Predicting Oral Beta-lactam susceptibilities against Streptococcus pneumoniae.

BACKGROUND: Oral beta-lactam antimicrobials are not routinely tested against Streptococcus pneumoniae due to presumed susceptibility based upon penicillin minimum inhibitory concentration (MIC) testing. Currently, Clinical and Laboratory Standards Institute provides comments to use penicillin MIC ≤0.06 to predict oral cephalosporin susceptibility. However, no guidance is provided when cefotaxime MIC is known, leading to uncertainty with interpretation. The purpose of this study was to evaluate cefotaxime and penicillin MICs and their respective correlation to oral beta-lactam categorical susceptibility patterns. METHODS: 249 S. pneumoniae isolates were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF) and then tested by broth microdilution method to penicillin, cefotaxime, amoxicillin, cefdinir, cefpodoxime, and cefuroxime. RESULTS: Using Clinical and Laboratory Standards Institute (CLSI) non-meningitis breakpoints for cefotaxime, 240/249 isolates were classified as susceptible. Of the cefotaxime susceptible isolates, 23% of the isolates are misrepresented as cefdinir susceptible. Amoxicillin correlated well with penicillin MIC breakpoints with only 1 discordant isolate out of 249. CONCLUSION: The correlation between amoxicillin and penicillin creates a very reliable predictor to determine categorical susceptibility. However oral cephalosporins were not well predicted by either penicillin or cefotaxime leading to the possible risk of treatment failures. Caution should be used when transitioning to oral cephalosporins in cefotaxime susceptible isolates, especially with higher cefotaxime MICs.

Classifying cephalosporins: from generation to cross-reactivity.

PURPOSE OF REVIEW: To review the most recent literature studying the classifications, immunochemistry, and crossreactivity of allergy reactions to cephalosporins. RECENT FINDINGS: Over the last five years, research interest has focused on three areas related to cephalosporin allergy: cross-reactivity among cephalosporins and with other beta-lactams; the incidence of adverse reactions in penicillin allergy patients or in reported penicillin allergy labels; and new cephalosporins structures involved in the immunological recognition. SUMMARY: Meta-analysis of a substantial number of studies shows that cephalosporins are safer than previously thought. Evidence supports two main conclusions in that regard. First, there is a relatively low percentage of cross-reactivity between cephalosporins and other beta-lactams with penicillins in penicillin allergy patients. Second, there is a very low incidence of allergy reactions in nonselected as well as in selected penicillin allergy patients when cephalosporins are used prior to surgical intervention.On the other hand, few structures have been discovered related to the immune mechanism of cephalosporin allergy reactions, and these are far from being ready to use in clinical practice.

Surrogate testing of oral third-generation cephalosporin susceptibility to common uropathogens.

Cefazolin susceptibility of urine isolates of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis predicts susceptibility to oral cephalosporins, but cefazolin-resistant isolates may be susceptible to oral third-generation cephalosporins. Among 194 urine isolates, we found >95% categorical agreement among oral third-generation cephalosporins. Surrogate testing of cefpodoxime for cefdinir, and vice versa, resulted in no major or very major errors, while combinations involving cefixime produced rare major and very major errors.

[Susceptibility to first-generation Cephalosporins in Enterobacteriaceae isolated from urine culture according to CLSI and EUCAST breakpoints]. / Estudio de susceptibilidad a cefalosporinas de primera generación en enterobacterias aisladas de urocultivo, según criterios CLSI y EUCAST.

Currently, the use of cefazolin is recommended to determine the susceptibility to first-generation oral cephalosporins in strains of enterobacteria in uncomplicated UTI. We determined susceptibility differences to oral cephalosporins in urinary strains according to cefazolin or cefalotin breakpoints and the correlation of susceptibility between cefazolin and cefadroxil. We studied 52 strains with cefalotin and cefazolin by disk-diffusion and MIC (Kirby-Bauer and Vitek XL) and a subgroup by disk-diffusion for cefadroxil. Agreement among different methods was 100% for K. pneumoniae and Proteus spp. In Escherichia coli, agreement for Vitek and disk-diffusion were 0 and 50% respectively. Susceptibility to first generation cephalosporins in E. coli should be determined with cefazolin. Agreement between cefazolin and cefadroxil suggests that cefazolin could also predict the susceptibility of cefadroxil.

