Do dietary interventions exert clinically important effects on the bioavailability of ß-lactam antibiotics? A systematic review with meta-analyses.

BACKGROUND: Managing drug-food interactions may help to achieve the optimal action and safety profile of ß-lactam antibiotics. METHODS: We conducted a systematic review with meta-analyses in adherence to PRISMA guidelines for 32 ß-lactams. We included 166 studies assessing the impact of food, beverages, antacids or mineral supplements on the pharmacokinetic (PK) parameters or PK/pharmacodynamic (PK/PD) indices. RESULTS: Eighteen of 25 ß-lactams for which data on food impact were available had clinically important interactions. We observed the highest negative influence of food (AUC or Cmax decreased by >40%) for ampicillin, cefaclor (immediate-release formulations), cefroxadine, cefradine, cloxacillin, oxacillin, penicillin V (liquid formulations and tablets) and sultamicillin, whereas the highest positive influence (AUC or Cmax increased by >45%) for cefditoren pivoxil, cefuroxime and tebipenem pivoxil (extended-release tablets). Significantly lower bioavailability in the presence of antacids or mineral supplements occurred for 4 of 13 analysed ß-lactams, with the highest negative impact for cefdinir (with iron salts) and moderate for cefpodoxime proxetil (with antacids). Data on beverage impact were limited to 11 antibiotics. With milk, the extent of absorption was decreased by >40% for cefalexin, cefradine, penicillin G and penicillin V, whereas it was moderately increased for cefuroxime. No significant interaction occurred with cranberry juice for two tested drugs (amoxicillin and cefaclor). CONCLUSIONS: Factors such as physicochemical features of antibiotics, drug formulation, type of intervention, and patient's health state may influence interactions. Due to the poor actuality and diverse methodology of included studies and unproportionate data availability for individual drugs, we judged the quality of evidence as low.

Well-Orientation Strategy Biosynthesis of Cefuroxime-Silver Nanoantibiotic for Reinforced Biodentine™ and Its Dental Application against Streptococcus mutans.

Dental caries results from the bacterial pathogen Streptococcus mutans (S. mutans) and is the maximum critical reason for caries formation. Consequently, the present study aims to evaluate the antibacterial activity of a newly synthesized nanoantibiotic-Biodentine formulation. The silver nanoparticles (ROE-AgNPs) were biosynthesized from the usage of Rosmarinus officinalis L. extract (ROE) and conjugated with cefuroxime to form Cefuroxime-ROE-AgNPs. Using Biodentine™ (BIOD), five groups of dental materials were prepared, in which Group A included conventional BIOD, Group B included BIOD with ROE-AgNPs, Groups C and D included BIOD with Cefuroxime-ROE-AgNPs at concentrations of 0.5% and 1.5% cefuroxime, respectively, and Group E included BIOD with 1.5% cefuroxime. The synthesized ROE-AgNPs or Cefuroxime-ROE-AgNPs were characterized for conjugating efficiency, morphology, particle size, and in vitro release. Minimum inhibitory concentration (MIC) of the cefuroxime, ROE-AgNPs, and Cefuroxime-ROE-AgNPs were additionally evaluated against cefuroxime resistant S. mutans, which furthered antibacterial efficacy of the five groups of dental materials. The UV-Visible spectrum showed the ROE-AgNPs or Cefuroxime-ROE-AgNPs peaks and their formation displayed through transmission electron microscopy (TEM), X-ray diffraction (XRD) pattern, and Fourier transforms infrared (FTIR) analysis. The end result of Cefuroxime-ROE-AgNPs showed conjugating efficiency up to 79%. Cefuroxime-ROE-AgNPs displayed the highest antibacterial efficacy against S. mutans as compared to cefuroxime or ROE-AgNPs alone. Moreover, the MIC of ROE-AgNPs and Cefuroxime-ROE-AgNPs was detected against S. mutans to be 25 and 8.5 µg/mL, respectively. Consequently, Cefuroxime-ROE-AgNPs displayed that a decrease in the MIC reached to more than three-fold less than MIC of ROE-AgNPs on the tested strain. Moreover, Cefuroxime-ROE-AgNPs/BIOD was employed as a novel dental material that showed maximum antimicrobial activity. Groups C and D of novel materials showed inhibitory zones of 19 and 26 mm, respectively, against S. mutans and showed high antimicrobial rates of 85.78% and 91.17%, respectively. These data reinforce the utility of conjugating cefuroxime with ROE-AgNPs to retrieve its efficiency against resistant S. mutant. Moreover, the nanoantibiotic delivered an advantageous antibacterial effect to BIOD, and this may open the door for future conjugation therapy of dental materials against bacteria that cause dental caries.

