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Corona virus disease-2019 (COVID-19) emerged in Wuhan, China in December 2019 and was declared as a pandemic by the World Health Organization in March 2020. Although there is no complete treatment protocol for COVID-19, studies on this topic are ongoing, and it is known that broad-spectrum antibiotics such as cephalosporins are used for coinfections and symptoms in COVID-19 patients. Studies have shown that Staphylococcus aureus and Escherichia coli bacteria can cause symptoms such as diarrhea and coinfections accompanying COVID-19. Therefore, in this study, colon-targeted cefaclor monohydrate (CEF)-loaded poly(lactic- co -glycolic acid) ( PLGA)-Eudragit S100 nanoparticles (NPs) were prepared using a nanoprecipitation technique. The particle sizes of the CEF-loaded NPs were between 171.4 and 198.8 nm. The encapsulation efficiency was in the range of 58.4%-81.2%. With dissolution studies, it has been concluded that formulations prepared with Eudragit S100 (E-coded) and Eudragit S100+PLGA (EP-coded) are pH-sensitive formulations and they are targetable to the colon, whereas the formulation prepared only with PLGA (P-coded) can release a higher CEF rate in the colon owing to the slow release properties of PLGA. The release kinetics were fitted to the Korsmeyer-Peppas and Weibull models. The antibacterial activity of E-, EP-, and P-coded formulations was 16-fold, 16-fold, and 2-fold higher than CEF, respectively, for S. aureus and E. coli according to the microdilution results. As a result of the time killing experiment, all formulations prepared were found to be more effective than the antibiotic itself for long periods. Consequently, all formulations prepared in this study hope to guide researchers/clinicians in treating both gram-positive and gram-negative bacteria-induced infections, as well as COVID-19 associated coinfections and symptoms.

Endodontic revascularization is based on cell recruitment into the necrotic root canal of immature teeth after chemical disinfection. The clinical outcome depends on the ability of surviving cells from the apical tissue to differentiate and promote hard tissue deposition inside the dentinal walls., Objective: To investigate the effect of calcium hydroxide (CH) and modified triple antibiotic paste (mTAP - ciprofloxacin, metronidazole and cefaclor) on the viability and mineralization potential of apical papilla cells (APC) in vitro ., Material and Methods: APC cultures were kept in contact with CH or mTAP (250-1000 µg/mL) for 5 days, after which cell viability was assessed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Next, APCs were subjected to CH or mTAP at 250 µg/mL for 5 days before inducing the differentiation assay. After 14 and 21 days, calcium deposition was assessed by the Alizarin Red S staining method, followed by elution and quantification using spectrophotometry. Data were analyzed using ANOVA followed by Tukey post hoc test., Results: CH induced cell proliferation, whereas mTAP showed significant cytotoxicity at all concentrations tested. APC treated with CH demonstrated improved mineralization capacity at 14 days, while, for mTAP, significant reduction on the mineralization rate was observed for both experimental periods (14 and 21 days)., Conclusion: Our findings showed that CH induces cell proliferation and improves early mineralization, whereas mTAP was found cytotoxic and reduced the mineralization potential in vitro of APCs.

An increase in the copper pool in body fluids has been related to a number of pathological conditions, including infections. Copper ions may affect antibiotics via the formation of coordination bonds and/or redox reactions. Herein, we analyzed the interactions of Cu 2+ with eight β-lactam antibiotics using UV-Vis spectrophotometry, EPR spectroscopy, and electrochemical methods. Penicillin G did not show any detectable interactions with Cu 2+ . Ampicillin, amoxicillin and cephalexin formed stable colored complexes with octahedral coordination environment of Cu 2+ with tetragonal distortion, and primary amine group as the site of coordinate bond formation. These β-lactams increased the solubility of Cu 2+ in the phosphate buffer. Ceftazidime and Cu 2+ formed a complex with a similar geometry and gave rise to an organic radical. Ceftriaxone-Cu 2+ complex appears to exhibit different geometry. All complexes showed 1:1 stoichiometry. Cefaclor reduced Cu 2+ to Cu 1+ that further reacted with molecular oxygen to produce hydrogen peroxide. Finally, meropenem underwent degradation in the presence of copper. The analysis of activity against Escherichia coli and Staphylococcus aureus showed that the effects of meropenem, amoxicillin, ampicillin, and ceftriaxone were significantly hindered in the presence of copper ions. The interactions with copper ions should be taken into account regarding the problem of antibiotic resistance and in the selection of the most efficient antimicrobial therapy for patients with altered copper homeostasis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Isolated Agrobacterium tumefaciens was exposed to different extremely low frequencies of square amplitude modulated waves (QAMW) from two generators to determine the resonance frequency that causes growth inhibition. The carrier was 10 MHz sine wave with amplitude ±10 Vpp which was modulated by a second wave generator with a modulation depth of ± 2Vpp and constant field strength of 200 V/m at 28 °C. The exposure of A. tumefaciens to 1.0 Hz QAMW for 90 min inhibited the bacterial growth by 49.2%. In addition, the tested antibiotics became more effective against A. tumefaciens after the exposure. Furthermore, results of DNA, dielectric relaxation and TEM showed highly significant molecular and morphological changes due to the exposure to 1.0 Hz QAMW for 90 min. An in-vivo study has been carried out on healthy tomato plants to test the pathogenicity of A. tumefaciens before and after the exposure to QAMW at the inhibiting frequency. Symptoms of crown gall and all pathological symptoms were more aggressive in tomato plants treated with non-exposed bacteria, comparing with those treated with exposed bacteria. We concluded that, the exposure of A. tumefaciens to 1.0 Hz QAMW for 90 min modified its cellular activity and DNA structure, which inhibited the growth and affected the microbe pathogenicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective This study was performed to assess the clinical and radiological outcomes of a revascularization procedure in immature teeth with apical periodontitis using platelet-rich plasma (PRP). The PRP protocol and conventional revascularization protocol, which used a blood clot as the scaffold, were compared. Methods Thirty non-vital immature permanent teeth were randomly categorized into two groups. After disinfecting the root canal space with triple antibiotic paste (1:1:1 ciprofloxacin, metronidazole, and cefaclor), a tissue scaffold was created using either PRP or a blood clot (control) and covered with white mineral trioxide aggregate. All cases were followed up clinically and radiographically for 12 months. Differences in bone density, root length, and lesion size were calculated using preoperative and postoperative computed tomography images. The means of the differences in individual parameters in the blood clot and PRP groups were compared using the Mann-Whitney U test. Results After 5 months, sensitivity tests (cold and electric pulp tests) elicited a delayed positive response in 23 sites. At 12 months, cone-beam computed tomography revealed resolution or a decrease in lesion size and an increase in bone density in all 30 (100%) teeth. Additionally, continued root development was observed in 22 (73%) teeth and early root growth was observed in the test group (mineral trioxide aggregate with PRP). Conclusions The results of this study suggest that PRP can serve as a successful scaffold for regenerative endodontic treatment. With the exception of a significant increase in root length, the results of treatment with PRP were not significantly different from those of the conventional protocol using a blood clot as the scaffold.