Epidemiological situation of enterobacteriaceae resistant to cephalosporins third generation in the region of Mahdia, Tunisia (2002-2014).

OBJECTIVES: To determine the prevalence and to monitor the trends of resistance to broad-spectrum cephalosporins among various species of enterobacteria in the region of Mahdia (Tunisia) from 2002 to 2014. METHODS: A retrospective study was carried out in the microbiology laboratory at Tahar Sfar Teaching Hospital in Mahdia. Data concerning a thirteen-year period (2002-2014). All clinical isolates of enterobacteriaceae were identified with the API 20 E system. Antimicrobial susceptibilities were determined by disk diffusion on Mueller Hinton agar according to CA-SFM recommendations. RESULTS: During the study period, 25040 non-duplicate clinical strains of enterobacteriacae were identified. 2584 (10,3%) clinical isolates showed acquired resistance to third generation cephalosporins (3rdGC). The overall frequency of resistance increased from 8% in 2002 to 16,3% in 2014. This increase was statistically significant. High prevalence rates of 3rdGC resistance have been observed in pediatric (25,1%), in gynecologyobstetrics (21,9%) and medecine (17,4%). E. coli (21,6%), K. pneumoniae (28,6%) and E. cloacae (30,5%) showed high prevalence rates of broad-spectrum cephalosporin resistance. CONCLUSION: The resistance rates ERC3G in our region seems to be increasing. Implementation of infection control measures and identification of the mechanism responsible for third generation cephalosporins resistance are necessary to limit the spreading of these resistant enterobacteriaceae in hospitals and community settings.

Validated LC-MS/MS method for simultaneous analysis of 21 cephalosporins in zebrafish for a drug toxicity study.

Zebrafish model was used to perform this drug toxicity study. In this study, we monitored the absorption of drugs in zebrafish. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed in this experiment. The LC-MS/MS method was used for the simultaneous quantification of 21 cephalosporins in zebrafish. To prepare samples, rapid protein precipitation was performed with 1% formic acid in methanol. All the analytes were separated on a C18 column. These analytes were analyzed by performing multiple-reaction monitoring (MRM) scans in positive electrospray ionization mode. The ranges for limits of detection (LOD) and quantification (LOQ) were as follows: 0.01-10 ng/mL (S/N ≥ 3) and 0.05-25 ng/mL. Intra-and inter-day accuracy of all 21 cephalosporins were within the range of 80%-120%. Intra-and inter-day precision were within the range of 0.4%-11.2%. All the 21 analytes were analyzed within 10 min. In drug toxicity studies, the present method can be used to determine the internal concentrations of cephalosporins in zebrafish following the administration of drugs.

Are third-generation cephalosporins associated with a better prognosis than amoxicillin-clavulanate in patients hospitalized in the medical ward for community-onset pneumonia?