Changes in Bacterial Resistance Patterns of Pediatric Urinary Tract Infections and Rationale for Empirical Antibiotic Therapy.

BACKGROUND: The causative agent spectrum and resistance patterns of urinary tract infections in children are affected by many factors. AIMS: To demonstrate antibiotic resistance in urinary tract infections and changing ratio in antibiotic resistance by years. STUDY DESIGN: Retrospective cross-sectional study. METHODS: We analysed antibiotic resistance patterns of isolated Gram (-) bacteria during the years 2011-2014 (study period 2) in children with urinary tract infections. We compared these findings with data collected in the same centre in 2001-2003 (study period 1). RESULTS: Four hundred and sixty-five uncomplicated community-acquired Gram (-) urinary tract infections were analysed from 2001-2003 and 400 from 2011-2014. Sixty-one percent of patients were female (1.5 girls : 1 boy). The mean age of children included in the study was 3 years and 9 months. Escherichia coli was the predominant bacteria isolated during both periods of the study (60% in study period 1 and 73% in study period 2). Bacteria other than E. coli demonstrated a higher level of resistance to all of the antimicrobials except trimethoprim-sulfamethoxazole than E. coli bacteria during the years 2011-2014. In our study, we found increasing resistance trends of urinary pathogens for cefixime (from 1% to 15%, p<0.05), amikacin (from 0% to 4%, p<0.05) and ciprofloxacin (from 0% to 3%, p<0.05) between the two periods. Urinary pathogens showed a decreasing trend for nitrofurantoin (from 17% to 7%, p=0.0001). No significant trends were detected for ampicillin (from 69% to 71%), amoxicillin-clavulanate (from 44% to 43%), cefazolin (from 39% to 32%), trimethoprim-sulfamethoxazole (from 32% to 31%), cefuroxime (from 21% to 18%) and ceftriaxone (from 10% to 14%) between the two periods (p>0.05). CONCLUSION: In childhood urinary tract infections, antibiotic resistance should be evaluated periodically and empiric antimicrobial therapy should be decided according to antibiotic sensitivity results.

Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.

BACKGROUND: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years. OBJECTIVES: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs. METHODS: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate. RESULTS: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins. CONCLUSIONS: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome.

In vitro compatibility study of cephalosporin with intraocular irrigating solutions and intracameral medications.

BACKGROUND: To study the compatibility of cephalosporins with intraocular irrigating solutions and intracameral medications commonly used in cataract surgery. DESIGN: The was an in vitro experiment conducted in the Research Laboratory of the Department of Microbiology, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. SAMPLES: Three cephalosporins--cefazolin, cefuroxime and ceftazidime--were separately diluted and mixed with irrigating solutions and intracameral medications to form 192 samples and 12 control solutions. METHODS: The cephalosporins were dissolved in normal saline and further diluted to the concentration of 1 mg in 0.1 mL with normal saline, Ringer's solution, balanced salt solution and fortified balanced salt solutions. These were mixed with balanced salt solutions or fortified balanced salt solutions, with adrenaline, acetylcholine or carbachol and kept at 37°C for 2 h. The concentrations of free cephalosporins were measured with rapid high-performance liquid chromatography at baseline (0 h) and at 2 h. MAIN OUTCOME MEASURES: Free concentrations of cephalosporins at 2 h were compared with mean baseline (0 h) value. A difference of 3 standard deviations or more was considered statistically significant. RESULTS: At 2 h there was a significant drop in the cefuroxime concentration in preparations in which cefuroxime was diluted with normal saline (P < 0.01). In all preparations, the final concentrations of cephalosporins were higher than the minimal inhibitory concentrations (MIC(90)) for microbials commonly isolated from the external eye. CONCLUSION: Cefazolin, cefuroxime and ceftazidime were compatible with irrigating solutions and intracameral medications commonly used in cataract surgery.