The activity of daptomycin (DAP) against methicillin-resistant Staphylococcus aureus (MRSA) is enhanced in the presence of β-lactam antibiotics. This effect is more pronounced with β-lactam antibiotics that exhibit avid binding to penicillin binding protein 1 (PBP1). Here, we present evidence that PBP1 has a significant role in responding to DAP-induced stress on the cell. Expression of the pbpA transcript, encoding PBP1, was specifically induced by DAP exposure whereas expression of pbpB, pbpC, and pbpD, encoding PBP2, PBP3, and PBP4, respectively, remained unchanged. Using a MRSA COL strain with pbpA under an inducible promoter, increased pbpA transcription was accompanied by reduced susceptibility to, and killing by, DAP in vitro. Exposure to β-lactams that preferentially inactivate PBP1 was not associated with increased DAP binding, suggesting that synergy in the setting of anti-PBP1 pharmacotherapy results from increased DAP potency on a per-molecule basis. Combination exposure in an in vitro pharmacokinetic/pharmacodynamic model system with β-lactams that preferentially inactivate PBP1 (DAP-meropenem [MEM] or DAP-imipenem [IPM]) resulted in more-rapid killing than did combination exposure with DAP-nafcillin (NAF) (nonselective), DAP-ceftriaxone (CRO) or DAP-cefotaxime (CTX) (PBP2 selective), DAP-cefaclor (CEC) (PBP3 selective), or DAP-cefoxitin (FOX) (PBP4 selective). Compared to β-lactams with poor PBP1 binding specificity, exposure of S. aureus to DAP plus PBP1-selective β-lactams resulted in an increased frequency of septation and cell wall abnormalities. These data suggest that PBP1 activity may contribute to survival during DAP-induced metabolic stress. Therefore, targeted inactivation of PBP1 may enhance the antimicrobial efficiency of DAP, supporting the use of DAP-β-lactam combination therapy for serious MRSA infections, particularly when the β-lactam undermines the PBP1-mediated compensatory response., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Streptococcus agalactiae (GBS) has been implicated in urinary tract infections but the microbiological characteristics and antimicrobial susceptibility of these strains are poorly investigated. In this study, 87 isolates recovered from urine samples of patients who had attended the Spedali Civili of Brescia (Italy) and had single organism GBS cultured were submitted to antimicrobial susceptibility testing, molecular characterization of macrolide and levofloxacin resistance, PCR-based capsular typing and analysis of surface protein genes. By automated broth microdilution method, all isolates were susceptible to penicillin, cefuroxime, cefaclor, and ceftriaxone; 80%, 19.5% and 3.4% of isolates were non-susceptible to tetracycline, erythromycin, and levofloxacin, respectively. Macrolide resistance determinants were iMLS(B) (n=1), cMLS(B) (n=10) and M (n=5), associated with ermTR, ermB and mefA/E. Levofloxacin resistance was linked to mutations in gyrA and parC genes. Predominant capsular types were III, Ia, V, Ib and IX. Type III was associated with tetracycline resistance, while type Ib was associated with levofloxacin resistance. Different capsular type-surface protein gene combinations (serotype V-alp2, 3; serotype III-rib; serotype Ia-epsilon) were detected. A variety of capsular types are involved in significant bacteriuria. The emergence of multidrug resistant GBS may become a significant public health concern and highlights the importance of careful surveillance to prevent the emergence of these virulent GBS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Covalent irreversible inhibitors can successfully treat antibiotic-resistant infections by targeting serine β-lactamases. However, this strategy is useless for New Delhi metallo-β-lactamase (NDM), which uses a non-covalent catalytic mechanism and lacks an active-site serine. Here, NDM-1 was irreversibly inactivated by three β-lactam substrates: cephalothin, moxalactam, and cefaclor, albeit at supratherapeutic doses (e.g., cefaclor KI =2.3 ± 0.1 mM; k(inact) =0.024 ± 0.001 min(-1)). Inactivation by cephalothin and moxalactam was mediated through Cys208. Inactivation by cefaclor proceeded through multiple pathways, in part mediated by Lys211. Use of a cefaclor metabolite enabled mass spectrometric identification of a +346.0735 Da covalent adduct on Lys211, and an inactivation mechanism is proposed. Lys211 was identified as a promising "handhold" for developing covalent NDM-1 inhibitors and serves as a conceptual example for creating covalent inhibitors for enzymes with non-covalent mechanisms., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel family of tetraaza macrocyclic Cu(II) complexes [CuLX(2)] (where L = N(4) donor macrocyclic ligands) and (X = Cl(-), NO(3) (-)) have been synthesized and characterized by elemental analysis, magnetic moments, IR, EPR, mass, electronic spectra and thermal studies. The magnetic moments and electronic spectral studies suggest square planar geometry for [Cu(DBACDT)]Cl(2) and [Cu(DBACDT)](NO(3))(2) complexes and distorted octahedral geometry to the rest of the ten complexes. The biological activity of all these complexes against gram-positive and gram-negative bacteria was compared with the activity of existing commercial antibacterial compounds like Linezolid and Cefaclor. Six complexes out of twelve were found to be most potent against both gram-positive as well as gram-negative bacteria due to the presence of thio group in the coordinated ligands.

The effect of temperature stresses on Cefaclor suspensions under different storage conditions for a duration of 14 days was tested. The degradation of Cefaclor was determined on the 2nd, 7th and 14th day after reconstitution using a sensitive and precise Reversed phase High Performance Liquid Chromatographic (RP-HPLC) method. The RSD values for Forticef, Midocef, Ceclor, Cefabac and Cloracef, indicated a good precision of the RP-HPLC method. The limit of detection (LOD) and the limit of quantification (LOQ) were found 0.008 mg/ml and 0.03mg/ml respectively. The antimicrobial effect of Cefaclor suspension was also tested against pathogenic bacteria using the cylinder diffusion method. The RSD values range of the antimicrobial assay for all the Cefaclor compounds were 1.47-3.7%. The LOD and LOQ were 0.2mg/ml and 1mg/ml respectively. During the normal use of Ceclor, Midocef, and Forticef the loss of activity and the degradation were less than 5% on the 14th day of preservation at 4°C. However, the percentage of degradation for Cefabac and Cloracef on the 14th day reached 5 and 6%, respectively. Statistical multiple comparison between the effect of 4°C and 25°C indicated non significant mean differences (P>0.05) for Forticef, Cefabac, Ceclor and Cloraf and significant effect for Midocef (P <0.05). Significant effects were observed between (4oC and 37°C) and (25°C and 37°C) for all except Ceclor. Multiple comparisons between days of storage showed non significant mean difference values at 4°C except Cefabac. However significant results between days were found at 25°C and 37°C except for Midocef between (7th and 14th day). It was found that the pediatric suspensions of Cefaclor in the Jordanian market were stable and contained the amount of active ingredient specified by the United States pharmacopoeias specification (USP) and the British Pharmacopoeias specifications (BP).

Previous articles reported that beta-lactam antibiotics increase the expression of Staphylococcus aureus Panton-Valentine leukocidin (PVL) by activating its transcription. We investigated the mechanisms underlying the inductor effect of beta-lactams on PVL expression by determining targets and regulatory pathways possibly implicated in this process. We measured PVL production in the presence of oxacillin (nonselective), imipenem (penicillin-binding protein 1 [PBP1] selective), cefotaxime (PBP2 selective), cefaclore (PBP3 selective), and cefoxitin (PBP4 selective). In vitro, we observed increased PVL production consistent with luk-PV mRNA levels that were 20 to 25 times higher for community-acquired methicillin-resistant S. aureus (CA-MRSA) cultures treated with PBP1-binding oxacillin and imipenem than for cultures treated with other beta-lactams or no antibiotic at all. This effect was also observed in vivo, with increased PVL mRNA levels in lung tissues from CA-MRSA-infected mice treated with imipenem but not cefoxitin. To confirm the involvement of PBP1 inhibition in this pathway, PBP1 depletion by use of an inducible pbp1 antisense RNA showed a dose-dependent relationship between the level of pbp1 antisense RNA and the luk-PV mRNA level. Upon imipenem treatment of exponential-phase cultures, we observed an increased sarA mRNA level after 30 min of incubation followed by a decreased rot mRNA level after 1 to 4 h of incubation. Unlike the agr and saeRS positive regulators, which were nonessential for PVL induction by beta-lactams, the sarA (positive) and rot (negative) PVL regulators were necessary for PVL induction by imipenem. Our results suggest that antibiotics binding to PBP1 increase PVL expression by modulating sarA and rot, which are essential mediators of the inductor effect of beta-lactams on PVL expression.

We evaluated the efficacy of disk diffusion methods for detection of low-level β-lactamase-negative ampicillin-resistant (low-BLNAR) Haemophilus influenzae. Four hundred and seventy unselected, recent clinical isolates were tested with ampicillin (10 μg), cefaclor (30 μg) and cefuroxime (30 μg) on iso-Sensitest agar enriched with nicotinamide adenine dinucleotide (NAD) and horse blood [ST agar; Swedish Reference Group for Antibiotics (SRGA) guidelines], and on chocolate agar (in-house guidelines). Selected isolates (n = 147) were subjected to partial sequencing of the ftsI gene. Forty-seven strains (10.0%) were genotypically identified as low-BLNAR, which was confirmed by determination of minimal inhibitory concentration (MIC) using microbroth dilution method: only low level resistance to ampicillin was detected [MIC ≤1 μg/mL; MIC(50) = 0.5 μg/mL, implying susceptibility by Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antibiotic Susceptibility Testing (EUCAST) interpretative criteria]. The MIC of cefuroxime varied between 1 and 4 μg/mL (MIC(50) = 2 μg/mL), indicating susceptibility to cefuroxime by CLSI but not by EUCAST guidelines. Disk diffusion methods were able to discriminate low-BLNAR H. influenzae from the wild-type population with sensitivities ranging from 87% to 98% and specificities from 96% to 99%. Cefaclor was found to be superior to cefuroxime and ampicillin. Cefaclor zone diameter breakpoints of 30/29 and 23/22 mm are suggested for ST agar and chocolate agar, respectively., (© 2011 The Authors. APMIS © 2011 APMIS.)

