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• Seasonality in antimicrobial resistance (AMR) rates of community-acquired E. coli bloodstream isolates was examined. • E. coli isolates showed seasonal variation in AMR rates to four agents from frequently used classes in ambulatory settings. • The proportion of multidrug-resistant E. coli increased during peak of antimicrobial prescription in winter months. Seasonal variation in community antimicrobial consumption has been demonstrated, with the lowest utilisation rates during summer months. This retrospective cohort study examined seasonality in antimicrobial resistance (AMR) rates of community-acquired Escherichia coli bloodstream isolates. Escherichia coli bloodstream isolates (2010–2015) were identified through the central Palmetto Health microbiology laboratory database. Multivariate logistic regression was used to examine seasonal variation in AMR. Poisson regression was used to evaluate the association between proportion of multidrug-resistant (MDR) isolates and bimonthly ambulatory antimicrobial prescription rates. Among 339 unique patients with community-acquired E. coli bloodstream infection [median age 65 years; 205 (60.5%) female], AMR rates were lower during summer (June–September) than the rest of the year for amoxicillin/clavulanic acid (17% vs. 29%; aOR = 0.53, 95% CI 0.30–0.92; P = 0.02), cefazolin (6% vs. 19%; aOR = 0.26, 95% CI 0.10–0.58; P < 0.001), ceftriaxone (2% vs. 6%; aOR = 0.25, 95% CI 0.04–0.93; P = 0.04) and trimethoprim/sulfamethoxazole (9% vs. 27%; aOR = 0.27, 95% CI 0.13–0.53; P < 0.001). The proportion of MDR E. coli declined from 31–36% during peak antimicrobial prescription to 11–14% in summer months; a 6.8% decline per interval decrease in antimicrobial prescription rates of 10/100 person-years (P = 0.01). There is significant seasonal variation in AMR rates of E. coli bloodstream isolates to four agents from frequently utilised antimicrobial classes in the community. Examination of seasonal variation in dominant serotypes of community-acquired E. coli bloodstream isolates in future will be valuable. [ABSTRACT FROM AUTHOR]

Third-generation cephalosporins (3GCs) [ceftriaxone (CRO) and cefotaxime (CTX)] have remarkable potency against Enterobacteriaceae and are commonly prescribed for the treatment of community-onset bacteraemia. However, clinical evidence supporting the updated interpretive criteria of the Clinical and Laboratory Standards Institute (CLSI) is limited. Adults with community-onset monomicrobial Enterobacteriaceae bacteraemia treated empirically with CRO or CTX were recruited. Clinical information was collected from medical records and CTX MICs were determined using the broth microdilution method. Eligible patients ( n = 409) were categorised into de-escalation (260; 63.6%), no switch (115; 28.1%) and escalation (34; 8.3%) groups according to the type of definitive antibiotics. Multivariate regression revealed five independent predictors of 28-day mortality: fatal co-morbidities based on McCabe classification [odds ratio (OR) = 19.96; P < 0.001]; high Pitt bacteraemia score (≥4) at bacteraemia onset (OR = 13.91; P < 0.001); bacteraemia because of pneumonia (OR = 5.45; P = 0.007); de-escalation after empirical therapy (OR = 0.28; P = 0.03); and isolates with a CTX MIC ≤ 1 mg/L (OR = 0.17; P = 0.02). Of note, isolates with a CTX MIC ≤ 8 mg/L (indicated as susceptible by previous CLSI breakpoints) were not associated with mortality. Furthermore, clinical failure and 28-day mortality rates had a tendency to increase with increasing CTX MIC ( γ = 1.00; P = 0.01). Conclusively, focusing on patients with community-onset Enterobacteriaceae bacteraemia receiving empirical 3GC therapy, the present study provides clinically critical evidence to validate the proposed reduction in the susceptibility breakpoint of CTX to MIC ≤ 1 mg/L. [ABSTRACT FROM AUTHOR]

