Robert C Moellering

• Beth Israel Deaconess Medical Center

Daptomycin resistance (DAP(R)) in Staphylococcus aureus is associated with mutations in genes that are also implicated in staphylococcal pathogenesis. Using a laboratory-derived series of DAP exposed strains, we showed a relationship between increasing DAP MIC and reduced virulence in a Galleria mellonella infection model. Point mutations in walK a...

Four dimeric sterolpolyamine conjugates have been synthesized from the homo- and hetero-connection of monomeric sterolpolyamine analogs in a head-to-tail manner. These dimeric conjugates show strong antibacterial activity against a broad spectrum of Gram-positive bacteria, whereas their corresponding activities against Gram-negative bacteria are...

The genetic mechanisms that contribute to reduced susceptibility to vancomycin in Staphylococcus aureus are complex and heterogeneous. In addition, debate is emerging as to the true effect of reduced susceptibility to vancomycin on staphylococcal virulence. To investigate this, comparative genomics was performed on a collection of vancomycin-expose...

Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus. Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed...

More detailed methods. (DOCX)

Phylogenetic analysis of 1230 common single copy genes found in 12 daptomycin-susceptible Staphylococcus aureus parent strains, with Staphylococcus epidermidis ATCC 12228 and RP62A used as outgroups for the analysis. (PPT)

Mutations identified between daptomycin-susceptible and isogenic daptomycin-nonsusceptible strains of Staphylococcus aureus . (DOC)

Fifty years ago methicillin-resistant Staphylococcus aureus (MRSA) first revealed themselves to the medical community, having been described in a landmark article published in the British Medical Journal. Among other things, their discovery set off a major response from the scientific and medical professions to control or even eliminate them as maj...

NDM-1 (New Delhi metallo-beta-lactamase 1), a genetic element encoding multiple-resistance genes, has been found in various Enterobacteriaceae, rendering them resistant to nearly all antimicrobial agents. Success in combating antibiotic-resistant superbugs has been limited.

Although there has been a relentless increase in resistance to antimicrobial agents amongst important bacterial pathogens throughout the world, it is well known that the number of new antimicrobial agents being brought to the market has undergone a steady decline in the past several decades. There are a number of reasons for this, which are detaile...

Complicated skin and skin structure infections (cSSSIs) continue to pose a significant clinical challenge. The most frequent cause of these infections is Staphylococcus aureus, although other organisms, including Streptococcus pyogenes and, in certain circumstances, Enterobacteriaceae, are also involved. The relentless increase in methicillin resis...

With the current high prevalence of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) strains but in light of the general belief that β-lactam antibiotics are more effective than vancomycin against infections caused by methicillin-susceptible S. aureus (MSSA) isolates, clinicians may utilize antistaphylococcal penicillins in co...

Vancomycin is a commonly used antibiotic due to its effectiveness in treating serious gram-positive infections caused by methicillin-resistant Staphylococcus aureus. As commercial drug assays and a multitude of pharmacokinetic data from a variety of patient populations are widely available, therapeutic monitoring of serum vancomycin concentrations...

Vancomycin is a commonly used antibiotic due to its effectiveness in treating serious gram-positive infections caused by methicillin-resistant Staphylococcus aureus. As commercial drug assays and a multitude of pharmacokinetic data from a variety of patient populations are widely available, therapeutic monitoring of serum vancomycin concentrations...

Most cases of reduced vancomycin susceptibility in Staphylococcus aureus reported in the literature have been in methicillin-resistant strains. We report the development of reduced vancomycin susceptibility in a series of clonally related, methicillin-susceptible S. aureus (MSSA) clinical isolates. This isogenic series permitted us to determine whe...

Practice guidelines for therapeutic monitoring of vancomycin treatment for Staphylococcus aureus infection in adult patients were reviewed by an expert panel of the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. A literature review of existing evidence r...

Methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been associated with infections in hospitals. Recently, a new strain of MRSA has emerged and rapidly spread in the community, causing serious infections among young, healthy individuals. Preliminary reports imply that a particular clone (USA300) of a community-acquired MRSA (CA-MR...

Recently, we [E.M.C. D’Agata, G.F. Webb, M.A. Horn, R.C. Moellering Jr., and S. Ruan, Modellingthe invasion of community-acquired methicillin-resistant Staphylococcus aureus into the hospital setting, Clin. Infect. Dis. 48 (2009), pp. 274–284] proposed a deterministic mathematical model to characterize the factors contributing to the replacement of...

Vancomycin is a glycopeptide antibiotic that has been in clinical use for nearly 50 years as a penicillin alternative to treat penicillinaseproducing strains of Staphylococcus aureus. It is one of the most widely used antibiotics in the United States for the treatment of serious gram-positive infections involving methicillin-resistant S. aureus (MR...

In the present study, we demonstrated the utility of the nonmammalian model system Galleria mellonella for studying the pathogenesis of Staphylococcus aureus infection. By use of clinical and laboratory strains that had been exposed to vancomycin, we showed that both agr functional status and vancomycin minimum inhibitory concentration are determin...

Nonmammalian model systems of infection such as Galleria mellonella (caterpillars of the greater wax moth) have significant logistical and ethical advantages over mammalian models. In this study, we utilize G. mellonella caterpillars to study host-pathogen interactions with the gram-negative organism Acinetobacter baumannii and determine the utilit...

Prokaryote–eukaryote interactions are ubiquitous and have important medical and environmental significance. Despite this, a paucity of data exists on the mechanisms and pathogenic consequences of bacterial–fungal encounters within a living host. We used the nematode Caenorhabditis elegans as a substitute host to study the interactions between two e...

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...

Vancomycin use has increased dramatically worldwide since the mid-1980s, largely as a result of empirical and directed therapy against burgeoning methicillin-resistant Staphylococcus aureus (MRSA) infections. With limited choices, clinicians have traditionally relied on vancomycin alone in the management of serious MRSA infections and have enjoyed...

During the past decade, there has been a marked increase in the prevalence of community-acquired methicillin-resistant Staphylococcus aureus infection in the United States and elsewhere. The most common such infections are those involving the skin and skin structures. Although a number of these lesions (including small furuncles and abscesses) resp...

The case of Mr M, a previously healthy 39-year-old man with erythema and swelling of his finger, illustrates the issues involved in treating community-acquired skin and soft tissue infections since the emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the community. Most community-acquired infections of the skin and soft tissues ar...

We examined sequential methicillin-susceptible Staphylococcus aureus isolates from a patient with mitral valve endocarditis recovered during persistent bacteremia on standard therapy and relapse after treatment with daptomycin. An isolate obtained after 5 days of antimicrobial therapy, but before exposure to daptomycin, showed subtle physiological...

Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. It is a worldwide problem that spans the range of human pathogens, including bacteria, fungi, and viruses. This update from the Antimicrobial Resistance Prevention Initiative (ARPI) provides a review of some import...

The G2576T mutation in domain V of 23S rRNA has been most often associated with the rare cases of linezolid resistance in Staphylococcus aureus. In a linezolid-susceptible S. aureus (A8761B) possessing a single mutated (G2576T) copy, originally derived from a resistant clinical isolate, we assessed the persistence of the mutation on further passage...

The Clinical and Laboratory Standards Institute (formerly, the NCCLS) established the susceptibility and resistance breakpoints for minimal inhibitory concentration (MIC) and disk diffusion testing of vancomycin against isolates of Staphylococcus aureus >20 years ago. The disk diffusion breakpoints were modified in 1998 when it was recognized that...

A previous study documented the presence of mutations in mprF that accompanied the loss of daptomycin susceptibility among Staphylococcus aureus isolates following exposure to the drug. An association between the development of glycopeptide-intermediate S. aureus and daptomycin nonsusceptibility has also been recently described. We report that amon...

