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BackgroundThe COVID-19 pandemic and the associated containment measures had a substantial impact on pathogens causing pneumonia in adults. The objective of this study was to determine the etiology of hospitalized community-acquired pneumonia (CAP) among adults in Germany in 2021, the second year of the COVID-19 pandemic.MethodsSince January 2021, this on-going, prospective, population-based surveillances study enrolled adult patients with clinically and radiographically confirmed CAP at three hospitals in Thuringia, Germany, serving a population of approximately 280,000. Urine samples were collected from patients and tested forS. pneumoniaeusing the pneumococcal urinary antigen test (PUAT, BinaxNOWS. pneumoniae) and the proprietary serotype-specific urinary antigen detection (UAD) assays. Nasopharyngeal swabs were tested for 10 respiratory viruses by PCR.ResultsA total of 797 patients were enrolled, of whom 760 were included in the analysis. The median age of patients with CAP was 67 years; in-hospital case-fatality rate was 8.4%. A respiratory pathogen was detected in 553 (72.8%) patients. The most common pathogen was SARS-CoV-2 (n=498, 68.2%), followed byS. pneumoniae(n=40, 6.4%). Serotypes contained in the 13-valent, 15-valent and 20-valent pneumococcal conjugate vaccine were detected in 42.5%, 45.0%, and 70.0% of the pneumococcal CAP cases. Between the first and second half of 2021, the proportion of CAP cases associated withS. pneumoniaeincreased from 1.1% to 5.6% in patients aged 18-59 years and from 2.5% to 12.4% in those aged ≥60 years; coinfection of SARS-CoV-2 andS. pneumoniaeamong COVID-19 patients increased from 0.7% (2/283 cases) to 6.0% (13/215) in patients aged ≥18 years, and from 1.0% (2/195) to 8.7% (11/127) in those aged ≥60 years.ConclusionIn Germany, the proportion of CAP cases associated withS. pneumoniaerebounded to a near-pandemic level in the second half of 2021 and many pneumococcal infections occurred in patients with COVID-19. Vaccination uptake against respiratory pathogens, includingS. pneumoniae, should be strengthened.

Clostridioides difficile infection (CDI) often manifests as diarrhea, particularly in adults of older age or with underlying comorbidities. However, only severe cases are notifiable in Germany. Moreover, failure to collect a stool specimen from inpatients with diarrhea or incomplete testing may lead to underdiagnosis and underreporting of CDI. We assessed the frequency of diarrhea, stool specimen collection, and CDI testing to estimate CDI underdiagnosis and underreporting among hospitalized adults. In a ten-day point-prevalence study (2019–2021) of nine hospitals in a defined area (Muenster/Coesfeld, North Rhine-Westphalia, Germany), all diarrhea cases (≥ 3 loose stools in 24 h) among adult inpatients were captured via medical record screening and nurse interviews. Patient characteristics, symptom onset, putative origin, antibiotic consumption, and diagnostic stool sampling were collected in a case report form (CRF). Diagnostic results were retrieved from the respective hospital laboratories. Among 6998 patients screened, 476 (7%) diarrhea patients were identified, yielding a hospital-based incidence of 201 cases per 10,000 patient-days. Of the diarrheal patients, 186 (39%) had a stool sample collected, of which 160 (86%) were tested for CDI, meaning that the overall CDI testing rate among diarrhea patients was 34%. Toxigenic C. difficile was detected in 18 (11%) of the tested samples. The frequency of stool specimen collection and CDI testing among hospitalized diarrhea patients was suboptimal. Thus, CDI incidence in Germany is likely underestimated. To assess the complete burden of CDI in German hospitals, further investigations are needed.