Dietary protein is a major stimulant for cholecystokinin (CCK) secretion by the intestinal I cell, however, the mechanism by which protein is detected is unknown. Indirect functional evidence suggests that PepT1 may play a role in CCK-mediated changes in gastric motor function. However, it is unclear whether this oligopeptide transporter directly or indirectly activates the I cell. Using both the CCK-expressing enteroendocrine STC-1 cell and acutely isolated native I cells from CCK-enhanced green fluorescent protein (eGFP) mice, we aimed to determine whether PepT1 directly activates the enteroendocrine cell to elicit CCK secretion in response to oligopeptides. Both STC-1 cells and isolated CCK-eGFP cells expressed PepT1 transcripts. STC-1 cells were activated, as measured by ERK(1/2) phosphorylation, by both peptone and the PepT1 substrate Cefaclor; however, the PepT1 inhibitor 4-aminomethyl benzoic acid (AMBA) had no effect on STC-1 cell activity. The PepT1-transportable substrate glycyl-sarcosine dose-dependently decreased gastric motility in anesthetized rats but had no affect on activation of STC-1 cells or on CCK secretion by CCK-eGFP cells. CCK secretion was significantly increased in response to peptone but not to Cefaclor, cephalexin, or Phe-Ala in CCK-eGFP cells. Taken together, the data suggest that PepT1 does not directly mediate CCK secretion in response to PepT1 specific substrates. PepT1, instead, may have an indirect role in protein sensing in the intestine.

Plasmid pB1000 is a small replicon recently identified as bearing bla(ROB-1) in animal and human Pasteurellaceae in Spain. We identified pB1000 in 11 bla(ROB-1)-positive Australian and North American Haemophilus influenzae isolates, suggesting a wider role for pB1000 in disseminating bla(ROB-1). Native H. influenzae conjugative elements can mobilize plasmids similar to pB1000 at a low frequency of 10(-8), and this might account for the infrequency of bla(ROB-1) compared to the rate of occurrence of bla(TEM-1). Altered penicillin-binding protein 3 was associated with an increased cefaclor MIC in 3 isolates.

Currently, beta-lactamase-negative (BLN) ampicillin-resistant (AR) strains of Haemophilus influenzae are prevalent in Japan. BLNAR strains are defined by the presence of specific mutation(s) in the ftsI gene but are not phenotypically distinguishable by ampicillin (ABPC) susceptibility. In the present study, we showed that cephalexin (CEX), cefsulodin (CFS), and cefaclor (CCL) disk diffusion tests can be effectively used to identify BLNAR strains. A total of 169 clinical isolates of BLN H. influenzae, consisting of 113 of BLNAR and 56 of BLN, ampicillin-susceptible (AS), were included. All the isolates were genetically defined by detection of the TEM gene and partial sequencing of the ftsI gene. The Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution and disk diffusion tests for ABPC provided 20% and 19% false susceptible rates, respectively. Alternatively, 34 cephem agents were tested using disk diffusion. Of the agents tested, CEX, CFS, and CCL disks could effectively discriminate between BLNAR and BLNAS isolates. All the BLNAS isolates showed visible growth inhibitory zones around CEX and CFS disks, but 108 (95.6%) and 106 (93.8%) BLNAR isolates did not. The results indicated 100% predictive values (PVs) for BLNAR and PVs for BLNAS were 91.8% for CEX and 88.9% for CFS. The CLSI-based interpretations for CCL (> or =20 mm) also highly correlated with BLNAR and BLNAS, PVs for BLNAR and for BLNAS being 100% and 93.3%, respectively. With simplicity and discriminability of the test method, we recommend a CEX disk diffusion test in combination with a rapid beta-lactamase test to identify BLNAR isolates in clinical laboratories.

Plasmid pB1000 is a mobilizable replicon bearing the bla(ROB-1) beta-lactamase gene that we have recently described in Haemophilus parasuis and Pasteurella multocida animal isolates. Here we report the presence of pB1000 and a derivative plasmid, pB1000', in four Haemophilus influenzae clinical isolates of human origin. Pulsed-field gel electrophoresis showed unrelated patterns in all strains, indicating that the existence of pB1000 in H. influenzae isolates is not the consequence of clonal dissemination. The replicon can be transferred both by transformation and by conjugation into H. influenzae, giving rise to recipients resistant to ampicillin and cefaclor (MICs, > or =64 microg/ml). Stability experiments showed that pB1000 is stable in H. influenzae without antimicrobial pressure for at least 60 generations. Competition experiments between isogenic H. influenzae strains with and without pB1000 revealed a competitive disadvantage of 9% per 10 generations for the transformant versus the recipient. The complete nucleotide sequences of nine pB1000 plasmids from human and animal isolates, as well as the epidemiological data, suggest that animal isolates belonging to the Pasteurellaceae act as an antimicrobial resistance reservoir for H. influenzae. Further, since P. multocida is the only member of this family that can colonize both humans and animals, we propose that P. multocida is the vehicle for the transport of pB1000 between animal- and human-adapted members of the Pasteurellaceae.

The antibacterial susceptibility to frequently prescribed antibiotics of Streptococcus pneumoniae isolated from the pediatric patients with acute respiratory infectious diseases was investigated in a study of three medical institutions in Korea. Total 143 clinical isolates of S. pneumoniae were available for susceptibility tests between May 2003 and July 2007. Antimicrobial susceptibility data for S. pneumoniae were analyzed by using agents of amoxicillin, cefaclor, cefuroxime, cefdinir, and cefditoren as the test antibiotics. The prevalence of each resistance class, penicillin-resistant S. pneumoniae (PRSP) were high with the proportion of MIC range (susceptible = 8.4%, intermediate resistance = 18.2%, resistance = 73.4%). MIC90 and susceptible (S) rate of antimicrobial agents to the strains tested were amoxicillin (MIC90 = 4 microg/ml, S = 76.2%), cefaclor (MIC90 = 128 microg/ml, S=8.4%), cefuroxime (MIC90 = 16 microg/ml, S = 24.5%), cefdinir (MIC90 = 16 microg/ml, S = 21.8%), and cefditoren (MIC90 = 0.5 microg/ml, S=90.2%) respectively. Against clinical isolates including PRSP, cefditoren demonstrated the strongest antibacterial activity intrinsically among the antibiotics tested. Conclusively, the antimicrobial activity of cefditoren to S. pneumoniae strains isolated from pediatric patients with acute respiratory infection is very high. In South Korea, where the antibiotic resistance ofS. pneumoniae is issued, cefditoren is expected to be used as a primary or secondary antibiotic. Moreover, cefditoren may serve as a useful option for secondary antibiotics after failure of amoxicillin treatment, which is most primarily used for acute respiratory S. pneumoniae infection in children.

Objective: To determine the pharmacokinetic interaction between cefaclor and bromhexine in healthy Chinese volunteers., Methods: Twelve subjects received a cefaclor (CEF) treatment, a bromhexine (BHX) treatment, and a co-treatment of CEF and BHX with a 3 x 3 Latin square design. The wash-out time between periods was 14 days. The plasma and urine drug concentrations of CEF and BHX were detected by HPLC-UV and LC/MS, respectively., Results: All the 12 volunteers completed the study. There were no significant differences in AUC 0-t and Cmax of CEF in logarithm between the single administration group of CEF and the co-administration group of CEF with BHX. Two one sided t-test showed that CEF was bioequivalent in the 2 groups. There were no significant differences in tmax, MRT, t1/2, and Clr between the 2 groups. Vd/F was significantly lower in the single CEF group than in the co-administration group of CEF and BHX. There were no significant differences of AUC 0-t and Cmax of BHX in logarithm between the single administration group of BHX and the co-administration group of BHX with CEF. Two one sided t-test showed that BHX was bioequivalent in the 2 groups. There were no significant differences in tmax, MRT, t1/2, Vd/F, and Clr between the 2 groups., Conclusion: There is no significant pharmacokinetic parameter change in the drug absorption, metabolism, and excretion, but Vd/F of CEF significant increases in the co-administration of CEF with BHX. The co-administration of CEF and BHX has no adverse drug interaction. The increase of Vd/F may be a favorable drug interaction, which may be the mechanism of the synergistic effect of the 2 drugs.