Drug-resistant Neisseria gonorrhoeae has become a global health concern that requires immediate attention. Due to increasing resistance to cephalosporins, pursuing novel alternatives for treating N. gonorrhoeae infections is paramount. Whilst new drug development is often cumbersome, reviving antiquated antibiotic agents for treatment of modern infections has become prevalent in clinical practice. Fosfomycin exhibits bactericidal activity through a unique mechanism of action, and a variety of organisms including N. gonorrhoeae are susceptible. In vitro studies have demonstrated that fosfomycin can retain activity against ceftriaxone-resistant N. gonorrhoeae ; however, it remains unclear whether there is synergy between fosfomycin and other antibiotics. Clinical investigations evaluating fosfomycin for the treatment of N. gonorrhoeae infections are confounded by methodological limitations, none the less they do provide some perspective on its potential role in therapy. Future studies are needed to establish a safe, convenient and effective fosfomycin regimen for treating N. gonorrhoeae infections. [ABSTRACT FROM AUTHOR]

Abstract: Antibiotic stewardship is universally agreed to be desirable, but optimal models for stewardship remain uncertain. UK stewardship targets the particular antibiotic families—cephalosporins and fluoroquinolones—blamed for the selection of Clostridium-difficile-associated disease. To balance this there have been dramatic increases in the use of penicillin–β-lactamase inhibitor combinations. By channelling selection pressure in this way, we hazard destroying the utility of these antibiotic classes in turn, as happened with gonorrhoea where penicillins, fluoroquinolones and cefixime were sequentially lost as therapies. Strikingly, in context, almost all carbapenemase-producers are highly resistant to penicillin–β-lactamase inhibitor combinations, which may select for them. There is an urgent need to explore an alternative stewardship model, seeking to limit total antibiotic use but to maintain heterogeneity in what is used, avoiding concentrated selection pressure. There is also a great need to improve and accelerate diagnostics for infection and resistance, reducing or removing the need for protracted empirical treatment with broad-spectrum agents. [Copyright &y& Elsevier]

Abstract: The aim of this study was to evaluate the in vitro efficacy of ceftobiprole and comparator antibiotics, either alone or in combination, in staphylococcal MBEC™ (minimum biofilm eradication concentration) and colony biofilm assays at dilutions of the maximum free-drug plasma concentration attained during clinical use (fC max). Staphylococci tested included meticillin-susceptible and meticillin-resistant Staphylococcus aureus (n =6) and Staphylococcus epidermidis (n =2). Relative to no-drug controls, after 7 days of exposure ceftobiprole concentrations from 1/4 fC max to fC max generally decreased CFUs in MBEC or colony biofilms of S. aureus isolates by ca. 1.5log10 to ≥2.5log10. Gentamicin reduced colony biofilm CFUs by ≥1.4log10 at these concentrations with gentamicin-susceptible isolates. Following 7 days of exposure, vancomycin and rifampicin were ineffective as single agents or in combination in the colony model, but yielded CFU decreases from 0 to 5log10 in the MBEC model. Treatment of biofilms with rifampicin for 7 days yielded rifampicin-resistant mutants, and the selection of rifampicin resistance was inhibited by co-treatment with ceftobiprole. Thus, ceftobiprole alone or in combination demonstrated promising activity against biofilms of meticillin-susceptible and -resistant staphylococci at clinically relevant concentrations. In contrast, vancomycin and rifampicin, two agents used clinically for the treatment of biofilm infections, tested separately or together gave inconsistent results and generally had little impact on cell viability. [Copyright &y& Elsevier]

Abstract: Early appropriate antibiotic treatment reduces mortality in severe sepsis, but current methods to identify antibiotic resistance still generally rely on bacterial culture. Modern diagnostics promise rapid gene detection, but the apparent diversity of relevant resistance genes in Enterobacteriaceae is a problem. Local surveys and analysis of publicly available data sets suggested that the resistance gene pool is dominated by a relatively small subset of genes, with a very high positive predictive value for phenotype. In this study, 152 Escherichia coli and 115 Klebsiella pneumoniae consecutive isolates with a cefotaxime, ceftriaxone and/or ceftazidime minimum inhibitory concentration (MIC) of ≥2μg/mL were collected from seven major hospitals in Sydney (Australia) in 2008–2009. Nearly all of those with a MIC in excess of European Committee on Antimicrobial Susceptibility Testing (EUCAST) resistance breakpoints contained one or more representatives of only seven gene types capable of explaining this phenotype, and this included 96% of those with a MIC≥2μg/mL to any one of these drugs. Similarly, 97% of associated gentamicin-non-susceptibility (MIC≥8μg/mL) could be explained by three gene types. In a country like Australia, with a background prevalence of resistance to third-generation cephalosporins of 5–10%, this equates to a negative predictive value of >99.5% for non-susceptibility and is therefore suitable for diagnostic application. This is an important proof-of-principle that should be tested in other geographic locations. [Copyright &y& Elsevier]