To evaluate microbiological properties of methicillin-resistant Staphylococcus aureus (MRSA) during prolonged vancomycin therapy. We evaluated vancomycin susceptibility and heteroresistance, accessory gene regulator (agr) function, autolysis, biofilm production and in vitro vancomycin killing in serial MRSA bloodstream isolates obtained over a 30 m...

For the past 2 decades, vancomycin has served as the cornerstone of therapy against serious methicillin-resistant Staphylococcus aureus infections. This role is increasingly challenged by questions of efficacy, including reduced efficacy against infections caused by glycopeptide-intermediate S. aureus strains. In an evaluation of clinical glycopept...

We studied vancomycin and daptomycin susceptibility in methicillin-resistant Staphylococcus aureus from patients exposed to vancomycin, glycopeptide-intermediate S. aureus, and S. aureus passaged in vancomycin-containing medium. A correlation between vancomycin and daptomycin heteroresistance was noted in some strains, suggesting that exposure of S...

Loss of agr function, vancomycin exposure, and abnormal autolysis have been linked with both development of the GISA phenotype and low-level resistance in vitro to thrombin-induced platelet microbicidal proteins (tPMPs). We examined the potential in vitro interrelationships among these parameters in well-characterized, isogenic laboratory-derived a...

Although a considerable amount of research has gone into the study of the role of bactericidal versus bacteriostatic antimicrobial agents in the treatment of different infectious diseases, there is no accepted standard of practice. A panel of infectious diseases specialists reviewed the available literature to try to define specific recommendations...

Linezolid resistance in rare isolates of Staphylococcus aureus has been associated with G2576T mutations in domain V of the 23S rRNA gene. We report the analysis of a clinical S. aureus isolate that developed linezolid resistance (MIC of linezolid of 12 mg/L) after a 25 day course of the drug. Sequencing identified G2576T mutations in four of the f...

Biofilm production is frequently dependent on such environmental factors as cell density and glucose concentration. The Enterococcus faecalis quorum-sensing locus (fsr) increases enterococcal virulence in multiple animal models. To date, fsr has been shown to regulate the transcription of 2 downstream protease genes.We demonstrate that the effect o...

Linezolid is an important therapeutic option for infections caused by resistant gram-positive bacteria. We report the characterization of sequential methicillin-resistant Staphylococcus aureus (MRSA) bloodstream isolates that developed resistance in a patient treated with a prolonged course of linezolid. Analysis of this series of clinical MRSA iso...

We studied methicillin-resistant Staphylococcus aureus (MRSA) isolates to determine if the group II polymorphism at the accessory gene regulator (agr) locus demonstrated any relationship with the clinical efficacy of vancomycin. One hundred twenty-two MRSA isolates from 87 patients treated with vancomycin were evaluated. Forty-five of 87 patients h...

We attempted to find a relationship between the microbiological properties of bloodstream isolates of methicillin-resistant Staphylococcus aureus (MRSA) and the efficacy of vancomycin in the treatment of bacteremia. Vancomycin susceptibility testing was performed, and bactericidal activity was determined for 30 isolates from 30 different patients w...

We previously determined that all 6 Staphylococcus aureus strains with confirmed intermediate-level resistance to glycopeptides (glycopeptide intermediate S. aureus [GISA]) from the United States that we tested belonged to accessory gene regulator (agr) group II. In the present study, we found that 56% of surveyed bloodstream methicillin-resistant...

Linezolid is an important therapeutic option for treatment of infections caused by glycopeptide- and β-lactam–resistant gram-positive organisms. Linezolid resistance is caused by mutations within the domain V region of the 23S ribosomal RNA (rRNA) gene, which is present in multiple copies in most bacteria. Among clinical Staphylococcus aureus isola...

The majority of infections with glycopeptide intermediate-level resistant Staphylococcus aureus (GISA) originate in biomedical devices, suggesting a possible increased ability of these strains to produce biofilm. Loss of function of the accessory gene regulator (agr) of S. aureus has been suggested to confer an enhanced ability to bind to polystyre...