The proper and coordinated response of the host immune system to bacterial infections is known to play a central role in the eradication of an infection. Therefore, the impact of antibiotics on both innate and acquired host immunity may be involved in the therapeutic outcome. The aim of this study was to evaluate the effects of the widely used cephalosporin cefaclor on some parameters of the immune system in ex vivo conditions. The results demonstrated that short-term (3 to 6 days) treatment with this antibiotic induced pleiotropic modification of rat spleen cells upon ex vivo stimulation with the polyclonal mitogen PHA, entailing increased lymphoproliferative responses, augmented IFN-gamma, IL-2 and IL-10 synthesis and decreased production of IL-4 and IL-6 in comparison to spleen cells from control rats. The mononuclear spleen cells of healthy rats released larger amounts of IFN-gamma and IL-2 in culture supernatants in response to polyclonal mitogenic stimulation with PHA compared to the spleens of the control rats receiving vehicle only. Simultaneously, the treatment with cefaclor augmented PHA-induced lymphoproliferative responses and reduced the synthesis of IL-4 and IL-6. These data depict a type 1 cytokine inducing and immunostimulatory pharmacological profile that, by activating the innate and acquired immune system, would be synergistic with cefaclor antibacterial activity.

Amoxicillin and cefaclor are two of the widely used beta-lactam antibiotics in the treatment of urinary tract infections. Both drugs are eliminated mainly by the kidney and rely on renal excretion to exert their antibacterial activities in the urinary tract. Previous studies have suggested the involvement of organic anion and oligopeptide transporters in membrane transport of beta-lactams. The objective of the current study was to examine the kinetics of amoxicillin and cefaclor interactions with human renal transporters human organic anion transporter 1 (hOAT1), human peptide transporter 1 (hPepT1), and human peptide transporter 2 (hPepT2) in detail, both as substrates and as inhibitors. Using fluorescence protein tagging and cell sorting, we established Madin-Darby canine kidney cell lines stably expressing highly functional hOAT1, hPepT1, and hPepT2. Amoxicillin and cefaclor inhibited hOAT1-mediated [(3)H]para-aminohippuric acid uptake (K(i) = 11.0 and 1.15 mM, respectively). However, our uptake study revealed that neither drug was transported by hOAT1. Amoxicillin and cefaclor competitively inhibited hPepT2-mediated [(3)H]glycylsarcosine uptake (K(i) = 733 and 65 muM, respectively), whereas much lower affinity for hPepT1 was observed with both antibiotics. Direct uptake studies demonstrated that amoxicillin and cefaclor were transported by hPepT1 and hPepT2. Kinetic analysis showed that hPepT2-mediated uptake of both drugs was saturable with K(m) of 1.04 mM for amoxicillin and 70.2 muM for cefaclor. hPepT2, and to a lesser extent hPepT1, may play an important role in apical transport of amoxicillin and cefaclor in the renal tubule. hOAT1, in contrast, is not involved in basolateral uptake of these antibiotics.

Objective: Nasopharyngeal microflora contains some beta-lactamase-producing microorganisms. In this study, we investigated in vitro on the indirect pathogenicities of Haemophilus parainfluenzae (H. parainfluenzae) and Moraxella catarrhalis (M. catarrhalis) against the antipneumococcul activities of some beta-lactams., Methods: We compared the antimicrobial and bactericidal activities of beta-lactams against penicillin-susceptible Streptococcus pneumoniae (PSSP) with or without presence of the enzymes of two species of beta-lactamase-producing microorganisms, H. parainfluenzae and M. catarrhalis., Results: When adding the enzymes extracted from these two beta-lactamase-producing microorganisms in equivalent amounts of 10(7) CFU/spot, the minimum inhibitory concentrations of amoxicillin (AMPC) and cefaclor (CCL) increased to >64 microg/mL. Even third-generation cephalosporins, such as cefditren (CDTR) and ceftriaxone (CTRX) showed marked increases with the enzyme of M. catarrhalis. In time-kill kinetics, same phenomenon was observed in mixed culture indicating the indirect pathogenicities of distinct bacteria, not extracted enzymes, on the cidal activities of beta-lactams against PSSP. Clavulanic acid (CVA)/AMPC, faropenem (FRPM), and imipenem (IPM) were not affected by these beta-lactamase-producing strains with respect to their activities against PSSP. However, these two beta-lactamase-producing strains and their enzymes did not show any significant influence on the antipneumococcul activities of beta-lactams, until the number of bacterial cells reached >10(8) CFU/mL., Conclusion: Our results suggest that these two species of beta-lactamase-producing microorganisms in the nasopharyngeal microflora may act as indirect pathogens on the antipneumococcul activities of beta-lactams with reflecting their substrate profiles, but this is dependent on sufficient amounts of enzyme for their influence as indirect pathogens.

Objective: To compare the pharmacokinetics/pharmacodynamics property of cefdinir, cefpodoxime proxetil and cefaclor against common bacteria of community acquired infections and evaluate the recommended regimens., Methods: The antibacterial activities of 3 agents against 238 clinical isolates were determined by standard agar dilution test and the pharmacokinetics of these antibiotics in male healthy volunteers were conducted in Latin-square manner. The time over MIC (T > MIC) of serum antibiotic concentrations were calculated with pharmacokinetic equation and MIC., Results: The value of MIC90 s cefdinir against these bacterial strains except penicillin non-sensitive pneumococci were 0.031-1 mg/L. Cefpodoxime held similar antibacterial activity with cefdinir, but was less potent against staphylococci. Cefaclor had much higher MIC values than other two drugs. After oral administration of 250 mg cefaclor, the drug concentration quickly reached peak concentration of 4.95 mg/L +/- 2.41 mg/L and the eliminative half time was 0.69 h +/- 0.6 h; the Tmax, Cmax and T1/2beta of cefdinir and cefpodoxime after oral administration of 100 mg were 2.5 h +/- 0.48 h, 0.81 mg/L +/- 0.19 mg/L, 1.73 h +/- 0.3 h and 2.38 h +/- 0.43 h, 1.12 mg/L +/- 0.28 mg/L, 1.92 h +/- 0.55 h, respectively. T > MIC of cefdinir in thrice daily administration were longer than 40% of medication interval against most of the tested isolates; no T > MIC period was found in cefpodoxime against staphylococci and the T > MICs of cefaclor after 250 mg oral administration were shorter than expected values against most bacteria., Conclusion: With powerful antibacterial activity, the T > MICs of cefdinir after 100 mg oral administration can meet with the clinical requirement in most infections; PK/PD value of cefpodoxime proxetil against staphylococci is lower than expectancy and 250 mg cefaclor 3 times daily is not enough to the treatment of common community acquired infections, the regimens of cefpodoxime proxetil and cefclor should be furtherly optimized.

We previously reported that standard methods overestimate cefaclor minimum inhibitory concentrations (MICs) for Streptococcus pneumoniae due to in vitro chemical instability. This study aimed to ascertain if standard methods accurately measure cefaclor MICs to Haemophilus influenzae. Cefuroxime was used as a comparator. Standard NCCLS broth microdilution and E-Test MICs were determined for eight isolates of H. influenzae. Kill curves determined the "bacteriostatic" MIC, defined as the concentration showing no significant growth or kill over six hours taking into account cefaclor instability. On average, cefaclor and cefuroxime bacteriostatic MICs were 0.2 x MIC and 0.6 x MIC determined by NCCLS methodology respectively. The mean MIC determined by NCCLS methodology was 3.0 mg/L for cefaclor and 0.8 mg/L for cefuroxime. Cefaclor MICs by NCCLS methodology were overestimated due to chemical instability over 18-24 hours. The bacteriostatic MICs by kill curve were not significantly different from those of cefuroxime.

The purpose of this study was to determine effect of repeated exposure to sub-inhibitory concentrations of amoxicillin/clavulanic acid on the development of resistance in Streptococcus pneumoniae. Other agents, azithromycin, cefaclor and levofloxacin, were also tested. Twenty S. pneumoniae were passaged for 9 days in the presence of sub-inhibitory concentrations of each antimicrobial agent and MICs determined by NCCLS macro-dilution method. There was a four-fold increase in amoxicillin/clavulanic acid MICs for 2 of 20 isolates. Three of 9 tested against cefaclor, 11 of 13 tested against azithromycin and 9 of 20 tested against levofloxacin showed > or =4-fold increase. Amoxicillin/clavulanic acid was the most stable of the agents tested. Cefaclor MICs were also fairly stable. Azithromycin and levofloxacin MICs were most affected.