OBJECTIVES: We aimed to assess whether treatment with ceftriaxone/cefotaxime is associated with lower in-hospital mortality than amoxicillin-clavulanate in pati0ents hospitalized in medical wards for community-onset pneumonia. METHODS: We conducted a retrospective and multicentre study of patients hospitalized in French medical wards for community-onset pneumonia between 2002 and 2015. Treatments with ceftriaxone/cefotaxime or amoxicillin-clavulanate were defined by their start in the emergency department for a duration of 5 days or more with no other ß-lactam. A logistic regression analysis was performed on the overall population, and a propensity score analysis was restricted to patients treated with either ceftriaxone/cefotaxime or amoxicillin-clavulanate. RESULTS: 1698 patients (median age, 80 y) were included, of which 716 and 198 were treated with amoxicillin-clavulanate and ceftriaxone/cefotaxime, respectively. In-hospital mortality was 10% (9-12%). In multivariate analysis, factors associated with in-hospital mortality were treatment with ceftriaxone/cefotaxime (aOR 2.9; (1.4-5.7)), pneumonia severity index class 4 or 5 (aOR 7.8 (4.3-15.7)), do-not-resuscitate order (aOR 8.7 (5.2-14.6)) and fluid therapy (aOR 6.3 (2.5-15.1)). The propensity score analysis was performed on 178 patients treated with ceftriaxone/cefotaxime matched with 178 patients treated with amoxicillin-clavulanate; no significant association between treatment with ceftriaxone/cefotaxime and in-hospital mortality was found (OR 1.5 (0.7-3.0)). CONCLUSION: In the largest study aiming to compare amoxicillin-clavulanate and ceftriaxone/cefotaxime in community-onset pneumonia, ceftriaxone/cefotaxime was not associated with lower in-hospital mortality than amoxicillin-clavulanate. Our results suggest that ceftriaxone/cefotaxime should not be preferred over amoxicillin-clavulanate for patients hospitalized in medical wards with community-onset pneumonia.

Estudio de susceptibilidad a cefalosporinas de primera generación en enterobacterias aisladas de urocultivo, según criterios CLSI y EUCAST / Susceptibility to first-generation Cephalosporins in Enterobacteriaceae isolated from urine culture according to CLSI and EUCAST breakpoints

Resumen Actualmente se recomienda el uso de cefazolina para determinar la susceptibilidad a cefalosporinas orales de primera generación en cepas de enterobacterias en ITU no complicada. Nuestro objetivo fue establecer la susceptibilidad a cefalosporinas orales en cepas urinarias según puntos de corte para cefalotina o cefazolina y la correlación de susceptibilidad entre cefazolina y cefadroxilo. Se estudió la concordancia entre cefalotina y cefazolina en 52 cepas por método de Kirby-Bauer y Vitek XL. En Escherichia coli fue de 0% para VitekXL y 50% para Kirby-Bauer. La concordancia entre cefazolina y cefadroxilo fue 95,6%. En el laboratorio debiera usarse cefazolina para determinar susceptibilidad a cefalosporinas orales de primera generación. La concordancia entre cefazolina y cefadroxilo sugiere que cefazolina podría predecir susceptibilidad para cefadroxilo.

Currently, the use of cefazolin is recommended to determine the susceptibility to first-generation oral cephalosporins in strains of enterobacteria in uncomplicated UTI. We determined susceptibility differences to oral cephalosporins in urinary strains according to cefazolin or cefalotin breakpoints and the correlation of susceptibility between cefazolin and cefadroxil. We studied 52 strains with cefalotin and cefazolin by disk-diffusion and MIC (Kirby-Bauer and Vitek XL) and a subgroup by disk-diffusion for cefadroxil. Agreement among different methods was 100% for K. pneumoniae and Proteus spp. In Escherichia coli, agreement for Vitek and disk-diffusion were 0 and 50% respectively. Susceptibility to first generation cephalosporins in E. coli should be determined with cefazolin. Agreement between cefazolin and cefadroxil suggests that cefazolin could also predict the susceptibility of cefadroxil.

IgE-mediated hypersensitivity to cephalosporins: Cross-reactivity and tolerability of alternative cephalosporins.