Abstract: Although cephalosporins are recommended as primary agents, moxifloxacin may be a suitable second-line antibiotic in cardiac surgery, especially if additional Gram-negative coverage is warranted. Cardiopulmonary bypass (CPB) may alter the pharmacokinetics of drugs in numerous ways. Since no such data exist, the aim of this study was to assess the serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing cardiac surgery with CPB. Fourteen coronary artery bypass graft surgery patients received an intravenous infusion of 400mg moxifloxacin as peri-operative antibiotic prophylaxis. At 15 time points throughout a 24-h period, serum samples were obtained to measure moxifloxacin concentrations using high-performance liquid chromatography. In addition, a non-compartmental pharmacokinetic analysis, i.e. area under the concentration–time curve (AUC), volume of distribution at steady state (V SS), drug clearance (CL), elimination half-life (t 1/2) and mean residence time (MRT), was performed in five patients. Apart from a slight transient decrease in moxifloxacin concentration at the onset, CPB did not affect the concentration–time curve. Mean±standard deviation maximum drug concentration (C max) (5.12±1.58μg/mL), AUC (36.5±5.40μgh/mL), V SS (2.03±0.30L/kg), CL (11.2±1.91L/h), t 1/2 (9.47±0.92h) and MRT (12.9±1.52h) were comparable with historical data for healthy volunteers. We conclude that CPB does not alter the pharmacokinetics of moxifloxacin. No dose adjustments, especially with regard to the CPB circuit and its priming volume, are necessary in cardiac surgical patients. [Copyright &y& Elsevier]

Abstract: Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a novel cephalosporin exhibiting bactericidal activity in vitro against Gram-positive organisms, including meticillin-susceptible Staphylococcus aureus (MSSA), meticillin-resistant S. aureus (MRSA), β-haemolytic streptococci, viridans group streptococci (VGS) and Streptococcus pneumoniae, as well as against many common Gram-negative organisms. The objective of this study was to determine the spectrum and potency of ceftaroline against recent (2010) leading pathogens causing complicated skin and soft-tissue infections (cSSTIs) isolated in Europe. A total of 2438 isolates from the Assessing Worldwide Antimicrobial Resistance and Evaluation (AWARE) programme were identified as cSSTI pathogens. Isolates were collected from patients in 52 medical centres in 19 European countries. Reference susceptibility testing for ceftaroline and commonly used antimicrobials was performed by broth microdilution methodologies. Ceftaroline was very active overall against S. aureus (MIC50/90 =0.25/1mg/L) and inhibited 100.0% of isolates at a MIC of ≤2mg/L. Activity against MRSA was documented (MIC50/90 =1/2mg/L) but was lower than that observed against MSSA (MIC50/90 =0.25/0.25mg/L). Ceftaroline was also very active against 460 β-haemolytic streptococci and 93 VGS (MIC90 =0.015mg/L and 0.06mg/L, respectively). Ceftaroline was active against Escherichia coli (MIC50 =0.12mg/L) and Klebsiella pneumoniae (MIC50 =0.06mg/L) not expressing extended-spectrum β-lactamases, with activity similar to ceftriaxone and ceftazidime. In summary, this study documents the potent in vitro activity of ceftaroline when tested against recent pathogens isolated from patients with cSSTI in Europe. [Copyright &y& Elsevier]