Discrepancies between proven clinical success of cefaclor and its relatively poor activity in vitro were investigated against eight pneumococcal isolates. The bacteriostatic minimum inhibitory concentration (MIC) (the concentration resulting in no growth/kill relative to the starting inoculum) was derived from time kill studies. Bioassay results demonstrated an in vitro half-life of >24 and 9 h for cefuroxime and cefaclor, respectively. The mean NCCLS MIC for cefaclor was 1.4 and 0.3 mg/l for cefuroxime. The corresponding mean bacteriostatic MICs were 0.24 and 0.16 mg/l. Whilst cefaclor NCCLS MICs were significantly higher compared with cefuroxime MICs (P = 0.00058) there was no statistical differences between the bacteriostatic MICs (P = 0.259). Bacteriostatic MIC determination established that cefaclor and cefuroxime are equally active against pneumococci.

The effect of cefaclor against relevant bacterial strains was studied by employing a combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) approach. For this purpose selected isolates of Escherichia coli, Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae were exposed in vitro to the interstitial cefaclor profile obtained in vivo in the interstitial space fluid of human tissue after administration of commonly used doses of cefaclor and the change in the number of colony forming units per millilitre (CFU/ml) versus time was monitored. Fitting of the data using a modified E(max)-model resulted in a set of mean pharmacodynamic parameters (k0, k(max), EC50) for each bacterial strain. The parameters derived from these experiments were used in a computer-simulation of the antibacterial effects for different dosing regimens and formulations of cefaclor, notably an immediate (IR) and a modified (MR) release formulation. Dosage regimens were compared using the ratio between the number of bacteria remaining after 24 h of a given treatment (N24h). The results indicate that the number of bacteria of all investigated strains killed per day is equivalent when the same daily dose is administered twice a day with the MR dosage form than when given three times a day with the IR dosage form, in spite of the fact that the MR dosage form has approximately 20% lower bioavailability. Best results were obtained with the three-times a day regimen of the MR formulation. In conclusion, the present in vivo-PK/in vitro-PD simulations of the antimicrobial effects of cefaclor indicate that a twice-daily treatment with a MR formulation may offer a convenient and safe alternative to the conventional tid treatment.

Three isolates of beta-lactam-resistant streptococci from the saliva of healthy adults were identified as Streptococcus mitis. Minimum inhibitory concentrations (MICs) were 2 to 4 micro g/ml for ampicillin (ABPC) and 64 to more than 128 micro g/ml for cefaclor (CCL). To determine the position of base alterations of the penicillin-binding protein 2b ( pbp2b) gene, upstream primers containing possible mutation points were designed, and used for polymerase chain reaction (PCR), together with a downstream primer. Alterations adjacent to the conserved motifs of the pbp2b gene were apparent. DNA sequencing data indicated replacements in deduced amino acid sequences in all resistant isolates: from threonine to alanine just after the serine-serine-asparagine (SSN) motif, and from alanine to glycine two residues downstream of the lysine-threonine-glycine (KTG) motif. These changes were the same as those in penicillin-resistant Streptococcus pneumoniae (PRSP), suggesting importance for the enzymatic activity of the protein. Thus, Beta-lactam susceptibility of S. mitis may be partially predicted by PCR using our primer set for pbp2b.

A total of 98 isolates of Branhamella catarrhalis were examined for their susceptibility to antibiotics using serial dilution method. Nitrocefin test was employed for detection of beta-lactamase activity. It was found that most of the isolates (71%) were resistant to ampicillin. Resistance to this antibiotic was accompanied by ability to beta-lactamase production. On the other hand, all isolates were susceptible to amoxicillin + clavulanic acid combination. Almost all isolates were susceptible to cefaclor (99%), cefuroxime (94%), cefotaxime (100%), ciprofloxacin (100%), tetracycline (91%), cotrimoxazole (93%) and erythromycin (93%).

The purpose of this study was to examine the percentage of Beta-lactam-resistant streptococcal carriers in healthy adults, and to investigate the relationships among minimum inhibitory concentrations (MICs) of Beta-lactams, alterations in the penicillin-binding protein genes ( pbp genes), and the affinity of penicillin-binding proteins (PBPs) for ampicillin (ABPC) in Streptococcus mitis. We also compared numbers of surviving bacteria at various ABPC concentrations in both ABPC-susceptible and -resistant S. mitis strains. The percentages of subjects carrying ABPC- and cefaclor (CCL)-resistant streptococci were 52% (27 of 52 subjects) and 100%, respectively. S. mitis, including both antibiotic-susceptible and -resistant strains, were classified into five groups according to the pbp gene mutations that resulted in alterations of the deduced amino-acid sequence in the homology boxes of PBPs. All ABPC-resistant strains showed alterations in PBP1A, 2X, and 2B, while no or only PBP2X alterations were detected in the susceptible strains. These results suggest that the accumulation of pbp gene mutations is strongly related to the MIC of ABPC for S. mitis. In the resistant strains, the affinity of PBPs for ABPC was reduced in comparison with that in the susceptible strains, and the bactericidal effect of ABPC was also reduced. Therefore, we should be aware of conditions such as infective endocarditis that are caused by Beta-lactam-nonsusceptible streptococci in the normal oral flora.

The purpose of the present study was to investigate the correlation between the composition of the bacterial flora isolated from infected root canals of teeth with apical periodontitis with the presence of clinical signs and symptoms, and to test the antibiotic susceptibility of five anaerobic bacteria mostly commonly found in the root canals of symptomatic teeth against various substances using the E-test. Microbial samples were taken from 48 root canals, 29 symptomatic and 19 asymptomatic, using adequate techniques. A total of 218 cultivable isolates were recovered from 48 different microbial species and 19 different genera. Root canals from symptomatic teeth harbored more obligate anaerobes and a bigger number of bacterial species than the asymptomatic teeth. More than 70% of the bacterial isolates were strict anaerobes. Statistical analysis used a Pearson Chi-squared test or a one-sided Fisher's Exact test as appropriate. Suggested relationships were found between specific microorganisms, especially gram-negative anaerobes, and the presence of spontaneous or previous pain, tenderness to percussion, pain on palpation and swelling amoxicillin, amoxicillin + clavulanate and cephaclor were effective against all the strains tested. The lowest susceptibility rate was presented by Prevotella intermedia/nigrescens against Penicillin G. Our results suggested that specific bacteria are associated with endodontic symptoms of infected teeth with periapical periodontitis and the majority of the anaerobic bacterial species tested were susceptible to all antibiotics studied.

The clinical use of cefaclor has been shown to enrich Haemophilus influenzae populations harboring cefaclor-hydrolyzing ROB-1 beta-lactamase. Such a selective process may lead to the increased use of extended-spectrum cephalosporins or beta-lactams plus beta-lactamase inhibitors and, eventually, resistance to these agents, which has not previously been observed in H. influenzae. In order to establish which bla(ROB-1) mutations, if any, could confer resistance to extended-spectrum cephalosporins and/or to beta-lactamase inhibitors, a plasmid harboring bla(ROB-1) was transformed into hypermutagenic strain Escherichia coli GB20 (DeltaampC mutS::Tn10), and this construct was used in place of H. influenzae bla(ROB-1). Strain GB20 with the cloned gene was submitted to serial passages in tubes containing broth with increasing concentrations of selected beta-lactams (cefotaxime or amoxicillin-clavulanate). Different mutations in the bla(ROB-1) gene were obtained during the passages in the presence of the different concentrations of the selective agents. Mutants resistant to extended-spectrum cephalosporins harbored either the Leu169-->Ser169 or the Arg164-->Trp164 substitution or the double amino acid change Arg164-->Trp164 and Ala237-->Thr237. ROB-1 mutants that were resistant to beta-lactams plus beta-lactamase inhibitors and that harbored the Arg244-->Cys244 or the Ser130-->Gly130 replacement were also obtained. The cefaclor-hydrolyzing efficiencies of the ROB-1 variants were strongly decreased in all mutants, suggesting that if bla(ROB-1) mutants were selected by cefaclor, this drug would prevent the further evolution of this beta-lactamase toward molecular forms able to resist extended-spectrum cephalosporins or beta-lactamase inhibitors.