Background In August 2015, the German Standing Committee on Vaccination (STIKO) changed the pneumococcal conjugate vaccination (PCV) schedule for mature infants from a 3+1 scheme to a 2+1 scheme. It was expected that a reduction of doses would be associated with a higher acceptance of the vaccination. Aim of this study was to assess vaccination rates and adherence for PCV after the change of recommendation based on real-world data. Methods A retrospective claims data analysis using the InGef Research Database was conducted. The study population consisted of all mature infants born in 2013 (last birth cohort completely under 3+1 recommendation) or 2016 (first birth cohort completely under 2+1 recommendation) with an individual follow-up of 24 months. Hexavalent combination vaccination (HEXA) with a consistent 3+1 recommendation was analyzed as reference. Results After follow-up of 24 months, 90.9% (91.2%) of the 2016 (2013) cohort received at least one dose of PCV. At the same age, 67.7% of the 2013 cohort received a booster dose according to the 3+1 schedule and 75.6% of the 2016 cohort received a booster dose presumably either according to the 2+1 (71.7%) or 3+1 (3.9%) schedule. Of those receiving the booster dose, only 46.3% (2016) and 45.1% (2013) received the booster dose on time as recommended. The HEXA vaccination rate increased from 88.9% (2013) to 91.6% (2016) with a full series completion in 69.1% (2013) vs 72.9% (2016). The proportion of infants receiving the booster vaccination on time rose to 50.0% in 2016 (47.8% in 2013). Conclusions Although the rate for the PCV booster dose slightly increased, nearly a quarter of the infants born in 2016 did not receive a booster dose at all. Furthermore, vaccinations were still frequently delayed, and the rate of unvaccinated infants remained constant.

BACKGROUND Tick-borne encephalitis (TBE) is an arboviral infection of the central nervous system. As there is no causal treatment of TBE, disease prevention by vaccination is especially important. Immunization consists of a three-dose primary vaccination schedule, followed by regular booster doses. In Germany, the Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute recommends TBE vaccination for all those at high risk of contracting TBE. This includes individuals living in, traveling to and/or working in risk areas, and being exposed to ticks. To our knowledge, there are currently no reliable data on TBE vaccination rates in Germany available. METHODS This retrospective cohort study based on anonymized German health claims data was conducted to determine vaccination rates of TBE primary immunization in 2012 to 2015 by federal state, compliance with the vaccination schedule, and TBE vaccination uptake for the 2011 birth cohort. Vaccination protection rates for each federal state were simulated based on a compartmental model. RESULTS Vaccination rates of an initiated primary immunization ranged from about 3% in the southern federal states to

Background Pneumococcal vaccination is recommended by the German Standing Committee on Vaccination (STIKO) for infants, elderly 60+ years and patients at risk. In 2016, a sequential pneumococcal vaccination schedule (conjugate vaccine followed by polysaccharide vaccine 6–12 months later) supplemented this recommendation for immunocompromised patients ≥2 years of age. Previous research showed low pneumococcal vaccination rates (pnc-VR) in this vulnerable group. Moreover, no evidence is available on adherence to the newer sequential schedule. This study aimed to analyze the development of pnc-VRs in immunocompromised patients and rates of sequential vaccinations according to the STIKO recommendations. Methods Using a representative health claims database, we assigned incident immunocompromised patients ≥2 years of age to one of two successive cohorts to observe trends over time: cohort A (first diagnosis of immunocompromised condition between 01/2013 and 12/2014), and cohort B (first diagnosis between 01/ 2015 and 12/2017). Pnc-VR within two years after first diagnosis and cumulative pnc-VR was compared among both cohorts. In cohort B, we assessed sequential pnc-VR within 15 months of the first vaccination. For additional analyses, patients were stratified by age, gender and immunocompromising condition. Results Cohort A and B comprised 193,521 and 289,279 patients, respectively. Overall pnc-VR increased over time from 4.3% (cohort A; 95%-confidence interval: 4.3%-4.4%) to 6.0% (cohort B; 5.9%-6.1%), with highest pnc-VRs in men ≥60 years (11.3%: 11.1%-11.6%) and HIV patients (15.2%: 13.1%-17.4%). Cumulative pnc-VRs in cohort B were higher in any quarter following diagnosis when compared with cohort A. Overall sequential pnc-VR in cohort B was 4.0% (3.7%-4.3%), with a higher rate observed in patients aged 16–59 (6.8%: 6.0%-7.7%) vs. patients aged ≥60 years (3.1%: 2.8%-3.4%). Conclusion While some improvements were seen over time, pnc-VRs remain very low in immunocompromised patients, as did sequential vaccination rates. Current recommendations to protect immunocompromised patients from pneumococcal infections are not being sufficiently implemented.