Abstract: Some bacteria that possess chromosomally determined AmpC β-lactamases may express these enzymes at a high level following exposure to β-lactams, either by induction or selection for derepressed mutants. This may lead to clinical failure even if an isolate initially tests susceptible in vitro, a phenomenon best characterised by third-generation cephalosporin therapy for Enterobacter bacteraemia or meningitis. Several other Enterobacteriaceae, such as Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (often termed the ‘ESCPM’ group), may also express high levels of AmpC. However, the risk of clinical failure with β-lactams that test susceptible in vitro is less clear in these species than for Enterobacter. Laboratories frequently do not report β-lactam or β-lactamase inhibitor combination drug susceptibilities for ESCPM organisms, encouraging alternative therapy with quinolones, aminoglycosides or carbapenems. However, quinolones and carbapenems present problems with selective pressure for multiresistant organisms, and aminoglycosides with potential toxicity. The risk of emergent AmpC-mediated resistance for non-Enterobacter spp. appears rare in clinical studies. Piperacillin/tazobactam may remain effective and may be less selective for AmpC derepressed mutants than cephalosporins. The potential roles for agents such as cefepime or trimethoprim/sulfamethoxazole are also discussed. Clinical studies that better define optimal treatment for this group of bacteria are required. [Copyright &y& Elsevier]

Abstract: Uncomplicated urinary tract infections (UTIs) in otherwise healthy premenopausal women are one of the most frequent infections in the community. Therefore any improvement in management will have a high impact not only on the quality of life of the individual patient but also on the health system. In placebo-controlled studies antimicrobial treatment was significantly more effective than placebo, but on the other hand showed more adverse events. The choice of antibiotic depends on the spectrum and susceptibility patterns of the uropathogens, its effectiveness for this indication, its tolerability, its collateral effects and cost. After a systematic literature search, recommendations for empiric treatment of acute uncomplicated cystitis and acute uncomplicated pyelonephritis and for follow-up strategies were developed. [Copyright &y& Elsevier]

Abstract: Acute haematogenous osteomyelitis (AHOM) of childhood usually affects the long bones of the lower limbs. Although almost any agent may cause AHOM, Staphylococcus aureus is the most common bacterium, followed by Streptococcus pneumoniae and, in some countries, Salmonella spp. and Kingella kingae. Magnetic resonance imaging (MRI) has improved the diagnostic accuracy of traditional radiography and scintigraphy. Except for the pre-treatment diagnostic sample from bone before the institution of antibiotic therapy, no other surgery is usually required. Traditionally, non-neonatal AHOM has been treated with a 1–3-month course of antibiotics, including an intravenous (i.v.) phase for the first weeks, but recent prospective randomised studies challenge this approach. For most uncomplicated cases, a course of 20 days including an i.v. period of 2–4 days suffices, provided large enough doses of a well-absorbed agent (clindamycin or a first-generation cephalosporin, local resistance permitting) are used, administration is four times daily and most symptoms and signs subside within a few days. Serum C-reactive protein (CRP) is a good guide in monitoring the course of illness, and the antimicrobial can usually be discontinued if CRP has decreased to <20mg/L. Newer and costly agents, such as linezolid, should be reserved for cases due to resistant S. aureus strains. AHOM in neonates and immunocompromised patients probably requires a different approach. Because sequelae may develop slowly, follow-up for at least 1 year post hospitalisation is recommended. [Copyright &y& Elsevier]

Abstract: Ceftaroline is a novel broad-spectrum cephalosporin antibiotic currently under US Food and Drug Administration (FDA) review for a new drug application (NDA), filed by Cerexa, Inc. (a wholly owned subsidiary of Forest Laboratories), for the treatment of complicated skin and skin-structure infections (cSSSIs) and community-associated pneumonia (CAP). The antibiotic acts by binding to penicillin-binding proteins in bacteria, consistent with other β-lactams. The antimicrobial spectrum of ceftaroline ranges from aerobic and anaerobic Gram-positive bacteria, including drug-resistant isolates of staphylococci, i.e. heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), to anaerobic Gram-negative pathogens such as Moraxella catarrhalis and Haemophilus influenzae (including β-lactamase-positive strains), as well as bacteria with multiple resistance phenotypes. Ceftaroline fosamil is the prodrug that is rapidly dephosphorylated by in vivo plasma phosphatases to the active drug ceftaroline, which follows a two-compartmental pharmacokinetic model and is eliminated primarily by renal excretion, with a plasma half-life of ca. 2.5h. Ceftaroline is well tolerated, which is consistent with its good safety profile similar to other cephalosporins in clinical trials. Thus, it would be a promising drug to fight multidrug-resistant superbugs such as S. aureus and Streptococcus pneumoniae for the treatment of cSSSIs and CAP. [Copyright &y& Elsevier]