Lower respiratory tract infections have been a major cause of morbidity and mortality among humans since the dawn of history. The initial hope that the era of antibiotics would remove this scourge has been replaced by the more realistic view that although antimicrobial agents represent a major therapeutic advance, they have not yet solved all of th...

Three sets of carbapenem-resistant Serratia marcescensisolates have been identified in the United States: 1 isolate in Minnesota in 1985 (before approval of carbapenems for clinical use), 5 isolates in Los Angeles (University of California at Los Angeles [UCLA]) in 1992, and 19 isolates in Boston from 1994 to 1999. All isolates tested produced two...

This is an internationally edited and authored textbook of infectious diseases. It is structured to emphasize the approaches to be taken in recognition, diagnosis, and treatment when infections involve different organ systems or become generalized. Besides infectious diseases of different organ systems, those involving special risk groups (e.g. pos...

The in vivo activities of piperacillin-tazobactam and cefepime were compared with those of ticarcillin-clav- ulanate, ceftazidime, cefotaxime, and imipenem in a rat model of intra-abdominal abscess with a strain of Kleb- siella pneumoniae elaborating an extended-spectrum b-lactamase (TEM-26). With the exception of ceftazidime, all of the antimicrob...

The in vitro activity of levofloxacin against 506 Gram-positive bacteria was compared with those of D(−)-ofloxacin, ofloxacin, ciprofloxacin, and sparfloxacin. Levofloxacin was generally twice as active as ofloxacin against these organisms (range, 0–3 twofold dilutions). Sparfloxacin appeared to have the greatest activity overall, but for several g...

The in vitro activity of RP59500, a streptogramin antibiotic, against 146 clinical isolates of vancomycin-resistant gram-positive bacteria was examined. Five strains of the species Enterococcus casseliflavus and Enterococcus gallinarum, for which the MIC of vancomycin was 8 micrograms/ml, were also studied. Twenty-eight vancomycin-susceptible strai...

ALTHOUGH enterococci are normal inhabitants of the gastrointestinal and female genital tracts, they are now recognized as formidable pathogens in hospitalized patients.1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Many patients become infected with their own strains of enterococci after they are admitted to the hospital,18 but nosocomial transmission o...

The in-vitro activity of Sch 29482 (SCH) was compared with those of N-formimidoyi thienamycin, moxalactam, and seven oral antibiotics against skin and soft-tissue, respiratory, and gastro-intestinal tract pathogens. Ninety per cent of methicillinsusceptible strains of Staphylococcus aureus and streptococci of groups A, B, C and G were inhibited by...

Clinical isolates of enterococci (Streptococcus faecalis) with high-level resistance to both streptomycin and kanamycin (minimal inhibitory concentration >2,000 mug/ml), and resistant to synergism with penicillin and streptomycin or kanamycin were examined for aminoglycoside-inactivating enzymes. All of the 10 strains studied had streptomycin adeny...

Combinations of cephalothin and aminoglycoside antibiotics are not currently used in the therapy of serious enterococcal infections, because clinical trials of these combinations have been unsuccessful. Studies of 28 enterococci isolated from patients with enterococcal bacteremia suggested three possible mechanisms for this in vivo antibiotic failu...

A patient undergoing peritoneal dialysis for severe renal failure was treated with tobramycin. Peritoneal dialysis was inefficient in removing tobramycin from the serum. Tobramycin concentrations in the dialysis effluent were low. Despite acute oliguric renal failure, urine concentrations of tobramycin were sufficient to treat most gram-negative ur...

Combinations of penicillin plus tobramycin have been compared with penicillin plus gentamicin against 27 strains of enterococci isolated from blood cultures. Penicillin plus gentamicin was synergistic against all strains. The combination of penicillin plus tobramycin was equally effective against strains of Streptococcus facalis, but was ineffectiv...