Background In 2015, the German Standing Committee on Vaccination (STIKO) changed the pneumococcal conjugate vaccination (PCV) schedule for mature infants from a 3+1 scheme (2, 3, 4, and 11–14 months of age) to a 2+1 scheme (2, 4, and 11–14 months of age). For premature infants, the 3+1 scheme remained. The aim of this study was to assess vaccination rates, completeness, and timeliness for PCV in premature infants before and after the modified recommendation. Methods A retrospective claims data analysis using the “Institut fur angewandte Gesundheitsforschung Berlin” Research Database was conducted. Premature infants born in 2013 and 2016 with an individual follow-up of 24 months were included. Hexavalent combination (HEXA) vaccination with a consistent 3+1 recommendation for mature and premature infants was analyzed as reference vaccination. Results After 24 months, the PCV rate for at least one dose remained stable in premature newborns of 2016 compared to 2013, while the HEXA vaccination rate increased slightly. However, a significant decrease of a completed PCV schedule (4 doses) in premature infants was noted, whereas the completeness of HEXA vaccination did not change. The timeliness of PCV in premature newborns increased for the first and the booster PCV, while the timeliness of HEXA immunization did not change from 2013 to 2016. Conclusion Although STIKO still recommends a 3+1 PCV schedule for premature infants in Germany, premature infants were vaccinated according to the changed recommendations for mature born infants. A substantial share of premature infants remained unvaccinated, and their vaccinations were often delayed.

Background Little information on the current burden of community-acquired pneumonia (CAP) in adults in Germany is available. Methods We conducted a retrospective cohort study using a representative healthcare claims database of approx. 4 million adults to estimate the incidence rates (IR) and associated mortality of CAP in 2015. IR and mortality were stratified by treatment setting, age group, and risk group status. A pneumonia coded in the primary diagnosis position or in the second diagnosis position with another pneumonia-related condition coded in the primary position was used as the base cases definition for the study. Sensitivity analyses using broader and more restrictive case definitions were also performed. Results The overall IR of CAP in adults ≥18 years was 1,054 cases per 100,000 person-years of observation. In adults aged 16 to 59 years, IR for overall CAP, hospitalized CAP and outpatient CAP was 551, 96 and 466 (with a hospitalization rate of 17%). In adults aged ≥60 years, the respective IR were 2,032, 1,061 and 1,053 (with a hospitalization rate of 52%). If any pneumonia coded in the primary or secondary diagnosis position was considered for hospitalized patients, the IR increased 1.5-fold to 1,560 in the elderly ≥60 years. The incidence of CAP hospitalizations was substantially higher in adults ≥18 years with at-risk conditions and high-risk conditions (IR of 608 and 1,552, respectively), compared to adults without underlying risk conditions (IR 108). High mortality of hospitalized CAP in adults ≥18 was observed in-hospital (18.5%), at 30 days (22.9%) and at one-year (44.5%) after CAP onset. Mortality was more than double in older adults in comparison to younger patients. Conclusion CAP burden in older adults and individuals with underlying risk conditions was high. Maximizing uptake of existing vaccines for respiratory diseases may help to mitigate the disease burden, especially in times of strained healthcare resources.