Antibióticos profilácticos en cirugía urológica / Prophylactics antibiotics in urologic surgery

La infección es la complicación más temida de las cirugías, si bien éstas pueden presentarse en sitios alejados al operado, como el caso de las neumonías, lo más frecuente es que se relacione con la zona intervenida y en particular con la herida operatoria. Se prefiere hablar de Infección del Sitio Operatorio (ISO) en forma técnica para referirnos a esta afección. Se define como ISO: Infecciones que ocurren dentro de los 30 días después de la cirugía si no hay un implante o dentro de un año si hay un implante in situ. Además la infección parece, clínicamente, estar relacionada con la cirugía.

[The impact of antibiotic use on hospital-acquired pneumonia: data of etiology tests]. / Antibiotiku poveikis hospitalines pneumonijos etiologijos tyrimu duomenims.

AIM OF THE STUDY: To investigate most common pathogens isolated from the hospital-acquired pneumonia patients bronchoalveolar lavage fluid in Kaunas University of Medicine Hospital according to the previous antibiotic use and to estimate pathogens antibacterial susceptibility. MATERIALS AND METHODS: Results of 87 hospital-acquired pneumonia patients bronchoalveolar lavage fluid quantitative cultures were analyzed. Microorganisms isolated in clinically significant amount were considered as the etiological agents and included into analysis. Susceptibility was tested using the standard methods. Previously untreated patients were considered if the antibacterials were not administered at all or were used less than for 24 hours. RESULTS: H. influenzae isolation in significant amount rates were higher in previously untreated patients group comparing to previously treated (29.2%. (n=14) and 5.1% (n=2), respectively, p<0.05). Non-fermenters (P. aeruginosa and Acinetobacter spp.) isolation rates were higher in those previously treated comparing to untreated patients - (31.0% (n=13) and 4.2% (n=2), respectively, p<0.05). All H. influenzae strains were susceptible to ampicillin and cefuroxime. 22.2-44.4% of P. aeruginosa strains were resistant to ceftazidime, amikacin and ciprofloxacin. Estimated Acinetobacter spp. resistance to ciprofloxacin and gentamycin was 83.3% and to ampicillin/sulbactam - 16.7%. All methicillin-susceptible S.aureus were also susceptible to gentamycin and fucidin and methicillin resistant to rifampicin and vancomycin. CONCLUSIONS: Previous antibiotic treatment has an impact on pneumonia etiology testing. H. influenzae strains are more common isolated hospital-acquired pneumonia etiologic agents in previously untreated patients. The low antibacterial resistance was found enabling the use of aminopenicillins for treatment if H. influenzae infection suggested. The use of antibacterials increases non-fermenters isolation rates and combined antipseudomonal treatment is reasonable in these patients.

A simple infection model using pre-colonized implants to reproduce rat chronic Staphylococcus aureus osteomyelitis and study antibiotic treatment.

Staphylococcus aureus biofilms formed on medical implants represent a serious problem, being difficult to eradicate with antibiotic therapy and leading to chronic infections. Simplified in vivo and in vitro antibiotic susceptibility assays using biofilm bacteria are needed. In this work, a novel chronic osteomyelitis infection model was developed in rats in the absence of bacterial suspension, requiring the use of only 10(6) bacteria in biofilms at the site of surgery, with a full success in reproducing infection. Stainless-steel implants pre-colonized for 12 h with a highly adherent S. aureaus isolate were introduced into the rat tibiae. In animals not submitted to antibiotic treatment, infection was found in the implants and spread to bone in all cases, indicating the high efficacy of the model to reproduce osteomyelitis. The effect of a 21-day treatment with cefuroxime, vancomycin, tobramycin or ciprofloxacin on infection was studied in this model 42 days after surgery. Bone colonization was inhibited by vancomycin and cefuroxime. Cefuroxime (the most efficient antibiotic, able to sterilize 1 out of 8 implants) reduced the number of bacteria in biofilms adhered to implants at a higher extent than vancomycin, trobramycin and ciprofloxacin. Analogous observations were made in this work in vivo and in vitro on the relative antibiotic efficacy against S. aureus biofilm bacteria. suggesting the usefulness of both tests as a potential tool to study antibiotic suceptibility, and the need for new antimicrobials against these bacteria.

