB) has been described. Microorganisms such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae or Acinetobacter baumannii have been identified as causative pathogens of different respiratory tract infections. Several studies have detected MDR‐GNB in patients with community‐acquired and nosocomial pneumonia. Furthermore, MDR‐GNB have also been isolated in patients with chronic obstructive pulmonary disease and bronchiectasis having acute or chronic bronchial infection. Prevalence varies depending on the geographical area but MDR‐GNB has been reported in the Asia‐Pacific region, Europe and the United States, reaching rates of 70% in hospital‐acquired infection. The presence of MDR‐GNB has been related to poor clinical outcomes, including increased mortality, although data regarding this relationship are limited. This is probably linked to inappropriate selection of empiric antibiotic treatment; this poses a threat of widespread resistance. GNB antibiotic resistance and the absence of new antibiotics are a major concern given limited treatment options; an aspect that deserves future research. We review current literature, highlight prevalence of MDR‐GNB in different respiratory infections and explore their impact on clinical outcomes.     

Emerging issues in antibiotic resistant infections in long-term care facilities.

Managing patients infected with antibiotic resistant bacteria is becoming one of the major clinical obstacles facing physicians who treat patients in long-term care facilities (LTCFs). Penicillin-resistant pneumococci (PRP), vancomycin-resistant enterococci (VRE), gram-negative bacteria that produce extended-spectrum and ampC-type beta-lactamase enzymes, and quinolone-resistant gram-positive and gram-negative bacteria are the major resistant pathogens that are emerging in these settings. The mechanisms responsible for the evolution of these antibiotic resistant organisms (molecular rearrangement of penicillin binding protein genes, acquisition of a mobile genetic element, and point mutation that alter the active site) are reviewed. Vancomycin intermediate Staphylococcus aureus (VISA) and multidrug efflux pumps in gram-negative bacteria are also threatening our most potent antimicrobials. Aggressive screening, education, antibiotic-control measures, and immunization are advocated as important preventive measures. The combined efforts of the medical directors, infection-control personnel, and administrators are needed to stem this problem.     

Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease?

The interface between luminal contents and intestinal epithelium constitutes the largest area of interaction between the host and the environment. There is now strong evidence that the gene product of the multidrug resistant pump (MDR) plays a critical role in host-bacterial interactions in the gastrointestinal tract and maintenance of intestinal homeostasis. This review highlights the efflux mechanism in the intestinal epithelium which is mediated by the multidrug resistant pump, also known as P-glycoprotein 170. Current studies promise to provide further insights into the contribution of the MDR1 gene in the pathogenesis of inflammatory and malignant disorders of the gastrointestinal tract.     

Bacteriophage effectively kills multidrug resistant Staphylococcus aureus clinical isolates from chronic rhinosinusitis patients

Background

Bacteriophage (phage) therapy has been proposed as an alternative to antibiotics. Phages have been shown to kill antibiotic resistant Staphylococcus aureus strains; however, it is unknown whether stress‐induced antibiotic tolerance affects S. aureus susceptibility to phages. Our objective was to determine the effectiveness of 2 phages currently in clinical development, against antibiotic‐resistant and induced antibiotic‐tolerant clinical S. aureus isolates.

Methods

Antibiotic tolerant S. aureus strains were induced by incubation with increasing concentrations of gentamicin, mupirocin, and ciprofloxacin over time and their susceptibility to 2 clinically relevant phages (Sa83 and Sa87) was assessed. In addition, phage susceptibility was tested in relation to the antibiotic sensitivity of 65 clinical S. aureus isolates, harvested from the sinonasal cavities of chronic rhinosinusitis (CRS) patients. Phage sensitivity was assessed using a plaque spot assay and by measuring optical density values to observe planktonic S. aureus growth in the presence of the phage. Alamar Blue assays were used to assess biofilm viability after phage treatment.

Results

Frequency of antibiotic resistance amongst clinical S. aureus isolates was 90.7% (59/65) with 13 of 65 (20.0%) identified as multidrug‐resistant. Tolerance to gentamicin, mupirocin, and ciprofloxacin was rapidly induced by incubation with increasing concentrations of respective antibiotics. There was no significant difference in phage sensitivity between antibiotic‐sensitive and resistant/tolerant S. aureus clinical isolates in planktonic and biofilm form.