Nasal carriage of methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) represents both a source and a risk factor for subsequent infections. However, existing MRSA decolonization strategies and antibiotic treatment options are hampered by the duration of administration and particularly by the emergence of resistance. Moreover, beyond classical resistance mechanisms, functional resistance as the formation of the small-colony variant (SCV) phenotype may also impair the course and treatment of S. aureus infections. For the recombinant bacteriophage endolysin HY-133, rapid bactericidal and highly selective in vitro activities against MSSA and MRSA has been shown. In order to assess the in vitro efficacy of HY-133 against the SCV phenotype, minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were evaluated on clinical SCVs, their isogenic wild types, as well as on genetically derived and gentamicin-selected SCVs. For all strains and growth phases, HY-133 MIC and MBC ranged between 0.12 and 1 mg/L. Time-kill studies revealed a fast-acting bactericidal activity of HY-133 resulting in a ≥3 − log10 decrease in CFU/mL within 1 h compared to oxacillin, which required 4–24 h. Since the mode of action of HY-133 was independent of growth phase, resistance pattern, and phenotype, it is a promising candidate for future S. aureus decolonization strategies comprising rapid activity against phenotypic variants exhibiting functional resistance.

The Staphylococcus aureus small-colony variant (SCV) phenotype has been associated with relapsing and antibiotic-refractory infections. However, little is known about the activities of antibiotics on clinical SCVs. Here, we demonstrated that SCVs without detectable auxotrophies were at least as susceptible to most β-lactam and non-β-lactam antibiotics in vitro as their corresponding clonally identical strains with a normal phenotype. After prolonged incubation, a regrowth phenomenon has been observed in gradient diffusion inhibition zones irrespective of the strains' phenotype.

Staphylococcus aureus small-colony variants (SCVs) often persist despite antibiotic therapy. Against a 10 8 -CFU/ml methicillin-resistant S. aureus (MRSA) (strain COL) population of which 0%, 1%, 10%, 50%, or 100% was an isogenic hemB knockout (Ia48) subpopulation displaying the SCV phenotype, vancomycin achieved maximal reductions of 4.99, 5.39, 4.50, 3.28, and 1.66 log 10 CFU/ml over 48 h. Vancomycin at ≥16 mg/liter shifted a population from 50% SCV cells at 0 h to 100% SCV cells at 48 h, which was well characterized by a Hill-type model ( R 2 > 0.90).

Staphylococcus aureus is a frequent resident of human nose and skin in many individuals, but it is also able to cause a variety of serious infections including those of the skin and soft tissue. There is increasing evidence that particularly persistent, relapsing, and difficult-to-treat infections caused by S. aureus are associated with the formation of the small-colony variant (SCV) phenotype. The aim of this study was to investigate the hypothesis that (i) skin-derived antimicrobial peptides (AMPs) exhibit a reduced activity against SCVs and (ii) that switching into the SCV phenotype may endow S. aureus with a decreased susceptibility toward the killing activity of human stratum corneum. Here, we show that clinically derived S. aureus SCVs are less susceptible to the bactericidal activity of different human skin-derived AMPs as compared with their isogenic corresponding wild-type strains. Similarly, a S. aureus hemB mutant displaying the SCV phenotype was less susceptible to the antimicrobial activity of AMPs than its hemB-complemented mutant. These findings were accompanied by a higher resistance of SCVs to the killing activity of human stratum corneum. Switching into the SCV phenotype may help S. aureus to subvert cutaneous innate defense, thus contributing to the establishment and persistence of infection.