Abstract: Wide-spectrum quinolones such as moxifloxacin and levofloxacin as well as high-order cephalosporins such as cefoperazone and cefepime have increased antimicrobial activity. However, little is known about their distribution in fetal blood. Therefore, the aim of this study was to measure and compare maternal and fetal blood levels of these agents. For the measurement of blood levels, 9 pregnant women received cefepime hydrochloride, 10 received cefoperazone, 10 received moxifloxacin and 12 received levofloxacin intravenously. Maternal and umbilical cord blood samples were drawn during delivery. Antibiotic levels were analysed by high-performance liquid chromatography. Mean transplacental passage rates of moxifloxacin, levofloxacin, cefepime and cefoperazone were 74.84%, 66.53%, 23.21% and 12.68%, respectively, and mean transfetal passage rates were 90.78%, 84.22%, 79.17% and 79.78%, respectively. The transplacental passage rate for either quinolone was significantly higher than that of either cephalosporin, and the transplacental passage rate of cefoperazone was lower than that of cefepime. In conclusion, both quinolones have high transplacental passage rates. Cefepime and cefoperazone have a lower transplacental passage rate and thus may be used as prophylaxis in situations where transplacental passage is undesirable. [Copyright &y& Elsevier]

Abstract: Interference of cefditoren (CDN) and amoxicillin/clavulanic acid (AMC) with biofilm production was studied using 11 Streptococcus pneumoniae isolates with minimum inhibitory concentrations (MICs) ranging from 0.015μg/mL to 0.5μg/mL for CDN and from 0.06μg/mL to 2μg/mL for AMC (except for one isolate with an AMC MIC of 8μg/mL) and 5 Haemophilus influenzae isolates with MICs of 0.03–0.06μg/mL for CDN and 0.5–16μg/mL for AMC. Slime production was assessed in antibiotic-free medium and with 0.03μg/mL CDN or 1/0.5μg/mL AMC by measuring the optical density at 450nm (OD450). Significantly lower mean OD450 values were obtained for S. pneumoniae with antibiotics compared with controls (CDN, 0.088 vs. 0.118, P =0.003; and AMC, 0.095 vs. 0.112, P =0.003), with significant correlation between both antibiotics (r =0.752; P =0.008). Percent reduction in OD450 values was higher for CDN compared with AMC (24.02% vs. 15.92%; P =0.008). For H. influenzae, significantly lower mean OD450 values were obtained with CDN compared with controls (0.083 vs. 0.096; P =0.043) but not with AMC (0.086 vs. 0.095; P =0.08). Comparing percent reductions in S. pneumoniae versus H. influenzae for each antibiotic, no differences were found for AMC (15.92% vs. 9.40%; P =0.36), with a tendency for CDN (24.02% vs. 13.79%; P =0.069). Different β-lactams may have different capabilities of interfering with S. pneumoniae biofilm development when tested under the same experimental conditions. [Copyright &y& Elsevier]

Abstract: The advancing antimicrobial drug resistance among Enterobacteriaceae renders the evaluation of potential novel therapeutic options necessary. We sought to evaluate the in vitro antimicrobial activity of fosfomycin against multidrug-resistant (MDR) Enterobacteriaceae isolates. Antimicrobial susceptibility to fosfomycin and 12 additional antibiotics of MDR Enterobacteriaceae isolates collected between November 2007 and April 2009 at the University Hospital of Heraklion, Crete, Greece, was examined using the Etest method. A total of 152 MDR Enterobacteriaceae isolates were studied, including Klebsiella pneumoniae (76.3%), Escherichia coli (17.1%), Proteus mirabilis (4.6%) and other species (2.0%). Antimicrobial susceptibility rates were highest for fosfomycin (92.8%), tigecycline (92.1%) and colistin (73.0%) followed by imipenem (35.5%), tetracycline (20.4%), gentamicin (19.7%), trimethoprim/sulfamethoxazole (12.5%) and ciprofloxacin (10.5%). Of the 152 isolates, 85 (55.9%) were extensively drug-resistant (XDR), of which 78 (91.8%) remained susceptible to fosfomycin. Susceptibility to fosfomycin of the 79 carbapenemase-producing, 34 extended-spectrum β-lactamase-producing and 24 metallo-β-lactamase-producing isolates was 94.9%, 94.1% and 83.3%, respectively. In conclusion, in this study fosfomycin exhibited good in vitro antimicrobial activity against MDR and XDR Enterobacteriaceae. We suggest further evaluation of the potential clinical utility of fosfomycin against infections caused by these pathogens. [Copyright &y& Elsevier]