Antimicrobial treatment of an experimental otitis media caused by a beta-lactamase positive isolate of Haemophilus influenzae.

A gerbil model of otitis media induced by a beta-lactamase producing and non-serotypeable isolate of Haemophilus influenzae was used to assess the in-vivo efficacy of co-amoxiclav and cefuroxime at low (5 mg/kg) and high (20 mg/kg) doses. The MIC of the antibiotics tested against the pathogen was 1 mg/L (1/0.5 mg/L for co-amoxiclav). The organism was inoculated (+/-10(6) cfu) by transbullar challenge directly in the middle ear and antibiotic treatment was commenced 2 h post-inoculation and continued at 8 h intervals for three doses. Only high dose co-amoxiclav significantly reduced the number of culture-positive specimens as compared with untreated animals or with other treatment groups (91.7% as compared with 36.7% for high dose cefuroxime). The results obtained in any treatment group were related to middle ear antibiotic level/MIC. Antibiotic concentrations in the middle ear 90 min after administration were about 10% of serum levels at 15 min, probably related to a slight inflammatory response. Only after high dose co-amoxiclav did the concentration in the middle ear exceed the MIC by a factor of four. In otitis media with effusion, if indicated, antibiotics active in vitro should be administered in high doses and, to avoid side effects, probably in short courses.

[The influence of selected antibiotics on the central action of aminophyllines--experimental studies]. / Wplyw wybranych antybiotyków na osrodkowe dzialanie aminofiliny--badania doswiadczalne.

Methylxanthines and some antibiotics can cause side effects, provoked by their central action, e.g. seizures. The epileptogenic effects of given drugs can be intensified during combined treatment, as a result of pharmacological interactions. In the present study the author investigated the influence of some commonly used antibiotics: benzylpenicillin, cefuroxime, doxycycline and amikacin upon central activity of methylxanthines in mice. The obtained results suggest, that all tested antibiotics, mainly benzylpenicillin, enhanced epileptogenicity of aminophylline in chemical seizures test. benzylpenicillin as only one among chosen antibiotics presented her own convulsant activity. During electrostimulation test, benzylpenicillin, doxycycline and amikacin intensified convulsions induced by methylxanthines. Only cefuroxime had no influence upon central action of methylxanthines in that experiments. Analysis of drugs' plasma levels, with using immunofluorescence methods, excluded pharmacokinetic interactions between them. Results of present investigation indicate, that there is a possibility of intensification of drugs' convulsant activity during combined treatment-aminophylline with some antibiotics in medical practice.

Evaluation of the E test for antimicrobial susceptibility testing of Porphyromonas gingivalis.

The antimicrobial susceptibilities of 81 recent clinical Porphyromonas gingivalis isolates and two reference strains were determined by the E test, a new method, and were compared with the minimal inhibitory concentrations for these strains obtained by the reference agar dilution method on supplemented Brucella blood agar. The following agreements were obtained: benzylpenicillin 100%, ampicillin 96%, cefaclor 82%, cefuroxime 91%, erythromycin 93%, clindamycin 99%, tetracycline 66%, doxycycline 89%, metronidazole 77% and ciprofloxacin 77%. Very major discrepancies were observed with ciprofloxacin. This study indicates that the E test is an acceptable method to determine the susceptibility of P. gingivalis for most antimicrobials.

In vitro antimicrobial susceptibility of different serotypes of Actinobacillus actinomycetemcomitans.