Nasal carriage of methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) represents both a source and a risk factor for subsequent infections. However, existing MRSA decolonization strategies and antibiotic treatment options are hampered by the duration of administration and particularly by the emergence of resistance. Moreover, beyond classical resistance mechanisms, functional resistance as the formation of the small-colony variant (SCV) phenotype may also impair the course and treatment of S. aureus infections. For the recombinant bacteriophage endolysin HY-133, rapid bactericidal and highly selective in vitro activities against MSSA and MRSA has been shown. In order to assess the in vitro efficacy of HY-133 against the SCV phenotype, minimal inhibitory (MIC) and minimal bactericidal concentrations (MBC) were evaluated on clinical SCVs, their isogenic wild types, as well as on genetically derived and gentamicin-selected SCVs. For all strains and growth phases, HY-133 MIC and MBC ranged between 0.12 and 1 mg/L. Time-kill studies revealed a fast-acting bactericidal activity of HY-133 resulting in a &ge, 3 &minus, log10 decrease in CFU/mL within 1 h compared to oxacillin, which required 4&ndash, 24 h. Since the mode of action of HY-133 was independent of growth phase, resistance pattern, and phenotype, it is a promising candidate for future S. aureus decolonization strategies comprising rapid activity against phenotypic variants exhibiting functional resistance.

Staphylococcus aureus is a major human pathogen causing cutaneous infections to life-threatening bacteremia. These infections are often caused by strains derived from the own microflora suggesting that a disturbed epidermal barrier may promote invasion of S. aureus. Antimicrobial peptides and proteins (AMP) such as human beta-defensin-3 and RNase 7 contribute to control the colonization of S. aureus on the skin surface. This leads to the hypothesis that strains with a decreased susceptibility toward skin-derived AMP may better overcome the innate cutaneous defence barrier increasing the possibility of invading into the blood stream. To address this hypothesis we determined whether S. aureus strains from bacteremia patients are less susceptible to various skin-derived AMP than strains from healthy carriers. No differences in the AMP-killing activity against bacteremia-derived S. aureus and control strains were detected suggesting that the onset of S. aureus bacteremia is not based on the varying susceptibilities against skin-derived AMP.

Primary control of the staphylococcal virulon is mediated by the accessory gene regulator (agr) quorum-sensing system [1]. agr-defective mutants are attenuated for virulence in animal models of acute infection, and agents that block agr and quorum-sensing exhibit antiinfective properties [2]. However, agr-defective mutants are frequently recovered from patients with bacteremia, where the mutants are associated with persistent infection and poor outcome [3, 4]. The frequent recovery of agr− and mixtures of agr+ and agr− phenotypes from patients supports the idea that agr variation is selected for in vivo. However, it is unknown whether and to what extent loss-of-function mutations arise during the initial invasive stage of blood infection in human hosts. In the present work, we sought to determine the frequency of a within-host shift in agr functionality during infection by screening for mutational changes in the agr locus among 158 Staphylococcus aureus clone pairs obtained from blood and nasal sites of individual patients [5]. Additionally, when a clonal S. aureus isolate was recovered from the clinically presumed focus of infection, strains were characterized to determine their role as a reservoir for agr-defective mutants. To address the directionality of colonization and infection, we included in the analysis carriage strains isolated both before and after the detection of bacteremia. Finally, to determine whether fully virulent, agr+ strains were more likely to cause invasive disease than agr− strains, we compared the frequency of agr dysfunction in colonizing strains from bacteremic patients and uninfected controls. We report that agr− strains were frequently recovered from patients with S. aureus bacteremia and that clones having the same inactivating agr mutation were recovered from colonizing sites within the same individual. Furthermore, agr− strain frequencies were similar among carriers who developed bacteremia and controls who did not, providing evidence that variation in agr was not correlated with progression to disease. Taken together, these results support the importance of variables other than agr functionality, such as host risk factors, the mode of bloodstream invasion, and possibly inoculum size, in determining the invasiveness of S. aureus in hospitalized patients.