Abstract: Semi-synthetic penicillins and cephalosporins both derive from their respective chemical nuclei, 6-aminopenicillanic acid (6-APA) and 7-aminocephalosporanic acid (7-ACA). Work leading to their isolation was being carried out in parallel, but following very different pathways, during the last half of the 1950s. The development of 6-APA was reviewed recently in this journal, and in the present article I take a closer look at early work on ‘penicillin amidase’ and revisit the steps that led to 7-ACA. [Copyright &y& Elsevier]

Abstract: This nationwide study assessed the antimicrobial susceptibility and seroprevalence of Streptococcus pneumoniae in paediatric carriage isolates and in clinical isolates from adult pneumococcal disease in Greece during the years 2004–2006. Among 780 isolates recovered from the nasopharynx of children <6 years old attending day-care centres, non-susceptibility rates to penicillin, cefuroxime, ceftriaxone, erythromycin, tetracycline and trimethoprim/sulfamethoxazole were 34.7%, 25.1%, 1.0%, 33.5%, 26.4% and 44.2%, respectively. Among 89 adult clinical isolates, the respective rates were 48.3%, 46.1%, 5.6%, 48.3%, 32.6% and 40.4%. High-level resistance to penicillin, cefuroxime and ceftriaxone was recorded for 14.4%, 23.3% and 0.1% of paediatric carriage isolates, whereas for clinical adult isolates the respective rates were 25.8%, 38.2% and 2.2%. No resistance to levofloxacin and moxifloxacin was recorded, although 3.5% of paediatric carriage isolates and 23.2% of adult clinical isolates had minimum inhibitory concentrations of ciprofloxacin >2mg/L. Serotypes 19F, 14, 23F and 6B were the most prevalent among carriage and clinical isolates. The 7-valent pneumococcal conjugate vaccine was estimated to provide coverage against 71.7% of paediatric carriage isolates and 51.3% of adult clinical isolates. Resistance rates among clinical isolates from adult sources were higher than those recorded among paediatric carriage S. pneumoniae isolates and displayed an increasingly resistant profile compared with previous reports from our country, warranting continuous vigilance. [Copyright &y& Elsevier]

Abstract: Little is known about the in vitro activity of penems and carbapenems against the spirochete Borrelia burgdorferi. Here, faropenem, ertapenem, imipenem and meropenem as well as the third-generation cephalosporin ceftriaxone and tobramycin were tested in vitro against 11 isolates of the B. burgdorferi sensu lato complex. On a μg/mL basis, ertapenem was the most potent carbapenem (minimal inhibitory concentration (MIC) range: 0.015–0.125μg/mL), with in vitro activity comparable with that of ceftriaxone against Borrelia. These findings are supported by the results of time–kill experiments in a Borrelia afzelii skin isolate, demonstrating a >3 log10 unit (99.9%) reduction of the inoculum after 96h of exposure to either drug at a concentration of three log2 unit dilutions above the respective MIC. [Copyright &y& Elsevier]

Abstract: Sepsis and nosocomial infections continue to be a significant problem in intensive care, contributing heavily to mortality and prolonged hospital stay. Early and appropriate antibiotic therapy is critical for optimising outcomes. However, the emergence of highly resistant bacteria, coupled with reduced development of novel antibiotics, means that there is a real threat of development of untreatable nosocomial infections. Cefepime and ceftazidime are broad-spectrum cephalosporins that are widely used to treat Gram-negative nosocomial infections in critically ill patients. Available data suggest that cefepime may have advantages over ceftazidime owing to a broader spectrum of activity and reduced potential for development of bacterial resistance. However, whether either of these agents is superior can only be determined by a head-to-head study evaluating clinical and bacteriological outcomes. Such a study to determine whether apparent differences translate into clinically relevant differences in outcome is indicated. [Copyright &y& Elsevier]