In vitro susceptibility of Actinobacillus actinomycetemcomitans (A.a.) serotypes to selected antimicrobial agents was investigated by the agar dilution method on supplemented Mueller-Hinton test medium. Eighty-three A.a. strains, 80 recent isolates from 40 periodontally healthy or diseased subjects, and three type strains were included in the study. Serotype a represented 20, serotype b 32, serotype c 17, and serotype e 7 and nontypable 4 of the tested strains. The most effective drugs against all A.a. serotypes in vitro were cefaclor, cefuroxime, tetracycline hydrochloride, doxycycline, trimethoprim-sulfamethoxazole (cotrimoxazole), and ciprofloxacin, which inhibited 100% of the strains at 4.0 micrograms/ml, 4.0 micrograms/ml, 1.0 microgram/ml, 2.0 micrograms/ml, 0.06 microgram/ml, and 0.015 microgram/ml, respectively. Serotypes a and e were more susceptible to cefaclor and cefuroxime than were serotypes b and c; 100% of the first two groups were inhibited at 2.0 micrograms/ml and 1.0 microgram/ml. Ampicillin inhibited 92% of the tested strains at 1.0 microgram/ml. Serotype b was always susceptible to ampicillin. Metronidazole exhibited the best activity against serotype a strains. The lowest minimal inhibitory concentration values for benzylpenicillin, ampicillin, erythromycin, doxycycline, and metronidazole were encountered among serotype b isolates. The results of the present study indicate minor differences in the in vitro antimicrobial susceptibility patterns of different A.a. serotypes, except to metronidazole. Also, the new oral cephalosporins and cotrimoxazole, rare antimicrobial agents in periodontology, showed promising efficacy against all A.a. strains.

Cefdinir (FK482), an orally administered cephalosporin in vitro activity comparison against recent clinical isolates from five medical centers and determination of MIC quality control guidelines.

Cefdinir, a new oral cephalosporin, was compared to cefaclor, cefadroxil, cefixime, and cefuroxime against greater than 5000 recent aerobic clinical isolates. This multicenter study revealed broad-spectrum cefdinir activity against all Enterobacteriaceae (MIC50s, 0.06-2 micrograms/ml) except Enterobacter cloacae, Morganella morganii, Proteus vulgaris, and Serratia marcescens (MIC50s, greater than or equal to 4 micrograms/ml). Oxacillin-susceptible staphylococci (MIC90s, 0.5-2 micrograms/ml), beta-hemolytic Streptococcus group B (MIC90, 0.06 micrograms/ml), and Acinetobacter lwoffii were also susceptible to cefdinir. The activity of cefdinir was similar to that of cefixime and cefuroxime against Gram-negative organisms and superior to all tested oral cephems when tested against Gram-positive cocci. None of the cephalosporins were active against oxacillin-resistant Staphylococcus spp., enterococci, Pseudomonas spp., or Xanthomonas maltophilia. MIC quality control range guidelines were established for the strains recommended by the National Committee for Clinical Laboratory Standards documents.

Antibacterial activity of the investigational oral and parenteral cephalosporin BK-218.

BK-218 is a novel cephalosporin with a dual route of administration and spectrum of activity most similar to that of second-generation cephalosporins. BK-218 was active against Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis but strains resistant to penicillins had higher MICs. BK-218 had greater activity (8-fold) than cefuroxime or cefaclor against oxacillin-susceptible Staphylococcus spp. Moderate BK-218 activity was observed against Neisseria gonorrhoeae and commonly isolated Enterobacteriaceae such as Escherichia coli (MIC90, 1 mg/l), Klebsiella spp. (MIC90, 2 mg/l), and Proteus mirabilis (MIC90, 2 mg/l). The following organisms were generally BK-218-resistant (MIC90, greater than 16 mg/l): Bacteroides fragilis, Pseudomonas spp., Acinetobacter spp., Xanthomonas maltophilia, Citrobacter spp., Enterobacter spp., indole-positive Proteus, Serratia spp., enterococci and oxacillin-resistant staphylococci.

[Experimental study of the antibiotic activity of cefuroxime]. / Eksperimental'noe izuchenie antibakterial'noi aktivnosti tsefuroksima.

The antimicrobial spectrum of cefuroxime, an antibiotic of the cephalosporin family was studied in vitro with respect to 11 species (16 strains) of gram-positive and gram-negative bacteria and in vivo on albino mice with experimental salmonellosis or pneumococcal infections. The bacteria were either test cultures or isolates from patients. The studies showed that cefuroxime had a wide antibacterial spectrum in vitro. It inhibited the growth of Staph. aureus, Str. pneumoniae, E. coli, Salm. typhimurium, Kl. pneumoniae, Bac. subtilis and had no effect on Ps. aeruginosa, Pr. vulgaris, M. tuberculosis and M. fortuitum. Cefuroxime had also a high bacteriostatic effect with respect to the experimental pneumococcal infection and a lower bacteriostatic effect with respect to the experimental salmonellosis infection.