Conclusion

Clinical S. aureus isolates from CRS patients have a high (20%) incidence of multidrug resistance. Antibiotic resistance or tolerance did not affect phage susceptibility of those isolates.

     

Trends in bacterial resistance in a tertiary university hospital over one decade

The objective of this study was to investigate bacterial resistance trends, infection sites and the relationship between resistance and admittance to the intensive care unit (ICU). A total of 53,316 bacteria identified between 1999 and 2008 were evaluated. Multidrug resistance was characterized when gram-negative bacilli (GNB) presented resistance to two or more classes of antibiotics. Gram-positive cocci (CPC) were assessed for resistance to penicillin, oxacillin and vancomycin. GNB were the most common (66.1%) isolate. There was a 3.7-fold overall increase in multidrug resistant GNB over the study period; Acinetobacter baumanii and Staphylococcus aureus were the most prevalent. Highest increases were recorded for Klebsiella pneumoniae (14.6-fold) and enterococci (73-fold). The resistance rates for GNB and GPC were 36% and 51.7%, respectively. Most multidrug resistant GNB and GPC were recovered from ICU patients (p-value < 0.001). Vancomycin-resistant enterococci were isolated during this decade with an increase of 18.7% by 2008. These data confirm the worldwide trend in multidrug bacterial resistance.     

Antibiotic Therapy in Neonatal and Pediatric Septic Shock

Severe sepsis accounts for nearly 4,500 deaths (mortality rate 10%), and is responsible for nearly $2 billion annual healthcare expenditure in the United States. Early and speedy treatment of critically ill septic patients can halt or reduce the likelihood of physiologic progression to multi-system organ failure. A cornerstone of this therapeutic strategy is antibiotic administration. In this review, we discuss the empirical treatment strategies for the treatment of early and late neonatal sepsis, along with pediatric sepsis. Furthermore, we discuss the rationale that underlies the adoption of such treatment strategies. The present article also discusses the emergence of multi-drug organisms as the causative agents for sepsis, i.e. methicillin-resistant Staphylococcus aureus (MRSA), resistant enterococci and Klebsiella pneumoniae carbapenemases (KPC).     

The Increasing Role of Acinetobacter Species As Nosocomial Pathogens

Among gram-negative organisms playing a significant role in nosocomial infections, Acinetobacter species have attracted increasing attention in intensive care units during the past two decades. Acinetobacter species are implicated in a wide spectrum of infections (eg, bacteremia, nosocomial pneumonia, urinary tract infections, secondary meningitis, superinfections in burn patients). One of the most striking features of Acinetobacter species is their extraordinary ability to develop multiple resistance mechanisms against major antibiotic classes. They have become resistant to broad-spectrum β-lactams (third-generation cephalosporins, carboxypenicillins, and increasingly to carbapenems); they produce a wide range of aminoglycoside-inactivating enzymes; and most strains are resistant to fluoroquinolones. In Acinetobacter nosocomial infections, the major problems confronting clinicians in intensive care units are related to the severity of Acinetobacter nosocomial infections and to resistance to major antibiotic classes of these organisms.     

Microbial and metabolic interactions between the gastrointestinal tract and Clostridium difficile infection

Antibiotics disturb the gastrointestinal tract microbiota and in turn reduce colonization resistance against Clostridium difficile. The mechanism for this loss of colonization resistance is still unknown but likely reflects structural (microbial) and functional (metabolic) changes to the gastrointestinal tract. Members of the gut microbial community shape intestinal metabolism that provides nutrients and ultimately supports host immunity. This review will discuss how antibiotics alter the structure of the gut microbiota and how this impacts bacterial metabolism in the gut. It will also explore the chemical requirements for C. difficile germination, growth, toxin production and sporulation. Many of the metabolites that influence C. difficile physiology are products of gut microbial metabolism including bile acids, carbohydrates and amino acids. To restore colonization resistance against C. difficile after antibiotics a targeted approach restoring both the structure and function of the gastrointestinal tract is needed.     

Drug interactions modulate the potential for evolution of resistance

Antimicrobial treatments increasingly rely on multidrug combinations, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially on the frequency with which multidrug resistance arises. Yet, it is unknown how this propensity for resistance depends on cross-resistance and on epistatic interactions—ranging from synergy to antagonism—between the drugs. Here, we analyzed how interactions between pairs of drugs affect the spontaneous emergence of resistance in the medically important pathogen Staphylococcus aureus. Resistance is selected for within a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant mutants to grow. Introducing an experimental method for high-throughput colony imaging, we counted resistant colonies arising across a two-dimensional matrix of drug concentrations for each of three drug pairs. Our data show that these different drug combinations have significantly different impacts on the size of the window of drug concentrations where resistance is selected for. We framed these results in a mathematical model in which the frequencies of resistance to single drugs, cross-resistance, and epistasis combine to determine the propensity for multidrug resistance. The theory suggests that drug pairs which interact synergistically, preferred for their immediate efficacy, may in fact favor the future evolution of resistance. This framework reveals the central role of drug epistasis in the evolution of resistance and points to new strategies for combating the emergence of drug-resistant bacteria.     

Staphylococcus aureus and Other Bacteremias in Hemodialyis Patients: Antibiotic Therapy and Surgical Removal of Access Site

Summary Background: Bacteremia is commonplace in patients undergoing hemodialysis since the vascular access site is a ready source of infection. Mortality is notably high. However, uncertainties exist with respect to therapy including indications for surgical removal of vascular access site and duration of therapy. We therefore conducted a large-scale collaborative study of bacteremia in hemodialysis patients in six US academic medical centers to define the epidemiology of such infections and to address issues of management. Patients and Methods: We conducted a prospective observational study over 2 years. Severity of illness at onset of bacteremia was defined by objective criteria. Patients were followed for 90 days to assess late complications including endocarditis and mortality. Univariate and multivariate analyses were used to assess risk factors for mortality. Results: Patients experiencing 127 consecutive episodes of bacteremia were enrolled. The most common cause of bacteremia was Staphylococcus aureus (31%), followed by aerobic gram-negative bacilli (28%) and coagulase-negative staphylococci (13%). Polymicrobial bacteremia occurred in 6% of patients. The most frequent focus of infection was the access site for hemodialysis, although urinary tract, gastrointestinal tract and lung were also implicated. Aerobic gram-negative bacilli and enterococci usually originated from the urinary tract. S. aureus was significantly more likely to cause infection of the access site than other bacteria (p = 0.0001). S. aureus endocarditis was diagnosed in two patients who were receiving antibiotic therapy for S. aureus bacteremia. Removal of the infected access site (shunt, fistula, catheter) was performed for 86% of the patients (95% of the intravenous catheters and 80% of the arteriovenous fistulas/shunts). Overall mortality was 33% at 90 days and was significantly associated with severity of illness at onset of antibiotic therapy and age > 60 years. Mortality was not significantly different in patients undergoing surgical removal of infected access site versus those treated with antibiotics alone. Conclusion: When S. aureus was isolated from the blood, the access site was the most frequent source. Surgical removal of the access site did not have a notable impact on mortality. Until a randomized trial proves otherwise, it appears that surgical removal of the access site can be individualized. Selected patients who are less severely ill (based on objective criteria) can maintain their hemodialysis access site and be treated with 2 wweks of antibiotic therapy. Received: February 28, 2000 · Revision accepted: October 9, 2000     

Antibiotic Use and the Prevalence of Antibiotic Resistance in Bacteria from Healthy Volunteers in the Dutch Community

Background: Although most antibiotics are consumed in the community (80%), the relation of antibiotic consumption and resistance in the community has not been thoroughly studied. Materials and Methods: In the present study, antibiotic use was related to the prevalence of antibiotic resistance of Escherichia coli and enterococci isolated from healthy volunteers living in the southern part of the Netherlands in 1996 and 1999. Results: No change in the total antibiotic use in the Dutch community was observed between 1996 and 1999 (3,542 and 3,598 defined daily doses [DDD] per 1,000 inhabitants/year). However, the increased fluoroquinolone use (+ 18%) and the increased prevalence of ciprofloxacin resistance from 0 to 2% is a point of concern, especially since this was accompanied by a significant shift towards higher minimum inhibitory concentration (MIC) values (p < 0.05). A significant decrease in the prevalence of vancomycin-resistant enterococci (p < 0.05) was found in addition to a significant shift towards lower MIC valued for avoparcin, a gycopeptide previously used as growth promoter in animal husbandry (p < 0.05). This was very likely due to the banning of avoparcin for this purpose from April 1997 onwards. Conclusion: In order to maintain the low level of antibiotic use and resistance in The Netherlands, surveillance of antibiotic resistance in nonclinical isolates in relation to antibiotic use is very important. Received: February 18, 2002 · Revision accepted: November 4, 2002 E. Stobberingh (corresponding author)     