Abstract: This year (2007) marks the 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA), the precursor of all semi-synthetic penicillins and cephalosporins—the β-lactam antibiotics. This review, by a scientist who played a major part in the discovery and a physician who participated in the early clinical trials of these antibiotics, tells the story of the discovery and of the early development of the β-lactam antibiotics that revolutionised the treatment of infections. [Copyright &y& Elsevier]

Abstract: The antibiotic susceptibilities of 50 Francisella tularensis subsp. holarctica biovar II strains isolated from hares and human patients from the eastern part of Austria were examined. Minimum inhibitory concentrations (MICs) of 24 antimicrobial agents were determined using Etests™ on cysteine heart agar plates supplemented with 10% sheep blood. All isolates were sensitive to tetracyclines, aminoglycosides, quinolones, chloramphenicol and rifampicin. Resistance was observed in all isolates against macrolides, penicillins and aztreonam. Bacteria were resistant to cephalosporins and carbapenems, except for 8% of strains investigated that were susceptible or intermediately susceptible. Our in vitro susceptibility data can be applied for the detection and comparison of resistance development and to provide in vitro data for the guidance of therapy. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to determine the susceptibility of Borrelia afzelii strains to antibiotics, and to test the hypothesis that persistence of borrelia in skin, after therapy, is a consequence of resistance to the antibiotic used for treatment. Ten B. afzelii strains isolated from skin of seven adult patients (two with acrodermatitis chronica atrophicans, five with erythema migrans) were studied. In three patients B. afzelii was isolated from erythema migrans lesion before antibiotic therapy and 2–3 months after treatment with cefuroxime axetil (two patients) or with ceftriaxone (one patient). MICs and MBCs for amoxicillin, azithromycin, ceftriaxone, cefuroxime, doxycycline and amikacin were measured. There was total resistance to amikacin but isolates were susceptible to all other antibiotics except one isolate that was resistant to cefuroxime, MIC >4mg/L. Comparison of MBC values after 3 and 6 weeks’ incubation revealed comparible results for azithromycin and ceftriaxone while for amoxicillin, cefuroxime and doxycycline, some differences were found. In one of the patients from whom there were borrelia isolated before and after treatment with cefuroxime axetil, both isolates were resistant to cefuroxime. In the other two patients, the paired isolates were susceptible to the antibiotic used for therapy. [Copyright &y& Elsevier]

Abstract: Cefdinir is an oral cephalosporin approved by the US Food and Drug Administration in 1997 for the treatment of community-acquired (CA) respiratory tract and uncomplicated skin and soft tissue infections. The objective of the present study was to evaluate the in vitro activity of cefdinir against recent clinical isolates collected from CA-urinary tract infections (UTIs), a possible expanded indication. A total of 456 isolates from CA-UTI were collected from medical centres in North America (NA; United States and Canada) in 2003 and susceptibility tested by NCCLS reference broth microdilution methods. Cefdinir and cefpodoxime were the most active compounds tested against Escherichia coli (98.7% susceptibility), followed by nitrofurantoin (97.0%) and ciprofloxacin (95.0%). Cefdinir was 8- to 16-fold more potent than cefuroxime axetil and cefprozil against E. coli, Klebsiella spp. and Staphylococcus saprophyticus. The activity of cefdinir was most similar to that of cefpodoxime against E. coli and Klebsiella spp., but cefpodoxime showed inferior activity against S. saprophyticus. The cefdinir spectrum was significant superior (+3.8 to 16.5%) to that of trimethoprim/sulphamethoxazole against all pathogens evaluated. The cefdinir spectrum and potency were comparable or superior to other orally administered β-lactams tested against recent (2003) clinical isolates from CA-UTI. [Copyright &y& Elsevier]