This large prospective non-interventional study investigated the effects of tigecycline either as single agent or in combination with other antimicrobial agents in 1,025 patients treated in clinical routine at German hospitals. Sixty-five percent of the patients had APACHE II scores >15, indicating high overall disease severity. Complicated intra-abdominal infections (cIAI) or complicated skin and skin tissue infections (cSSTI) were the most common indications, with Staphylococcus aureus, Enterococcus faecium and Escherichia coli being the most frequently isolated pathogens. Clinical success was reported at the end of tigecycline therapy in 74.2% of the total population, in 75.4% of the cIAI and in 82.2% of the cSSTI patients. The subpopulation (28.0% of the patients) infected with multidrug-resistant pathogens (methicillin-resistant S. aureus, extended-spectrum β-lactamase producers and vancomycin-resistant enterococci) were treated with similar success rates as the overall population. Tigecycline was generally well tolerated. Drug-related adverse events (AEs) were reported in 7.7% of the total population; 2.5% had serious AEs mostly attributable to inefficacy of therapy or deterioration of the disease. Mortality rates were consistent with the types of infection and severity of illness. There was no indication of excessive mortality associated with tigecycline as had been suggested in previously performed meta-analyses. In this large non-interventional study performed in the clinical routine setting, tigecycline achieved favorable clinical success rates in a patient population with high severity of illness and a high prevalence of multidrug-resistant pathogens and showed a good safety and tolerability profile.

Small-colony variants (SCVs) of Staphylococcus aureus represent a slow-growing subpopulation causing chronic and relapsing infections due to their physiological adaptation on an intracellular lifestyle. In this first proteomic study on physiological changes associated with a natural, clinically derived SCV, its proteomic profile was investigated in comparison to corresponding isogenic strains displaying normal (clinical wild-type strain, complemented hemB mutant and spontaneous revertant of the clinical SCV) and SCV phenotypes (hemB mutant and gentamicin-induced SCV). Applying an ultra-high resolution chromatography and high mass accuracy MS(E) -based label-free relative and absolute protein quantification approach, the whole cytoplasmic proteome of this strain sextet was investigated in a growth phase-controlled manner covering early-exponential, late-exponential and stationary phases. Of 1019 cytoplasmic proteins identified, 154 were found to be differently regulated between strains. All SCV phenotypes showed down-regulation of the tricarboxylic acid (TCA) cycle-related proteins and of a protein cluster involved in purine/pyrimidine and folate metabolism. In contrast to hemB mutant and gentamicin-induced SCVs, the clinically derived SCVs showed no prominent up-regulation of glycolytic proteins. The spontaneous switch into the normal phenotype resulted in up-regulation of TCA cycle-related parts, while oxidative stress-related proteins were down-regulated. However, the natural revertant from the clinical SCV retained also dominant protein features of the clinical SCV phenotype. In conclusion, physiological changes between normal and SCV S. aureus phenotypes are more complex than reflected by defined electron transport chain-interrupting mutants and their complemented counterparts.

The small-colony-variant (SCV) phenotype of Staphylococcus aureus has been associated with difficult-to-treat infections, reduced antimicrobial susceptibility, and intracellular persistence. This study represents a detailed intra- and extracellular investigation of a clinical wild-type (WT) S. aureus strain and its counterpart with an SCV phenotype both in vitro and in vivo , using the THP-1 cell line model and the mouse peritonitis model, respectively. Bacteria of both phenotypes infected the mouse peritoneum intra- and extracellularly. The SCV phenotype was less virulent and showed distinct bacterial clearance, a reduced multiplication capacity, and a reduced internalization ability. However, some of the SCV-infected mice were still culture positive up to 96 h postinfection, and bacteria of this phenotype could spread to the mouse kidney and furthermore revert to the more virulent WT phenotype in both the mouse peritoneum and kidney. The SCV phenotype is therefore, despite reduced virulence, an important player in S. aureus pathogenesis. In the THP-1 cell line model, both dicloxacillin (DCX) and linezolid (LZD) reduced the intracellular inocula of bacteria of both phenotypes by approximately 1 to 1.5 log 10 in vitro , while DCX was considerably more effective against extracellular bacteria. In the mouse peritonitis model, DCX and LZD were also able to control both intra- and extracellular infections caused by either phenotype. Treatment with a single dose of DCX and LZD was, however, insufficient to clear the SCVs in the kidneys, and the risk of recurrent infection remained. This stresses the importance of an optimal dosing of the antibiotic when SCVs are present.