As the post-marketing surveillance of cefpodoxime proxetil (Banan), MICs of cefpodoxime (CPDX, an active form of Banan) against 1090 clinical isolates of 22 species from 15 medical institutions all over Japan from June 2000 to March 2001 were measured using the broth microdilution method approved by the Japanese Society of Chemotherapy and compared with those of oral cephem antibacterials, cefaclor, cefdinir, cefditoren, and cefcapene. In this study, remarkable change in the activity of CPDX was observed in Streptococcus pneumoniae and Haemophilus influenzae compared with the susceptibility in the studies before Banan was launched. This cause is considered to be the increase in the incidence of the following resistant strains: penicillin-intermediate S. pneumoniae (47.3%), penicillin-resistant S. pneumoniae (PRSP, 15.1%), and beta-lactamase-negative ampicillin-resistant (BLNAR) H. influenzae (24.0%), which were scarcely isolated in 1989 when Banan was launched. Other tested drugs also exhibited low activity against these resistant strains. However, CPDX showed comparatively good activity with MIC90 of 2 micrograms/mL against PRSP. Against methicillin-susceptible Staphylococcus spp., Streptococcus pyogenes, Streptococcus agalactiae, and Moraxella catarrhalis, CPDX also showed comparatively good activity with MIC90 of < or = 4 micrograms/mL, which was almost equal to that in the studies before its marketing. Against quinolones-resistant Neisseria gonorrhoeae, CPDX showed excellent activity with MIC90 of 0.5 microgram/mL. Against members of the family Enterobacteriaceae except for Citrobacter freundii, Enterobacter spp., Proteus vulgaris, and Morganella morganii, CPDX showed good activity. However, in Escherichia coli, Klebsiella spp. Proteus spp., and Providencia spp., there are some high-resistant strains to all tested drugs including CPDX. Against Peptostreptococcus spp., MIC90 of CPDX was 8 micrograms/mL and its MIC range was widely distributed from 0.03 to 32 micrograms/mL, which were similar to those in the studies before its marketing. In this study, CPDX showed the decrease in the activity against several species as did other drugs tested, but against most of species tested, CPDX maintained good activity. Furthermore, it is necessary to pay much attention to the trend of resistant strains.

Renal transplant recipients are at increased risk of malignancy and infection. We present the case of a 72-year-old-man with recurrent bladder carcinoma, abdominal aortic aneurysm repair, and end-stage renal failure due to renovascular disease. He received a cadaveric renal allograft into his left iliac fossa, was given cyclosporin A, azathioprine, and prednisolone triple therapy immunosuppression, and had no rejection episodes. He presented four years post-transplantation with a two-year history of intermittent sweats and fevers. Previous episodes had been investigated with no firm diagnosis made. This time he had right iliac fossa pain of three weeks' duration. Examination revealed a tender mass. Investigations showed unchanged graft function, but elevated inflammatory indices. Ultrasonography and computed tomography detailed an infiltrating mass associated with the sigmoid colon, which colonoscopy failed to visualise. At laparotomy a 6-cm tumor was removed, with adherent sigmoid colon and bladder dome. Macroscopically the mass was an abscess, and microscopy found acute and chronic inflammatory giant cells and fibrillary masses suggestive of actinomycosis, with no malignancy. The patient recovered uneventfully on antibiotics. At six months' follow-up, examination, inflammatory markers, and radiographic imaging showed no evidence of recurrence. Twelve months later the patient died of rupture of his proximal abdominal aorta. There was no evidence of recurrence at postmortem examination. We conclude with a brief review of actinomycosis in transplant recipients.

Objective: To study the influence of Cefaclor and Prednisonum to the expression of cell adhesion molecule in experimental otitis media with effusion (OME)., Method: SD rats models of OME were made using formalin killed nontypeable Hemophilus influenzae and the expression of adhesion molecules Mac-1 and L-Selectin was analysed by flow cytometry using white blood cell obtained by cardiac puncture in control, bacterial and medicine groups. The pathology of middle ear mucosa was investigated to understand the relationship between the expression of adhesion molecules and the pathology., Result: It was found that the expression of adhesion molecules Mac-1 and L-Selection in bacteria group increased obviously with pathological change of the middle ear mucosa. Cefaclor and Prednisonum could decrease the expression of adhesion molecules and inhibited the leukocyte accumulation in the middle ear cavity though there was no significant differences except for the L-Selectin in the Cefaclor group between the bacteria group and the medicine group., Conclusion: Dead bacteria in the middle ear may act as an antigen to induce the inflammatory response and effusion of the middle ear. The expression of adhesion molecules Mac-1 and L-Selectin is highly related to the inflammatory response. Cefaclor and Prednisonum may improve otitis media with effusion, which may related to the decreasing expression of Mac-1 and L-Selectin.

Epidemiological and microbiological studies were carried out using 575 strains of Haemophilus influenzae isolated from clinical specimens at Kitakyushu municipal medical center from January 1996 through December 1999. The strains isolated multiply were excluded. The strains of H. influenzae did not increase for 4 years, and were detected more in summer season, peaked in July, and less in winter season. Like the cases of Streptococcus pneumoniae, most (91.8%) of the strains was detected in the specimens from the respiratory tract, and also they were isolated mainly from infants under 4-years old (25.6%) and adults over 65-years old (24.2%) MICs of 7 antimicrobial agents, such as ampicillin (ABPC), sulbactam/ABPC, cefaclor, imipenem, panipenem, meropenem (MEPM), and levofloxacin (LVFX) were determined using broth microdilution methods. Among 575 strains of H. influenzae isolated from clinical specimens, 51 ABPC-resistant strains (8.9%) produced beta-lactamase, and 67 strains (11.6%) were beta-lactamase negative ampicillin resistant H. influenzae. The ABPC-resistant strains existed in 20.5%. Both of MEPM and LVFX showed excellent antimicrobial activity against H. influenzae including ABPC-resistant strains. Four cases of meningitis were reviewed. All of H. influenzae isolated possessed type b capsular antigen. All patients recovered by appropriate antimicrobial treatment. But one adult patient developed serious sequela.

Objective: To determine the antimicrobial activity of Cefaclor against common respiratory tract pathogens isolated from patients in Pakistan., Setting: Department of Microbiology, Liaquat National Postgraduate Medical Centre, Karachi., Method: A laboratory analysis was done on 466 isolates of respiratory tract pathogens collected from 13 laboratories from all over Pakistan. Antibiotic sensitivity test was done by Kirby Bauer disc diffusion method and MIC of Cefaclor was determined by 'E' test., Result: Of the 163 Streptococcus pneumoniae, 87 Moraxella catarrhalis and 216 Haemophilus influenzae > 95% isolates were susceptible to Cefaclor. The MIC 90 of all these pathogens were < 2 ug., Conclusion: Resistance of respiratory tract pathogens to the 2nd generation Cephalosporin, Cefaclor is very low. MIC 90 of Cefaclor against all three common respiratory tract pathogens is < 2 ug, which indicates that Cefaclor would be effective in more than 90% of cases infected with these bacteria.

Since the first strains of penicillin-resistant Streptococcus pneumoniae were isolated in the 1960s, the rate of resistance has increased world- wide, though with geographic variations. Currently, the prevalence and patterns of antibiotic resistance in this microorganism vary widely from one country to another, as well as within in the same country. In our study we evaluated the in vitro susceptibility of 299 isolates of S. pneumoniae from patients with community-acquired respiratory tract infections from 1998-2000 to different antimicrobial agents. The following resistance results were obtained: 32.11% to penicillin, 4.35% to amoxicillin, 3.68% to amoxicillin-clavulanic acid, 69.9% to cefaclor, 32.44% to cefpodoxime, 34.11% to cefuroxime, and 24.41% to azithromycin. For cefixime and ceftibuten there are no NCCLS breakpoint criteria.

The effect exerted on complex immunoregulatory functions of the immune system is an important criterion when selecting an antibiotic. When assessing the effect of an antibiotic on the immune system, one should also take into consideration the existence of functional relationships between the immune system and the nervous and hormonal systems. Among these three systems, there are common factors that modify biological processes. This makes it possible for the antibiotic not only to interact directly with the elements of the immune system, but also to exert indirect influences on potential neurotropic and endocrinotropic effects of the drug. Besides highly effective bactericidal activity, cefaclor demonstrates the ability to exert a favorable effect on some of the specific and non-specific immune responses and immunoregulation mechanisms, which may be important from a clinical point of view. Cefaclor enhances phagocytosis and bactericidal activity of granulocytes and macrophages, and favorably modifies the cooperation of monocytes and T lymphocytes. In this way, it corrects, both in vivo and in vitro, the immunoregulatory disturbances induced and aggravated by an infection. This effect is reflected by an improvement in the impaired immunoregulating activity of T lymphocytes, and is manifest both as an increase in suppressive activity and a correction of the monokine level ratio in relation to the decrease of proinflammatory monokine IL-1 and a relative increase of antiinflammatory IL-1ra. By normalizing the disturbed immunoregulation mechanism, cefaclor enhances the protective potential of the immune reaction while it also reduces the risk of immunogenic clinical complications such as persistent inflammatory conditions and allergic and/or autoaggressive responses. Such immunomodulating properties of cefaclor may be useful in the clinical treatment of patients with immune disorders leading to chronic inflammation and secondary allergic or autoaggressive reactions.