Bone infections, which can be acute or chronic, often require aggressive antibiotic therapy, whether treated at home or in the community. Surveillance programmes are essential tools in the monitoring of antimicrobial resistance and can act as a resource to maintain effective prescribing. The Surveillance Network® (TSN®), which collects organism and patient-specific data from a network of laboratories across the United States, was used to analyse susceptibility of common bacterial species isolated from bone infections during 2000–2002. Narrow-spectrum antimicrobials such as vancomycin, quinupristin-dalfopristin and linezolid demonstrated good activity against Staphylococcus aureus and streptococci, and were active against 100% of isolates. However, Gram-negative species were also commonly isolated from these sites of infection. Later-generation cephalosporins, represented by ceftriaxone, cefotaxime and cefepime, exhibited a broad spectrum of activity including Enterobacteriaceae, streptococci and methicillin-susceptible S. aureus, but they were not active against methicillin-resistant S. aureus (MRSA) and showed variable activity against Pseudomonas aeruginosa. Using ceftazidime as a marker for extended spectrum β-lactamase (ESBL) expression, less than 3% of Escherichia coli or Klebsiella pneumoniae expressed this phenotype. Based on current in vitro activity, the third-generation cephalosporins provide broad-spectrum coverage useful for the empirical therapy of suspected bone infections, especially for patients treated in the community or hospitalised with community-acquired infections. [Copyright &y& Elsevier]

Two hundred and forty-nine patients with monomicrobial bacteraemia due to third-generation cephalosporin (TGC)-resistant Citrobacter freundii (42), E. aerogenes (23), E. cloacae (143), and Serratia marcescens (41) were analyzed for antibiotic therapy used and outcome. For isolates with resistance to any of the TGCs, all β-lactams, except imipenem, were considered ineffective. Of 152 patients given appropriate treatment, the mortality rates were 10.9% for 128 patients given monotherapy and 25.0% for 24 patients given combination therapy (P=0.09). Of patients given monotherapy, there were no significant differences in mortality between imipenem, aminoglycoside, and ciprofloxacin treatment groups (P=0.57). Only shock was associated with mortality in multivariate analysis. In conclusion, for patients with TGC-resistant Gram-negative bacteraemia, no significant difference in outcome was observed between single antibiotic therapy groups or monotherapy and combination therapy groups. [Copyright &y& Elsevier]

The study was designed to evaluate rational antibiotic use in relation to diagnosis and bacteriological findings. All hospitalized patients who received antibiotics were evaluated by a cross-sectional study. Of the 713 patients hospitalized, 281 (39.4%) patients received 377 antibiotics. Among 30 different antibiotics the most frequently requested were first generation cephalosporins (19.9%), ampicillin–sulbactam (19.1%) and aminoglycosides (11.7%). Antibiotic use was appropriate in 64.2% of antibiotic requests. In analysis of appropriate use, a request after an infectious diseases consultation was a frequent reason (OR=14, P<0.001, CI=0.02–0.24). Antibiotics requested in conjunction with susceptibility results were found to be more appropriate than those ordered empirically (OR=4.5, P=0.017, CI=0.06–0.76). Inappropriate antibiotic use was significantly higher among unrestricted antibiotics than restricted ones (P<0.001). Irrational antibiotic use was high for unrestricted antibiotics. Additional interventions such as postgraduate training programmes and elaboration of local guidelines could be beneficial. [Copyright &y& Elsevier]

Abstract: Infections caused by meticillin-resistant Staphylococcus aureus (MRSA) remain a major problem worldwide. In England, the Department of Health set a target for decreasing MRSA bloodstream infections throughout the country by 50% by 2008, based on the 2003/2004 national figure. To aid hospitals in achieving their individual targets, guidance was provided in the form of care bundles, which were initially related to infection-control practices. Several studies have shown that decreasing the use of fluoroquinolones and/or cephalosporins results in a decrease in MRSA infection rates. In 2007 the Department of Health published guidance on antibiotic prescribing, following which the MRSA bloodstream infection rate dropped more rapidly than in 2006, and the target was met. [Copyright &y& Elsevier]

Abstract: The cumulative ecological damage, both to the individual patient and to patient populations, secondary to antibiotic prescribing is increasingly recognised. The impact of antibiotics on pathogens and normal flora should be a criterion for antimicrobial selection. Measures to reduce the use of third-generation cephalosporins and fluoroquinolones should be considered. Increased reliance on carbapenems may accelerate the emergence of extremely resistant isolates, and these antimicrobials should be restricted to key scenarios. There is a clear need for new agents with novel modes of action and low ecological damage potential to treat nosocomial infections. Tigecycline has a spectrum of activity that theoretically may reduce the selection pressure for key nosocomial pathogens, and represents an alternative to carbapenems. Further studies are needed to confirm this potentially low selection pressure. [Copyright &y& Elsevier]