The Panton-Valentine leukocidin (PVL) of Staphylococcus aureus plays an important role in the pathogenesis of necrotizing pneumonia and recurrent skin and soft tissue infections. The gene encoding for PVL, lukS/F-PV, is distributed by prophages and can thus spread between isolates. Molecular methods have normally been used to identify lukS/F-PV-positive strains. Recently, however, a matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS)-based method has been described to identify PVL-positive S. aureus strains. The aim of this study was thus to investigate the association of distinct MALDI-TOF MS peaks to the toxin profile in molecularly characterized methicillin-susceptible (MSSA) and methicillin-resistant S. aureus (MRSA) strains harbouring lukS/F-PV. In contrast to the previous results, the MALDI-TOF MS peaks were detected in all 104 recently described molecularly divergent MRSA irrespective of the presence of PVL. Our result indicates that these described peaks seem to be independent of the presence of PVL.

An alignment of upstream regions of anaerobically induced genes in Staphylococcus aureus revealed the presence of an inverted repeat, corresponding to Rex binding sites in Streptomyces coelicolor. Gel shift experiments of selected upstream regions demonstrated that the redox-sensing regulator Rex of S. aureus binds to this inverted repeat. The binding sequence – TTGTGAAW4TTCACAA – is highly conserved in S. aureus. Rex binding to this sequence leads to the repression of genes located downstream. The binding activity of Rex is enhanced by NAD+ while NADH, which competes with NAD+ for Rex binding, decreases the activity of Rex. The impact of Rex on global protein synthesis and on the activity of fermentation pathways under aerobic and anaerobic conditions was analysed by using a rex-deficient strain. A direct regulatory effect of Rex on the expression of pathways that lead to anaerobic NAD+ regeneration, such as lactate, formate and ethanol formation, nitrate respiration, and ATP synthesis, is verified. Rex can be considered a central regulator of anaerobic metabolism in S. aureus. Since the activity of lactate dehydrogenase enables S. aureus to resist NO stress and thus the innate immune response, our data suggest that deactivation of Rex is a prerequisite for this phenomenon.

Background and Objectives The placement of megaprostheses in patients with bone sarcoma is associated with high rates of infection, despite prophylactic antibiotic administration. In individual cases, secondary amputation is unavoidable in the effort to cure infection. Methods The infection rate in 51 patients with sarcoma (proximal femur, n = 22; proximal tibia, n = 29) who underwent placement of a silver-coated megaprosthesis was assessed prospectively over a 5-year period, along with the treatment administered for infection. The infection rate was compared with the data for 74 patients in whom an uncoated titanium megaprosthesis (proximal femur, n = 33; proximal tibia, n = 41) was implanted. Results The infection rate was substantially reduced from 17.6% in the titanium to 5.9% in the silver group. Whereas 38.5% of patients in the titanium group ultimately had to undergo amputation when periprosthetic infection developed, these mutilating surgical procedures were not necessary in the study group. Conclusions The use of silver-coated prostheses reduced the infection rate in the medium term. In addition, less aggressive treatment of infection was possible in the group with silver-coated prostheses. Further studies with longer term follow-up periods and larger numbers of patients are warranted in order to confirm these encouraging results. J. Surg. Oncol. 2010; 101:389–395. © 2010 Wiley-Liss, Inc.

Catheter-related bloodstream infections due to slow-growing Staphylococcus epidermidis small-colony variants (SCVs) are extremely difficult to treat. Daptomycin and vancomycin pharmacodynamics were evaluated against a site-directed hemB mutant of S. epidermidis displaying the SCV phenotype and compared to that of the parental strain. The maximal killing effect decreased by 7.7-fold for vancomycin and 1.5-fold for daptomycin against the SCV mutant and were well characterized by a Hill-type mathematical model ( R 2 > 0.97).