REVIEW: Changes of In Vivo Gastrointestinal Motor Pattern in Pacemaker-Deficient (WsRC-Ws/Ws) Rats

In vitro studies on pacemaker-deficient W-mutants have revealed a disappearance of rhythmic contraction in their gastrointestinal tracts. Their contractile force has not been diminished, however. In contrast, W-mutants often present dysmoility-like symptoms with distension of the gastrointestinal tract in vivo. Gastrointestinal motility of W-mutant rats was examined in vivo by an extraluminal strain-gauge force transducer method. We examined a normal gastrointestinal motor pattern in the rats with two distinct motor phases, digestive and interdigestive. Moreover, we detected a failure to form an interdigestive contractile complex in pacemaker-deficient rats. The interdigestive motor activity of the gastrointestinal tract is important for cleaning gastrointestinal tract in preparation for the next meal. The impairment of the interdigestive contractile complex may be related to the dysmoility-like symptoms of W-mutant rats in vivo.     

Enterococcal infections in surgical patients: the mystery continues.

The frequency of isolation of enterococci from surgical patients has increased significantly during the past decade, although the role of these organisms as pathogens in mixed infections remains a mystery. Bacteremia and other infections in which enterococci are the only pathogens frequently result in high morbidity and mortality among patients unless specific antimicrobial therapy is initiated promptly. Debate continues concerning the necessity for treatment with such agents when this organism is isolated as a component of a polymicrobial infecting flora. Our recent data indicate that enterococci are rarely isolated in postoperative infections after penetrating abdominal trauma if no gastrointestinal perforation has occurred. However, they were found in 56% of postoperative infections of patients with gastrointestinal perforation. In contrast, enterococci were isolated in only 9% of cultures of specimens from patients with secondary suppurative peritonitis. The occurrence of superinfection after therapy with a cephalosporin appears to be an important factor in this finding. Future studies are necessary to evaluate the efficacy of antibiotic treatment of enterococcal infections and to assess the need for prophylaxis against enterococci.     

Antimicrobial susceptibility testing: special needs for fastidious organisms and difficult-to-detect resistance mechanisms.

Clinical microbiology laboratories are faced with the challenge of accurately detecting emerging antibiotic resistance among a number of bacterial pathogens. In recent years, vancomycin resistance among enterococci has become prevalent, as has penicillin resistance and multidrug resistance in pneumococci. More recently, strains of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin have been encountered. In addition, molecular techniques have demonstrated that there are still problems detecting methicillin resistance in staphylococci, especially in coagulase-negative species. Among members of the family Enterobacteriaceae, mutated beta-lactamase enzymes may confer difficult-to-detect resistance to later-generation penicillins and cephalosporins. Anaerobic bacteria are no longer entirely predictable in their susceptibility to agents that might be selected for empiric therapy. Therefore, clinical microbiology laboratories may not be able to rely on a single susceptibility testing method or system to detect all those emerging resistant or fastidious organisms. For reliable detection, laboratories may need to employ conventional, quantitative susceptibility testing methods or use specially developed, single concentration agar screening tests for some resistant species. Certain of these screening tests are highly specific, while others may require additional confirmatory testing for definitive results. Therefore, laboratories must retain the versatility to apply several different approaches to detect resistance in both common and infrequently encountered bacterial pathogens.     

Infecciones causadas por bacterias grampositivas multirresistentes (Staphylococcus aureus y Enterococcus spp.)

Methicillin -resistant Staphylocccus aureus (MRSA) and multirresistant entorococci are still problematic in nosocomial infections and new challenges have emerged for their containment. MRSA has increased the multiresistant profile; it has been described vancomycin and linezolid resistant isolates and isolates with decreased daptomycin susceptibility. Moreover, new clones (ST398) have emerged, initially associated with piggeries, and new mec variants (mecC) with livestock origin that escape to the detection with current molecular methods based on mecA gene have been detected. In enterococci, linzeolid resistant isolates and isolates with deceased susceptibility to daptomycin have been described. Moreover, ampicillin resistant Enterococcus faecium due to β-lactamase production has been recently found in Europe. Control of MRSA isolates and multiresistant enteroccocci should combined antibiotic stewardship strategies and epidemiological measures, including detection of colonized patients in order to reduce colonization pressure and their transmission.