The aim of this study was to evaluate the efficacy of cefaclor in the prophylaxis of recurrent acute otitis media (AOM) in human immunodeficiency virus (HIV)-infected children. The study was carried out in children born between 1 January 1986 and 31 December 1996 who had been vertically HIV infected Patients who had experienced recurrent AOM between October 1997 and March 1998 (period 1) were eligible for the trial. Recurrent AOM was defined as the occurrence in the same patient of three or more episodes of AOM within 6 months of the observation period. Patients recruited for this trial received cefaclor at a dose of 20 mg/kg once daily for 6 months between April and September 1998 (period 2). Clinical observation was carried out in periods 1 and 2 and for the first 6 months after prophylaxis, i.e. October 1998 - March 1999 (period 3). Natural killer-cell activity, phagocytosis and myeloperoxidase activity were determined before and at the end of the prophylactic period. For each period, CD4-cell count measurement and CD4-positive cell class were recorded. Seventeen children were recruited for this trial. No significant differences were observed in natural killer-cell activity between periods 1 and 2, nor were any significant differences observed in CD4-positive cell class or CD4-positive cell count between the three periods. However, cefaclor administration was associated with a reduction in the number of AOM episodes in 100% of cases and a mean increase in myeloperoxidase activity in 57% of cases. This suggests that cefaclor may be useful in the prophylaxis of recurrent AOM in HIV-infected children.

The frequency and the antibacterial sensitivity of Streptococcus pneumoniae strains isolated from 6 key hospitals (in 5 areas) and 1 otorhinolaryngology clinic in Gifu Prefecture from February to March, 1999, were investigated with several antibiotics. A total of 128 strains of Streptococcus pneumoniae were isolated throughout the study: 47 strains (36.7%) of penicillin-susceptible S. pneumoniae (PSSP), 51 strains (39.8%) of penicillin-intermediate S. pneumoniae (PISP), and 30 strains (23.4%) of penicillin-resistant S. pneumoniae (PRSP); the resistant bacteria being relatively prominent. In these hospitals, PSSP was isolated by 38.8% in all the key hospitals and by 30% in the otolaryngology clinic with almost no discernible difference. PISP was isolated by 63.3%, higher in the otolaryngology clinic and PRSP by 28.6%, higher in the key hospitals conversely. The MIC90s in PISP and PRSP were determined with the antibiotics. In result, only cefditoren (CDTR) showed favorable antibacterial activities with the MIC90 of 0.78 microgram/ml among penicillins or oral cephems. The MIC90s of carbapenems such as imipenem (IPM), meropenem (MEPM), and panipenem (PAPM) were less than 0.39 microgram/ml; particularly, PAPM showed the highest antibacterial activities. Among new quinolones such as tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), and ciprofloxacin (CPFX), TFLX showed the highest antibacterial activities with the MIC90 of 0.39 microgram/ml. Other agents showed very low antibacterial activities as the MIC90s were 25 micrograms/ml in minocycline (MINO) and more than 100 micrograms/ml in clarithromycin (CAM) and clindamycin (CLDM).

Studies in vitro suggest that cephalosporin antibiotics release the gut hormone cholecystokinin. Cholecystokinin is known to inhibit gastric emptying. Here we examine the effects of cefaclor on gastric emptying and intestinal motility. Male Sprague-Dawley rats were fitted with gastric cannulas. Following a 3-week recovery, the rate of gastric emptying of saline, peptone (4.5%) or cefaclor was determined after instillation into the gastric cannula, while intestinal transit was measured by using the propagation of arabic gum + charcoal mixture given intraduodenally. Gastric emptying of saline was significantly delayed by the addition of cefaclor (3, 10, 30 or 100 mM). The CCK-A antagonist SR-27897B (1 mg kg(-1), i.p.) reversed the delay induced by 10 mM cefaclor, whereas the CCK-B antagonist CI-988 (1 mg kg(-1), i.p.) had no significant effect. In capsaicin-treated rats, 10 mM cefaclor emptied more rapidly than in vehicle-treated animals. Thirty-minute intestinal transit was increased at 30 and 100 mM of cefaclor, while the gastric acid secretion following cefaclor instillation was no different than the group which received saline. The cephalosporin antibiotic cefaclor appears to be a potent stimulant of CCK release from gut endocrine cells, resembling the effects of peptone. Cefaclor delays gastric emptying via capsaicin-sensitive afferent pathways, which involve CCK-A receptor interaction.

Purpose: To evaluate the efficacy and safety of Cefaclor in respiratory tract infections amongst Pakistani children., Patients and Methods: Multicenter, open label and non-comparative study was done to evaluate the response in terms of symptoms (In vivo) and bacterial cultures (In Vitro) to Cefaclor amongst children with respiratory tract infection between the ages 2 months to 12 years. Each patient was asked to visit the doctor on three occasions i.e., Day 0 (Initial evaluation prior to commencement of study), Day 4 (During therapy assessment and confirmation of compliance) and Day 10 (End of therapy assessment and compliance evaluation). Representative swab specimens (Throat swabs, Ear swabs or Sputum) were collected from the infected site on day 0 and day 10 for culture and sensitivity. Patients were also assessed by the evaluators on each visit in terms of clinical symptomatic response and information collected was documented on a prescribed data base form., Results: A total of 160 patients were enrolled in the study, of whom 15 were lost to follow-up between the first and second visit and a further 38 were lost by the 3rd visit. Thus 107 patients completed the study as per protocol. Otitis media and Upper respiratory tract infection were the predominant ailments amongst the cases enrolled. One or more bacteria were isolated in 75 (46%) instances, the maximum number of isolates being from ear swabs of Otitis media patients. Beta haemolytic Streptococcus (group A,C,F,G) seen in 18 cases was the most common pathogen reported followed by Staphylococcus aureus, H. influenzae and Streptococcus pneumoniae in 13,12 and 11 cases respectively. Sensitivity of Cefaclor for bacteria commonly seen in the respiratory tract was greater than 90% in most of the cases. Evaluation of the 42 culture proven cases for patients who completed the study showed that Cefaclor had a 93% efficacy for indicated bacteria and 54% for non-indicated bacteria. In Vivo analysis of Cefaclor (i.e. on the basis of symptomatic response) showed that 96% cases had a symptomatic response by the second visit, which improved to 97% by the third visit. Only 15 non-serious adverse events were observed in 160 patients, none of the cases necessitated discontinuation of drug. Mild gastrointestinal symptom was the most common adverse event reported., Conclusion: Cefaclor was found to be a safe and efficacious drug in the treatment of bacterial respiratory tract infections amongst Pakistani children.

In vitro cefditoren antimicrobial activity was tested by broth microdilution and disk diffusion methods against 300 Streptococcus pneumoniae and 299 Haemophilus influenzae isolates. MICs were also determined for three comparison drugs. The MICs of cefditoren were very comparable to those of cefotaxime against both species. If penicillin-resistant pneumococci are to be considered not susceptible to cefditoren, the tentative MIC breakpoints for cefditoren of < or = 0.25 microg/ml for susceptible and > or 1.0 microg/ml for resistant could be selected. With these breakpoints, all penicillin-susceptible pneumococci were cefditoren-susceptible, as were 85% of penicillin-intermediate strains. Provisional zone diameter breakpoints would be > or = 26 mm for susceptible and < or = 20 mm for resistant. If penicillin-resistant pneumococcal infections are shown to clinically respond to cefditoren therapy, then a susceptible MIC breakpoint of < or = 1.0 microg/ml would be appropriate, with a corresponding zone diameter breakpoint of > or = 21 mm. A susceptible MIC breakpoint of < or = 0.5 or < or = 1.0 microg/ml is appropriate for H. influenzae, but lack of correlation between cefditoren MICs and disk diffusion zone diameters when testing H. influenzae leads us to make no recommendations at this time regarding cefditoren disk tests for H. influenzae.

Between July 1998 and July 1999, 2,644 clinical isolates of Streptococcus pneumoniae were collected from 27 study centers in 13 countries and their susceptibilities to penicillin, cefaclor and loracarbef were determined by E-test" (AB BIODISK, Solna, Sweden). Overall, 96.3% of isolates were penicillin-susceptible (79.8%) or -intermediate (16.6%) (MIC, < or = 1 microg/ml). Rates of penicillin-resistant S. pneumoniae isolation varied widely and were highest in the study centers tested in New Zealand (10.9%), Canada (10.0%), Mexico (9.1%) and the United States (5.1%). Low rates of penicillin-resistance were found in the study centers tested in Russia (0%), Turkey (0%), Brazil (0.5%), Germany (0.6%), Philippines (1.6%), Italy (2.1%), United Kingdom (2.3%), Australia (3.0%) and Poland (3.1%). Using recently published NCCLS interpretative breakpoints (M100-S10, 2000), 87.2% (median) of all isolates tested were cefaclor-susceptible and 87.8% (median) of all isolates tested were loracarbef-susceptible. Of the penicillin-susceptible S. pneumoniae isolates, 99.5% were susceptible to both cefaclor and loracarbef. Susceptibility to cefaclor and loracarbef was also retained by 30.8% and 32.9% of penicillin-intermediate isolates, respectively. These findings are in contrast to recent publications reporting lower cefaclor and loracarbef activities using non-validated interpretative criteria. In conclusion, rates of penicillin resistance among recent clinical isolates of pneumococci remain low in many centers worldwide. Cefaclor and loracarbef demonstrated excellent in vitro activity against recent clinical isolates of penicillin-susceptible and many isolates of penicillin-intermediate S. pneumoniae.

Objective: To evaluate the comparative activity of seven oral antimicrobial agents against 100 strains of Streptococcus pneumoniae (S. pneumoniae)., Methods: Total 100 strains of S. pneumoniae were collected from general hospitals in Beijing from June 1996 to June 1997. E test method was used to detect the minimum inhibitory concentration (MIC) values of the following seven drugs against S. pneumoniae: penicillin, amoxicillin/clavulanate, cefaclor, cefuroxime, ceftriaxone, azithromycin and ofloxacin. The breakpoint of susceptibility categories was defined according to NCCLS., Results: 74% of isolates were susceptible (S, MIC 0.06 mg/L) to penicillin, and 5% were penicillin resistant (R, MIC 2 mg/L). The intermediately resistant (I, MIC 0.1-1 mg/L) rate to penicillin was 21%. The total rates of R or I were 26% for penicillin, 6% for both amoxicillin/clavulanate and ceftriaxone, 9% for cefuroxime, 66% and 68% for azithromycin and ofloxacin respectively. Overall 94%, 94% and 91% of the pneumococcal isolates were susceptible to amoxicillin/clavulanate, ceftriaxone and cefuroxime respectively. S. pneumoniae was highly resistant to azithromycin tested as a representative of macrolides (MIC50 and MIC90 both > 256 mg/L, R rate 66%), and had a highly intermediately resistant rate to ofloxacin (I rate 62%)., Conclusions: Our data suggest that in vitro activity of oral amoxicillin/clavulanate was as good as ceftriaxone and cefuroxime. It can be considered as an alternative compound in the treatment of community acquired pneumoniae and other respiratory tract infections caused by multiresistant S. pneumoniae.

beta-Lactamase production in Canadian isolates of Haemophilus influenzae has remained relatively constant (25-35%) over the last decade despite increasing cefaclor resistance (MIC >/= 32 mg/L). TEM (294/324, 90.7%) and ROB-1 (30/324, 9.3%) prevalence rates among 324 isolates of H. influenzae obtained from across Canada in 1997-1998 were similar (P > 0.05) to previously published reports. However, 66. 7% (26/39) of cefaclor-resistant isolates were ROB-1-positive (P < 0. 001) and the remaining four ROB-1-positive isolates were cefaclor-intermediate (MIC 16 mg/L). Susceptibilities to loracarbef (P < 0.001) and cefprozil were also reduced in the presence of ROB-1 while the activities of cefuroxime, cefotaxime, cefixime and imipenem were similar in both TEM- and ROB-1-positive solates.

Cefaclor advanced formulation (cefaclor AF) is an extended-release form of the oral cephalosporin cefaclor. When cefaclor AF 750 mg twice-daily and cefaclor immediate release 500 mg three-times-a-day are compared there is a skew to the right of the pharmacokinetic profile and higher levels are achieved. Based on this pharmacokinetic finding, we examined the relationship between the bacterial susceptibility to cefaclor (MIC), the achieved cefaclor AF serum and sputum concentrations, and in vivo eradication of the bacteria in 36 patients with acute exacerbations of chronic bronchitis. The mean peak concentrations in serum and sputum 5 h after administration were 8.6 microg/ml (95% CI: 8.1 microg/ml - 9.1 microg/ml) and 1.5 microg/ml (95% CI: 1.4 microg/ml - 1.7 microg/ml), respectively. Cefaclor was always detectable 8 h after administration. At post therapy, treatment was successful in 31 (86.1%) patients. Cefaclor concentrations in serum persisted above the MIC for more than 40% of dosing interval in 31 subjects, and those in sputum in 24 patients. Treatment was successful in all subjects with percent of time above the MIC in serum of >40%, whereas the time that levels in sputum stayed above the MIC was not the pharmacodynamic parameter that correlated best with therapeutic efficacy for cefaclor. Our data demonstrate that when cefaclor AF is dosed twice-daily, the in vivo pharmacodynamic susceptibility breakpoint is 8 microg/ml. The good activity and pharmacokinetics of cefaclor AF provide serum concentrations higher than the MIC of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis for more than 40% of the validated dosing interval. Therefore, it might be considered for first choice treatment of acute exacerbations of chronic bronchitis.

Cefditoren, a third generation orally administered aminothiazolyl cephalosporin, has demonstrated bactericidal activity against many Gram positive and negative bacterial pathogens and stability against clinically important beta-lactamases. Cefditoren was compared to cefaclor, cefixime, and penicillins against 1 435 recently isolated strains of streptococci (312 Streptococcus pneumoniae, 165 viridans group streptococci, 142 beta-haemolytic streptococci), Haemophilus influenzae (521 strains), and Moraxella catarrhalis (295 strains). Streptococcus pneumoniae and viridans group streptococci had penicillin nonsusceptible rates of 37.8 and 35.8%, respectively. Cefditoren (MIC(90) in microg/ml/% susceptible) activity against all tested H. influenzae (0.03/100) and M. catarrhalis (0.06-0.5/100) was comparable to cefixime and significantly greater than cefaclor. Cefditoren (MIC(90), 0.5 microg/ml) was 4- to 128-fold more active than comparison beta-lactams against the pneumoococci and was the most potent beta-lactam (including penicillin) versus beta-haemolytic streptococci. Cefditoren pharmacokinetics demonstrate a T(1/2) of 1.5-2 h and C(max) values of 2.8 and 4.6 microg/ml, respectively with 200 or 400 mg doses of cefditoren pivoxil; plasma concentrations exceed 1 microg/ml for 4 to 6 hours (33-50% of dosing interval). Consequently, a susceptible MIC of /= 18 and >/= 15 mm (5-microg disk) for all cited fastidious species tested. Categorical agreement between MIC and disk tests was 94.6 to 100% with a correlation coefficient (r) range of 0.50 to 0.90 for streptococci. H. influenzae intermethod comparison results using the same interpretive criteria were in complete agreement, but exhibited a low r = 0.39. Cefditoren clearly possesses the most potent activity among currently studied oral cephalosporins or penicillin against commonly isolated bacterial pathogens causing bronchitis, pneumonia, sinusitis, or pharyngitis and was active against nearly all penicillin-resistant streptococci at

Enteroendocrine cells respond to nutrient and non-nutrient stimuli in the gut lumen. The intestinal hormone cholecystokinin (CCK) is secreted in response to luminal fatty acids, amino acids, peptides and proteins. The peptidomimetic cephalosporins have been reported to provide model, stable, compounds with similar secretagogue activity to peptide. Putative luminal stimuli also influence transcriptional activity in enteroendocrine cells, but the mechanisms are uncertain. In the present study we have investigated the control of c-fos expression in STC-1 cells (an enteroendocrine cell line). Peptidomimetics stimulated calcium-dependent release of CCK, and increased intracellular calcium, phosphorylation of p42/44 mitogen-activated protein kinase (MAP kinase) and c-fos mRNA abundance. Hypotonic stress also increased p42/44 MAP kinase phosphorylation and c-fos mRNA, but not CCK release. The increase in c-fos mRNA was strikingly potentiated by peptidomimetics in hypotonic medium. Increased c-fos expression, but not CCK release, was suppressed by the MAP kinase (MEK) inhibitor PD98059, and by the tyrosine kinase inhibitor genistein. We conclude that in STC-1 cells, peptidomimetics act through the p42/44 MAP kinase pathway to increase c-fos expression but not exocytosis. Moreover, a putative non-nutritive stimulus, hypotonic stress, may interact with this pathway to enhance c-fos expression, independently of hormone release.