There is ample evidence that Staphylococcus aureus capsular polysaccharide (CP) promotes virulence. Loss of capsule expression, however, may lead to S. aureus persistence in a chronically infected host. This study was conducted to determine the relative prevalence of nonencapsulated S. aureus in patients with chronic and acute osteomyelitis. Only 76/118 (64%) S. aureus isolates from patients with osteomyelitis expressed CP, whereas all 50 isolates from blood cultures of patients with infections other than osteoarticular infections expressed CP ( P = 0.0001). A significantly higher prevalence of nonencapsulated S. aureus was found in patients with chronic osteomyelitis (53%) than in those with acute osteomyelitis (21%) ( P = 0.0046). S. aureus isolates obtained from multiple specimens from five of six patients with chronic osteomyelitis exhibited phenotypic (expression of CP, α-hemolysin, β-hemolysin, slime, and the small-colony variant phenotype) and/or genotypic (pulsed-field gel electrophoresis and spa typing) differences. Nonencapsulated S. aureus was recovered from at least one specimen from each chronic osteomyelitis patient. Fourteen isolates obtained from two patients with acute osteomyelitis were indistinguishable from each other within each group, and all produced CP5. In conclusion, we demonstrated that nonencapsulated S. aureus is more frequently isolated from patients with chronic osteomyelitis than from those with acute osteomyelitis, suggesting that loss of CP expression may be advantageous to S. aureus during chronic infection. Our findings on multiple S. aureus isolates from individual patients allow us to suggest that selection of nonencapsulated S. aureus is likely to have occurred in the patient during long-term bone infection.

Staphylococcus aureus small colony variants (SCVs) are slow-growing morphological variants associated with persistent infections. While vancomycin activity has been shown to be attenuated against SCVs of S. aureus, few data exist regarding daptomycin. The objective was to evaluate the pharmacodynamics of daptomycin against defined S. aureus mutants displaying the SCV phenotype.Two S. aureus hemB mutants (Ia48 and III33) displaying the SCV phenotype and their parental strains (COL and Newman) were evaluated. Time-kill experiments were performed using a starting inoculum of 10(6) cfu/mL at 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32 and 64 times the MIC. Samples were obtained at 0, 1, 2, 4, 6, 8 and 24 h, plated and incubated to determine colony counts. A Hill-type pharmacodynamic mathematical model was fitted to the data to characterize the effect.Bactericidal activity for daptomycin was achieved and occurred in a concentration-dependent manner against both hemB mutants and their parental strains. Against strains with normal phenotype, bactericidal activity was achieved rapidly, within 2 h at concentrationsor =16 times the MIC, while against SCVs, bactericidal activity was achieved within 6 h at concentrationsor =16 times the MIC. Against both hemB mutants, daptomycin maintained bactericidal activity at 24 h, with similar profiles of killing activity when compared with their parental strains.Daptomycin achieved bactericidal activity against S. aureus hemB mutants and parenteral isolates. Daptomycin represents a potential therapeutic option for infections caused by S. aureus strains displaying the SCV phenotype and additional studies are warranted.

Astrocyte activation indicated by increased S100B is considered a potential pathogenic factor for schizophrenia. To investigate the relationship between astrocyte activation and cognitive performance, S100B serum concentration, memory performance, and psychopathology were assessed in 40 first-episode and 35 chronic schizophrenia patients upon admission and after four weeks of treatment. Chronic schizophrenia patients with high S100B were impaired concerning verbal memory performance (AVLT, Auditory Verbal Learning Test) compared to chronic and first-episode patients with low S100B levels. The findings support the hypothesis that astrocyte activation might contribute to the development of cognitive dysfunction in schizophrenia.