BACKGROUND: Studies regarding the cross-reactivity and tolerability of alternative cephalosporins in large samples of subjects with an IgE-mediated hypersensitivity to cephalosporins are lacking. OBJECTIVE: We sought to evaluate the possibility of using alternative cephalosporins in subjects with cephalosporin allergy who especially require them. METHODS: One hundred two subjects with immediate reactions to cephalosporins and positive skin test results to the responsible drugs underwent serum specific IgE assays with cefaclor and skin tests with different cephalosporins. Subjects were classified in 4 groups: group A, positive responses to 1 or more of ceftriaxone, cefuroxime, cefotaxime, cefepime, cefodizime, and ceftazidime; group B, positive responses to aminocephalosporins; group C, positive responses to cephalosporins other than those belonging to the aforementioned groups; and group D, positive responses to cephalosporins belonging to 2 different groups. Group A subjects underwent challenges with cefaclor, cefazolin, and ceftibuten; group B participants underwent challenges with cefuroxime axetil, ceftriaxone, cefazolin, and ceftibuten; and group C and D subjects underwent challenges with some of the aforementioned cephalosporins selected on the basis of their patterns of positivity. RESULTS: There were 73 subjects in group A, 13 in group B, 7 in group C, and 9 in group D. Challenges with alternative cephalosporins (ceftibuten in 101, cefazolin in 96, cefaclor in 82, and cefuroxime axetil and ceftriaxone in 22 subjects) were well tolerated. CONCLUSIONS: Cephalosporin hypersensitivity does not seem to be a class hypersensitivity. Subjects with cephalosporin allergy who especially require alternative cephalosporins might be treated with compounds that have side-chain determinants different from those of the responsible cephalosporins and have negative pretreatment skin test responses.

[Resistance to "last resort" antibiotics in Gram-positive cocci: The post-vancomycin era]. / Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina.

New therapeutic alternatives have been developed in the last years for the treatment of multidrug-resistant Gram-positive infections. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are considered a therapeutic challenge due to failures and lack of reliable antimicrobial options. Despite concerns related to the use of vancomycin in the treatment of severe MRSA infections in specific clinical scenarios, there is a paucity of solid clinical evidence that support the use of alternative agents (when compared to vancomycin). Linezolid, daptomycin and tigecycline are antibiotics approved in the last decade and newer cephalosporins (such as ceftaroline and ceftobiprole) and novel glycopeptides (dalvavancin, telavancin and oritavancin) have reached clinical approval or are in the late stages of clinical development. This review focuses on discussing these newer antibiotics used in the "post-vancomycin" era with emphasis on relevant chemical characteristics, spectrum of antimicrobial activity, mechanisms of action and resistance, as well as their clinical utility.

Resistencia a antibióticos de última línea en cocos Gram positivos: la era posterior a la vancomicina / Resistance to "last resort" antibiotics in Gram-positive cocci: The post-vancomycin era

En los últimos años se han desarrollado nuevas alternativas para el tratamiento de infecciones por patógenos Gram positivos multirresistentes, entre los cuales Staphylococcus aureus resistente a la meticilina (SARM) y los enterococos resistentes a la vancomicina (ERV) se consideran un verdadero reto terapéutico, y aunque el uso de la vancomicina en infecciones graves causadas por SARM ha generado serias dudas en los últimos años, continúa siendo escasa la información clínica de respaldo al uso de agentes terapéuticos que la superen en eficacia. El linezolid, la daptomicina y la tigeciclina son agentes que tienen actividad contra los cocos Gram positivos y que fueron aprobados e introducidos en la terapia clínica en la década pasada. Además, se han probado o están en las fases finales de desarrollo otros agentes como las cefalosporinas de última generación (ceftarolina y ceftobiprol). El propósito de esta revisión fue describir las nuevas alternativas terapéuticas, particularmente en la era posterior a la vancomicina, y repasar las características químicas más relevantes de los compuestos y su espectro de actividad, haciendo énfasis en sus mecanismos de acción y resistencia.

New therapeutic alternatives have been developed in the last years for the treatment of multidrug-resistant Gram-positive infections. Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) are considered a therapeutic challenge due to failures and lack of reliable antimicrobial options. Despite concerns related to the use of vancomycin in the treatment of severe MRSA infections in specific clinical scenarios, there is a paucity of solid clinical evidence that support the use of alternative agents (when compared to vancomycin). Linezolid, daptomycin and tigecycline are antibiotics approved in the last decade and newer cephalosporins (such as ceftaroline and ceftobiprole) and novel glycopeptides (dalvavancin, telavancin and oritavancin) have reached clinical approval or are in the late stages of clinical development. This review focuses on discussing these newer antibiotics used in the "post-vancomycin" era with emphasis on relevant chemical characteristics, spectrum of antimicrobial activity, mechanisms of action and resistance, as well as their clinical utility.

Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Hypersensitivity reactions to cephalosporins.

At present, cephalosporins represent one of the most prescribed classes of antibiotics. Although allergic reactions have been estimated to be infrequent, the number of reactions to cephalosporins is increasing due to their wide use. Cross-reactivity with penicillins has mainly been evaluated in patients with penicillin allergy. It is higher between first- and second-generation cephalosporins with the same or similar side chain than between cephalosporins with different side chains. Unlike penicillins, cephalosporin haptens or determinants have not been defined, and therefore the diagnosis is complicated. Nevertheless, skin tests with cephalosporins are useful in the evaluation of several allergic reactions. Although more studies are necessary, a negative result in skin testing to penicillin and cephalosporins with different side chains seems to be a good predictor of tolerance, and could be used in select cases.

[Reduced incidence of Staphylococcus isolation in nosocomial setting after introducing preoperative antibiotic prophylaxis guidelines]. / Riduzione dell'incidenza di isolamento di stafilococchi in ambiente nosocomiale dopo I'introduzione di linee-guida di antibioticoprofilassi preoperatoria.

We compare epidemiological data from two twelve-month periods, before and after the introduction of preoperative antibiotic prophylaxis guidelines at Carlo Poma hospital in Mantova, Italy, in June 2003. Considering the results from the microbiology laboratory and the data from the pharmacy, concerning the consumption of some antimicrobials, we noted a significant decrease in the incidence of methicillin-resistant Staphylococcus aureus (MRSA) in surgical wards, where the incidence of MRSA had previously exceeded that in medical wards. At the same time, analysis of antibiotic consumption revealed a considerable decrease in third and fourth-generation cephalosporins and an increasing use of cephazolin, in compliance with prophylaxis protocol rules. This trend was confirmed by analysis of the same data regarding the first six months of 2006.

Bacterial eradication rates with shortened courses of 2nd- and 3rd-generation cephalosporins versus 10 days of penicillin for treatment of group A streptococcal tonsillopharyngitis in adults.

In a meta-analysis of 5 randomized controlled trials involving 1030 adults, the likelihood of bacteriologic eradication in the treatment of group A beta-hemolytic streptococcal (GAS) tonsillopharyngitis with 5 days of select cephalosporins (cefpodoxime, cefuroxime, cefotiam, and cefdinir) was noninferior to 10 days of penicillin (odds ratio, 1.46; 95% confidence interval, 0.96-2.22, P = 0.08).

High rates of antimicrobial co-resistance among Enterobacteriaceae: comparative analysis between clinical isolates resistant and susceptible to third-generation cephalosporins.

We compared the antimicrobial co-resistance of 3,402 clinical isolates of Enterobacteriaceae resistant to third-generation cephalosporins (2,569 ESBL-producing and 833 AmpC overproducing) with that of 16,220 susceptible isolates, in order to determine the impact of resistance to third-generation cephalosporins on the likelihood of resistance to other antimicrobial classes. Enterobacteriaceae resistant to third-generation cephalosporins, independently of their mechanism of resistance, were significantly more resistant to other classes of antimicrobials than susceptible isolates (p <0.001). Percentages of co-resistance to ciprofloxacin, gentamicin, tobramycin and trimethoprim-sulfamethoxazole of resistant isolates were: 51%, 39%, 53% and 51%, respectively. However, among the susceptible isolates, percentages were 17%, 7%, 6% and 19%, respectively. Fosfomycin exhibited excellent in vitro activity against urinary isolates (92%), mainly against ESBL-producing organisms (90%), and is a good alternative treatment of infections caused by multidrug resistant Enterobacteriaceae. Amikacin and imipenem were the most active antimicrobials against all species tested.

The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants.

OBJECTIVES: Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individual's risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis. METHODS: We studied a cohort of extremely low birth-weight infants who survived > or = 72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns. RESULTS: There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant. CONCLUSIONS: Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk.