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PubMed2005

Combined application of amoxicillin and clavulanic acid after oral surgical interventions.

Antibiotics represent a powerful weapon against infections. As dentists we are faced almost on a daily basis with the need to prescribe antibiotics. At the same time, we can often see that the antibiotics use tends to get out of control or that they are used indiscriminately with no real need. The aim of this case study is to investigate the effectiveness of amoxicillin and clavulanic acid combination in various dental ailments but also to demonstrate possible difference in the severity of symptoms after the use of amoxicillin and antibiotic combination of amoxicillin and clavulanic acid after surgical and oral interventions. The investigation involved 102 patients who were divided into two groups (the first group consisting of 59 and the second one of 43 patients). Following surgical treatment the first group of patients was prescribed antibiotic combination of amoxicillin and clavulanic acid in the dosage of 625 mg, 3 times per day. The second group of 43 patients was prescribed amoxicillin in the dosage of 500 mg, 4 times per day. The recommended therapy for antibiotic combination of amoxicillin and clavulanic acid was 5 to 10 days after the operation and 8 to 10 days for amoxicillin. In other words, both groups of patients started to use antibiotics after the surgical or oral intervention such as operative removal of impacted wisdom teeth, apicoectomy or complicated extractions, and also after the treatment of odontogenic abscesses etc. The same parameters were measured prior to the surgical intervention in cases when patients demonstrated the symptoms before the operational treatment while in all other cases the parameters were measured 48 hours and seven days following the operation. The measured parameters were: pain, swelling, body temperature, dysfunction such as dysphagus trismus, chewing disorder and possible allergic or gastrointestinal reactions. All parameters observed were precisely set in order to harmonize the investigation criteria and facilitate statistical data processing. With respect to pain before the operation there was no substantial statistical difference, p>0.05 (t=0.56; t=0.69). With respect to the onset of pain and the use of antibiotics after 48 hours there is a significant difference in favor of antibiotic combination of amoxicillin and clavulanic acid (X= 14.83, p= 0.002; p <0.01). Thus, pain is less acute if antibiotic combination of amoxicillin and clavulanic acid is administered. With respect to swelling and administration of antibiotics 48 hours after the operation there is no significant difference between the use of the two antibiotic therapies (X= 4.89; p=0.18; p>0.05). The investigation conducted seven days after the operation with regard to pain and the use of either antibiotic therapies demonstrated significant statistical difference (X=9.35, p<0.01) in favor of antibiotic combination of amoxicillin and clavulanic acid. In other words, patients who used amoxicillin and clavulanic acid felt significantly less intense pain. With respect to swelling, significant statistical difference between the two groups of patients was established in favor of antibiotic combination of amoxicillin and clavulanic acid, i.e. p<0.05 (X=6.45, p=0.03). The combination of amoxicillin and clavulanic has proven to be significantly more effective in comparison with the use of amoxicillin after oral-surgical interventions, and therefore antibiotic combination of amoxicillin and clavulanic acid is recommended for use in further practice.

Amoxicillin↗
PubMed1996

Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid.

BACKGROUND: Amoxicillin-clavulanic acid combination-associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk. METHODS: A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93,433 users of the combination drug amoxicillin-clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested. RESULTS: They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.

Acute Disease↗
PubMed1982

Distribution of amoxicillin and clavulanic acid in infected animals and efficacy against experimental infections.

The therapeutic effects produced by formulations of amoxicillin plus clavulanic acid (BRL 25 000A and BRL 25 000G) were compared with those of amoxicillin and clavulanic acid separately against a variety of infections produced by amoxicillin-susceptible and beta-lactamase-producing (amoxicillin-resistant) bacteria. The infection models studied included intraperitoneal infections, a mouse pneumonia, experimental pyelonephritis, and local lesions caused by Staphylococcus aureus and Bacteroides fragilis. The distribution of amoxicillin and clavulanic acid in infected animals after the administration of amoxicillin-clavulanic acid was evaluated by measurement of the concentrations of the substances present in specimens collected at the sites of infection. The results showed that both amoxicillin and clavulanic acid were well distributed in the animal body after the administration of amoxicillin-clavulanic acid formulations, being present in significant concentrations at various sites of infection, e.g., peritoneal washings, pleural fluid, pus, and infected tissue homogenates. In a number of cases, the amoxicillin concentrations measured after the administration of BRL 25000 were higher than those found after treatment with amoxicillin alone, presumably as a result of inhibition of bacterial beta-lactamases by clavulanic acid at the site of infection. The ability of clavulanic acid to protect amoxicillin in vivo was confirmed by the efficacy of amoxicillin-clavulanic acid formulations in the treatment of the infections studied, most of which were refractory to therapy with amoxicillin.

Amoxicillin↗
PubMed2005

Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial.

CONTEXT: The high prevalence of resistance to trimethoprim-sulfamethoxazole and other antimicrobials among Escherichia coli causing acute cystitis in women has led to increased use of alternative antibiotics. One such antibiotic, amoxicillin-clavulanate, has not been well studied. OBJECTIVE: To compare the efficacy of a 3-day regimen of amoxicillin-clavulanate to that of a 3-day regimen of ciprofloxacin in the treatment of acute cystitis in women. The primary study hypothesis was that the amoxicillin-clavulanate and ciprofloxacin treatment groups would differ in clinical cure. DESIGN, SETTING, AND PATIENTS: Randomized, single-blind treatment trial of 370 women, aged 18 to 45 years, with symptoms of acute uncomplicated cystitis and a urine culture with at least 10(2) colony-forming units of uropathogens per milliliter from a university student health center or a health maintenance organization. INTERVENTIONS: Women were randomly assigned to receive amoxicillin-clavulanate (500 mg/125 mg twice daily) or ciprofloxacin (250 mg twice daily) for 3 days and were followed up for 4 months. MAIN OUTCOME MEASURES: The main outcome measure was clinical cure. Secondary study outcomes of interest were microbiological cure and vaginal E coli colonization at the 2-week follow-up visit. RESULTS: Clinical cure was observed in 93 (58%) of 160 women treated with amoxicillin-clavulanate compared with 124 (77%) of 162 women treated with ciprofloxacin (P<.001). Amoxicillin-clavulanate was not as effective as ciprofloxacin even among women infected with strains susceptible to amoxicillin-clavulanate (65 [60%] of 109 women in the amoxicillin-clavulanate group vs 114 [77%] of 149 women in the ciprofloxacin group; P = .004). The difference in clinical cure rates occurred almost entirely within the first 2 weeks after therapy. Microbiological cure at 2 weeks was observed in 118 (76%) of 156 women treated with amoxicillin-clavulanate compared with 153 (95%) of 161 women treated with ciprofloxacin (P<.001). At this visit, 45% of women in the amoxicillin-clavulanate group compared with 10% in the ciprofloxacin group had vaginal colonization with E coli (P<.001). CONCLUSIONS: A 3-day regimen of amoxicillin-clavulanate is not as effective as ciprofloxacin for the treatment of acute uncomplicated cystitis, even in women infected with susceptible strains. This difference may be due to the inferior ability of amoxicillin-clavulanate to eradicate vaginal E coli, facilitating early reinfection.

Adult↗
PubMed1992

Cefpodoxime proxetil compared with amoxicillin-clavulanate for the treatment of otitis media.

In a multicenter, randomized, investigator-blinded trial, patients were randomly selected to receive either cefpodoxime proxetil or amoxicillin-clavulanate potassium orally for the treatment of acute suppurative otitis media. Patients were seen before, during, and at the end of therapy, and 2 to 3 weeks after completion of therapy. A total of 229 patients, 153 receiving cefpodoxime and 76 receiving amoxicillin-clavulanate were entered into the study; all patients were examined to determine drug safety. A total of 146 patients, 98 in the cefpodoxime group and 48 in the amoxicillin-clavulanate group, completed the study and were examined to determine drug efficacy. End-of-therapy microbiologic eradication rates in assessable patients were 92% for cefpodoxime and 86% for amoxicillin-clavulanate (p = 0.14; 95% confidence interval (CI) on difference: -4.4%, 19.2%). End-of-therapy clinical response rates for assessable patients were as follows: cured, 68% for cefpodoxime and 65% for amoxicillin-clavulanate; improved, 24% for cefpodoxime and 23% for amoxicillin-clavulanate; and failed, 8% for cefpodoxime and 13% for amoxicillin-clavulanate (p = 0.57; 95% CI: -8.4%, 16.5%). Recurrence rates at long-term follow-up were 24% for cefpodoxime-treated patients and 25% for those given amoxicillin-clavulanate. Both drugs were well tolerated; 20.9% of those given cefpodoxime and 31.6% of amoxicillin-clavulanate-treated patients had drug-related adverse medical events (p = 0.102; 95% CI: -23.9%, 2.6%). Gastrointestinal complaints were the most frequently reported drug-related side effect in both groups: 11.8% of cefpodoxime-treated patients and 21.1% of those given amoxicillin-clavulanate (p = 0.076; 95% CI: -20.8%, 2.2%). Drug-related dermatologic side effects (e.g., diaper rash, pruritus, urticaria) were reported in 7.8% of cefpodoxime-treated patients and 14.5% of those who received amoxicillin-clavulanate (p = 0.160; 95% CI: -16.6%, 3.3%). Our findings suggest that clinical efficacy for cefpodoxime administered twice daily is equivalent to that of amoxicillin-clavulanate administered three times a day.

Acute Disease↗
PubMed1999

Streptococcus pneumoniae pneumonia in mice: optimal amoxicillin dosing predicted from a pharmacokinetic-pharmacodynamic model.

In an attempt to better understand the interaction of amoxicillin with Streptococcus pneumoniae in the lung, and to determine the parameters of therapeutic efficacy of the antimicrobial agent amoxicillin, we used a pharmacokinetic-pharmacodynamic model to describe the overall dose-effect relationship of amoxicillin against 12 strains of S. pneumoniae with penicillin minimum inhibitory concentrations ranging from <0.01 to 16 microg/ml in a neutropenic murine pneumonia model. We were able to correlate amoxicillin dosing, pharmacokinetics, and the temporal changes in bacterial count in lung. Moreover, survival rates measured in one strain at different dosing were significantly related to the number of bacteria in lung calculated from the pharmacokinetic-pharmacodynamic model. Disappearance of amoxicillin from the effect compartment appeared to be very slow and the rate constant (k(e0)) governing this process was significantly different between strains, ranging from 0.00131 to 0.03945 h(-1). These findings have two major implications: 1) after a single dose of amoxicillin, bacterial counts in lung rapidly decreased and the bacterial growth remained suppressed during a long period of time after cessation of exposure of microorganisms to amoxicillin; and 2) the duration of bacterial growth suppression was related to the intrinsic properties of S. pneumoniae strains rather than to host environment because k(e0) was significantly different between strains. These two premises clearly demonstrate that bacterial growth suppression is related to an in vivo postantibiotic effect. Furthermore, we have shown that the major determinant of amoxicillin in vivo bactericidal activity and therapeutic efficacy appeared to be the dose of amoxicillin because amoxicillin exhibits a rapid dose-dependent killing regardless of the S. pneumoniae strain. Our findings may have implications for the clinical use of amoxicillin. In view of our results, the guidance to increase the amoxicillin-loading dose in pneumococcal pneumonia appears to be immediately clinically relevant.

Amoxicillin↗
PubMed1997

Role of delayed cellular hypersensitivity and adhesion molecules in amoxicillin-induced morbilliform rashes.

BACKGROUND: Morbilliform rashes induced by amoxicillin are though to be caused by a delayed cell-mediated immune reaction. The importance of amoxicillin skin tests is not well defined. A better understanding of the mechanisms of amoxicillin-induced morbilliform rashes can be obtained by performing cutaneous immunohistological studies on specimens from amoxicillin-induced morbilliform rashes and positive amoxicillin skin test results. OBSERVATIONS: Skin biopsy specimens were obtained from 5 patients who had developed an amoxicillin-induced morbilliform rash. All patients underwent amoxicillin prick, patch, and intradermal tests. Similar immunohistological investigations were performed on amoxicillin-induced morbilliform rashes and positive skin test biopsy specimens, with a special focus on the expression of adhesion molecules. Three of the 5 patients developed delayed positive results to intradermal and patch tests and 2 patients developed delayed positive results to prick tests. Amoxicillin-induced morbilliform rashes were well reproduced by skin tests, with similar immunohistological results in amoxicillin-induced morbilliform rashes and skin test biopsy specimens. Keratinocytes were activated and expressed CD54 (intercellular adhesion molecule 1); perivascular lymphocytes were mostly CD2+, CD3+, and CD4+ and exhibited CD11a through CD18 (leukocyte function-associated antigen 1) and often HLA-DR and/or CD62L (leukocyte endothelial cell adhesion molecule 1); and endothelial cells were activated with a strong expression of CD54 (intercellular adhesion molecule 1), CD62E (endothelial leukocyte adhesion molecule 1), and CD31 (platelet endothelial cell adhesion molecule 1) in lesser amounts. CONCLUSIONS: Findings of this clinical and immunohistochemical study support the theory of a T-cell-mediated immune reaction in patients with amoxicillin-induced morbilliform rashes, with a strong involvement of adhesion molecules both on endothelial and infiltrating cells. Our findings emphasize the importance of delayed readings of amoxicillin prick, intradermal, and patch tests.

Amoxicillin↗
PubMed2005

In vitro and in vivo studies on mucoadhesive microspheres of amoxicillin.

Amoxicillin mucoadhesive microspheres (Amo-ad-ms) were prepared using ethylcellulose (Ec) as matrix and carbopol 934P as mucoadhesive polymer for the potential use of treating gastric and duodenal ulcers, which were associated with Helicobacter pylori. The morphological characteristics of the mucoadhesive microspheres were studied under scanning electron microscope. In vitro release test showed that amoxicillin released faster in pH 1.0 hydrochloric acid (HCl) than in pH 7.8 phosphate buffer. Yet, it would be degraded to some extent in a pH 1.0 HCl medium at 37 degrees C, which indicated that amoxicillin was not stable in an acidic surrounding. It was also found that amoxicillin entrapped within the microspheres could keep stable. In vitro and in vivo mucoadhesive tests showed that Amo-ad-ms adhered more strongly to gastric mucous layer than nonadhesive amoxicillin microspheres (Amo-Ec-ms) did and could retain in gastrointestinal tract for an extended period of time. Amo-ad-ms and amoxicillin powder were orally administered to rats. The amoxicillin concentration in gastric tissue was higher in the Amo-ad-ms group. In vivo H. pylori clearance tests were also carried out by administering, respectively, Amo-ad-ms or amoxicillin powder, to H. pylori infectious BALB/c mice under fed conditions at single or multiple dose(s) in oral administration. The results showed that Amo-ad-ms had a better clearance effect than amoxicillin powder did. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make contribution to H. pylori clearance.

Adhesives↗
PubMed2003

Exposure time-dependent bactericidal activities of amoxicillin against Actinobacillus pleuropneumoniae; an in vitro and In vivo pharmacodynamic model.

The pharmacodynamic effects of amoxicillin against Actinobacillus pleuropneumoniae at exposure concentration above and below minimum inhibitory concentration (MIC) were evaluated in both in vitro and in vivo. In vitro, the growth and morphological change of A. pleuropneumoniae in culture medium was observed. In vivo, the efficacy of amoxicillin on experimentally induced A. pleuropneumoniae infection in disease-free pigs was evaluated. Fifteen pigs were divided into three groups (n = 5 per group). After the onset of clinical respiratory disease symptoms, 6 h post-infection, amoxicillin sustained-release injectable formulation was injected intramuscularly at 7.5 mg/kg/day (group I) and 15 mg/kg/day (group II). Then the serum concentration of amoxicillin was measured. An untreated infected group served as controls. In each amoxicillin administration group, if symptoms were not absent after 48 h, the pig was injected with the amoxicillin sustained-release injectable formulation again using the same dosage. In vitro, the growth of A. pleuropneumoniae inhibited by amoxicillin exposure at the concentration above the MIC (1.28 x MIC), and the inhibition time was in directly proportion to the time of amoxicillin exposure. Moreover, all the cells were lysed. Whereas the bacterial growth inhibition at the amoxicillin exposure concentration below the MIC (0.25 x MIC) was not done, and the shape of cells were normal or long filamentous. In vivo, the group I clinical and pathological score was higher than the group II, and the group I weight gain was significantly less than the group II. Performance with respect to weight gain corresponded with clinical signs. The infected control group was severely affected with an 80% (4/5) mortality rate 24-96 h post-challenge. The duration of time above MIC (T > MIC) of serum amoxicillin concentration in the group I was less than group II. The present studies suggest that amoxicillin has exposure time-dependent bactericidal activity against A. pleuropneumoniae.

Actinobacillus Infections↗
PubMed1997

Continuous twice daily or once daily amoxicillin prophylaxis compared with placebo for children with recurrent acute otitis media.

OBJECTIVE: To determine the effectiveness of amoxicillin administered continuously twice daily vs. once daily vs. placebo to prevent new episodes of acute otitis media (AOM). DESIGN: Randomized, double blind, placebo-controlled clinical trial at a hospital-based general pediatric clinic and a private pediatric practice, both in Denver, CO. PARTICIPANTS: One hundred ninety-four children (age 3 months through 6 years) were enrolled with 3 documented AOM episodes within the prior 6 months, without ventilating tubes or associated anatomic defects, immunodeficiency disorders or allergy to penicillin. Thirty-six were noncompliant and were excluded from the study, leaving 158 evaluable subjects. INTERVENTIONS: The amoxicillin dosage was 20 mg/kg/day either bid or qd. After randomization to placebo twice daily (bid), amoxicillin once daily (qd)/placebo qd or amoxicillin bid, patients were followed monthly and were also seen for upper respiratory infection symptoms during enrollment in the trial. Development of two new AOM episodes terminated the patients from the study. MEASUREMENTS/MAIN RESULTS: Incidence density (ID) measurements were calculated for all study subjects and were stratified by age and season. Overall study subjects in all 3 arms of the trial had 7243 days at risk during which time they developed 56 new AOM episodes for a annual ID of 2.82. There were no significant differences in the IDs between amoxicillin qd vs. bid or amoxicillin (bid or qd) vs. placebo. After stratifying by age and season of enrollment, there were no significant differences in ID rates among the 3 groups. The proportion of subjects remaining otitis-free was 63% for the placebo group, 64% for once daily amoxicillin and 61% for twice daily amoxicillin. CONCLUSION: While once-a-day dosing was equivalent to twice-a-day dosing for amoxicillin prophylaxis, there was no benefit of amoxicillin prophylaxis compared with a placebo control in preventing new AOM episodes. Because of the potential of excessive antibiotic use to promote the acquisition of resistant pneumococci and the lack of effectiveness in this trial, routine use of amoxicillin prophylaxis should be discouraged.

Age Factors↗
PubMed2006

Multiple mutations in or adjacent to the conserved penicillin-binding protein motifs of the penicillin-binding protein 1A confer amoxicillin resistance to Helicobacter pylori.

BACKGROUND: Amoxicillin-based therapies are highly effective for the treatment of Helicobacter pylori infections, but the efficacy may decrease as the incidence of amoxicillin resistance is increasing. So far, the molecular mechanism underlying stable amoxicillin resistance has only been identified for a few naturally occurring amoxicillin-resistant (Amx) H. pylori isolates, and is mediated by mutations in penicillin-binding protein 1A (PBP1A). In this study the molecular mechanism underlying amoxicillin resistance of seven additional Amx H. pylori isolates has been established. METHODS: H. pylori strain 26695 (minimal inhibitory concentration (MIC) 0.125 mg/l) was naturally transformed with total DNA and pbp1A polymerase chain reaction (PCR) products from the seven Amx H. pylori isolates, and the MIC of amoxicillin and pbp1A gene sequence of the obtained Amx transformants were determined. RESULTS: Replacement of the wild-type pbp1A gene of H. pylori reference strain 26695 by the pbp1A gene of the Amx H. pylori isolates resulted in an increased MIC (0.5-1.0 mg/l). Sequence analysis of the smallest PBP1A fragments able to transfer the resistance indicated that several amino acid substitutions in or adjacent to the second (SKN402-404) and third (KTG555-557) conserved penicillin-binding protein motifs (PBP-motifs) mediate amoxicillin resistance in H. pylori. This was confirmed by site-directed mutagenesis using oligonucleotides that contained defined mutations in or adjacent to these PBP-motifs. CONCLUSION: In naturally occurring Amx H. pylori isolates, amoxicillin resistance is mediated by various mutational changes located in or adjacent to the second and third PBP-motifs of the PBP1A. Although we cannot exclude the role of the other genes in amoxicillin resistance, it is likely that multiple mutational changes in the PBP1A gene are the predominant cause of amoxicillin resistance in H. pylori. The findings of this study currently preclude the rapid detection of amoxicillin resistance in H. pylori by molecular tests.

Amoxicillin↗
PubMed1989

[Controlled multicentric study comparing cefixime and amoxicillin in the treatment of lower respiratory tract infections in adults].

This multicentre, randomized, double-blind study evaluated the effectiveness and safety of cefixime versus amoxicillin. Patients were admitted if they had lower respiratory tract infection with a bacterial pathogen susceptible to both study drugs. Diagnoses included acute respiratory tract infections with no underlying pulmonary pathology (cefixime 21, amoxicillin 27), acute exacerbation of chronic obstructive lung disease (cefixime 32, amoxicillin 42), superinfection of viral bronchitis or lung cancer, and pleuritis (cefixime 10, amoxicillin 6). Patients were treated for at least 10 days with either cefixime 200 mg b.d. or amoxicillin 1 g b.d. A clinical success rate of 80.7 per cent (50/62) in the cefixime group and 82.2 per cent (60/73) in the amoxicillin group was achieved in infections due to susceptible organisms. In acute infections with no underlying pathology, the clinical success rate was 90.5 per cent with cefixime and 81.5 per cent with amoxicillin. Twenty-three cefixime patients and 20 amoxicillin patients were seen 2 to 6 weeks after treatment: there were 2 and 1 clinical recurrences, respectively. All 3 patients were suffering from chronic obstructive lung disease. The bacteriological eradication rate at the end of treatment in assessable patients was 94.7 per cent (17/18) with cefixime and 80 per cent (16/20) with amoxicillin. Six and 11 new organisms appeared, responsible for 2 superinfections under cefixime and 7 under amoxicillin. Treatment was well tolerated by 96.4 per cent of cefixime patients and 90 per cent of amoxicillin patients. This study confirms the value of cefixime as a new oral antibiotic in the treatment of lower respiratory tract infections in adults.

Adolescent↗
PubMed2004

Assay of amoxicillin sustained release from matrix tablets containing different proportions of Carbopol 971P NF.

The sustained release of amoxicillin is desired because of its short biological half-life. Particularly to treat Helicobacter pylori infections, the sustained release is desired to be confined to the upper gastrointestinal tract. In vitro dissolution of amoxicillin has been evaluated utilizing a direct UV-absorption method. However, UV-absorption has been reported as not useful to determine amoxicillin in acidic dissolution test medium. To clarify the suitability of the assay method, the stability and dissolution behavior of amoxicillin sustained release tablets was determined by HPLC, iodometric titration and UV-absorption. Stability of amoxicillin studied under dissolution test conditions of pH 1.2, 37 degrees C and 50 rpm and determined by HPLC and titration showed considerable degradation of amoxicillin. On the other hand, the UV-absorption increased progressively as amoxicillin degradation proceeded. Amoxicillin release curves determined by different analytical methods show different release profiles, which can be corrected for amoxicillin degradation and change in the UV-absorption to produce similar dissolution results. Release curves determined by UV-absorption and obtained from tablets containing 1017 mg amoxicillin trihydrate and Carbopol 971P NF in a range from 180 to 680 mg showed increasing values of the exponent indicative of the release mechanism (n) and decreasing release constant values (k) as the matrix polymer content increased. The release constant (k) and the exponent (n) were found to be logarithmically related.

Acrylates↗
PubMed1998

Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media.

BACKGROUND: Acute otitis media (AOM) is a common childhood infectious disease. The efficacy of antibiotic dosing regimens is usually assessed by antibiotic plasma pharmacokinetics or middle ear fluid (MEF) concentration at one or two time points. Viral coinfection in AOM reduced antibacterial efficacy of antibiotics. OBJECTIVE: To determine amoxicillin MEF penetration and pharmacokinetics in bacterial and combined bacterial and viral AOM. METHODS: Thirty-four children with AOM were enrolled, and MEF was collected by tympanocentesis for bacterial culture and viral studies. Nasal wash and venous blood were also obtained for viral culture and serologic studies, respectively. Subjects were treated with amoxicillin 40 mg/kg/day orally, divided in equal doses every 8 h. During the second visit (48 to 72 h later) the subjects, with the regular morning amoxicillin dose withheld, were given an oral amoxicillin dose of 25 mg/kg. Thereafter two blood samples and one MEF sample by tympanocentesis were collected from each child at selected times between 0.5 and 4.0 h after dosing for bacterial and viral studies and amoxicillin concentration determination by high performance liquid chromatography. RESULTS: Eleven (37%) children had only bacterial infection, 6 (20%) had viral infection only, 6 (20%) had both bacterial and viral infections and in 7 (23%) neither bacterial nor viral pathogens were recovered. MEF bacterial culture was positive in 23 of 40 ears (57.5%) before treatment with amoxicillin (40 mg/kg/day) and was still positive in 4 of 38 ears (10.5%) after 2 to 3 days of treatment. Amoxicillin plasma concentration reached its peak at 1.0 to 1.5 h after a 25-mg/kg oral dose. The estimated MEF concentration peak occurred 3.0 h after the dose with MEF concentrations ranging from undetectable to 20.6 microg/ml and a mean of approximately 9.5 microg/ml. Geometric mean amoxicillin concentrations were lowest in virus-infected children (2.7 microg/ml), nearly the same in culture-negative samples from children without viral infection (2.9 microg/ml), higher in children with combined bacterial and viral infection (4.1 microg/ml) and highest in children with bacterial-only infection (5.7 microg/ml). CONCLUSIONS: MEF amoxicillin penetration tended to be lower in children with viral infection. The current amoxicillin dosing recommendation of 40 mg/kg/day in three divided dose is inadequate to effectively eradicate resistant Streptococcus pneumoniae, particularly during viral coinfection. A dosing regimen of 75 to 90 mg/kg/day is recommended for AOM.

Acute Disease↗
PubMed2005

A randomized, multicenter, double blind, double dummy trial of single dose azithromycin versus high dose amoxicillin for treatment of uncomplicated acute otitis media.

BACKGROUND: High dose amoxicillin is recommended for the initial treatment of children with acute otitis media (AOM), particularly patients at risk for having drug-resistant Streptococcus pneumoniae. Single dose azithromycin (30 mg/kg) is considered an alternative agent for the treatment of AOM. OBJECTIVE: To compare the clinical efficacy and safety of single dose azithromycin with that of high dose amoxicillin among children with uncomplicated AOM. METHODS: This was a double blind, double dummy, multinational, clinical trial in which children (6-30 months of age) with AOM were randomized to treatment with single dose azithromycin (30 mg/kg) or high dose amoxicillin (90 mg/kg/d, in 2 divided doses) for 10 days. Tympanocentesis was performed at baseline and clinical responses were assessed at days 12-14 (end of therapy) and at days 25-28 (end of study). RESULTS: The study enrolled 313 patients, and 83% of the patients were < or =2 years of age. A total of 158 patients in the azithromycin group and 154 in the amoxicillin group were considered clinical modified intent-to-treat patients. A middle ear pathogen was detected for 212 patients (68%). Haemophilus influenzae was the most common pathogen (isolated for 96 patients), followed by S. pneumoniae (92 patients), Moraxella catarrhalis (23 patients) and Streptococcus pyogenes (23 patients). beta-Lactamase production was observed for 17% of H. influenzae isolates and 100% of M. catarrhalis isolates. Thirty-five (38%) S. pneumoniae isolates were penicillin-nonsusceptible and 24 (26%) isolates were macrolide-resistant. At the end of therapy, clinical success rates for azithromycin and amoxicillin were comparable for all patients (84 and 84%, respectively) and for children < or =2 years of age (82 and 82%, respectively). At the end of therapy and end of study, clinical efficacies among all microbiologic modified intent-to-treat evaluable subjects were comparable for patients treated with azithromycin (80%) and patients treated with amoxicillin (83%). The rates of treatment-related adverse events for azithromycin and amoxicillin were 20% and 29%, respectively (P = 0.064). Diarrhea was more common in the amoxicillin group than in the azithromycin group (17.5 and 8.2%, respectively) (P = 0.017). Compliance, defined as completion of > or =80% of the study medication, was higher in the azithromycin group (100%) than in the amoxicillin group (90%) (P = 0.001). CONCLUSIONS: In this study, single dose azithromycin was as effective as high dose amoxicillin for the treatment of children with AOM, whereas rates of adverse events were lower and compliance improved with the simplified single dose regimen.

Amoxicillin↗
PubMed2006

Amoxicillin is effective against penicillin-resistant Streptococcus pneumoniae strains in a mouse pneumonia model simulating human pharmacokinetics.

High-dose oral amoxicillin (3 g/day) is the recommended empirical outpatient treatment of community-acquired pneumonia (CAP) in many European guidelines. To investigate the clinical efficacy of this treatment in CAP caused by Streptococcus pneumoniae strains with MICs of amoxicillin > or =2 microg/ml, we used a lethal bacteremic pneumonia model in leukopenic female Swiss mice with induced renal failure to replicate amoxicillin kinetics in humans given 1 g/8 h orally. Amoxicillin (15 mg/kg of body weight/8 h subcutaneously) was given for 3 days. We used four S. pneumoniae strains with differing amoxicillin susceptibility and tolerance profiles. Rapid bacterial killing occurred with an amoxicillin-susceptible nontolerant strain: after 4 h, blood cultures were negative and lung homogenate counts under the 2 log(10) CFU/ml detection threshold (6.5 log(10) CFU/ml in controls, P < 0.01). With an amoxicillin-intermediate nontolerant strain, significant pulmonary bacterial clearance was observed after 24 h (4.3 versus 7.9 log(10) CFU/ml, P < 0.01), and counts were undetectable 12 h after treatment completion. With an amoxicillin-intermediate tolerant strain, 24-h bacterial clearance was similar (5.4 versus 8.3 log(10) CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log(10) CFU/ml. Similar results were obtained with an amoxicillin-resistant and -tolerant strain. Day 10 survival rates were usually similar across strains. Amoxicillin with pharmacokinetics simulating 1 g/8 h orally in humans is bactericidal in mice with pneumonia due to S. pneumoniae for which MICs were 2 to 4 microg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.

Amoxicillin↗
PubMed1999

Efficacy of high-dose amoxicillin-clavulanate against experimental respiratory tract infections caused by strains of Streptococcus pneumoniae.

The purpose of the present investigation was to determine if the efficacy of amoxicillin-clavulanate against penicillin-resistant Streptococcus pneumoniae could be improved by increasing the pediatric amoxicillin unit dose (90 versus 45 mg/kg of body weight/day) while maintaining the clavulanate unit dose at 6.4 mg/kg/day. A rat pneumonia model was used. In that model approximately 6 log10 CFU of one of four strains of S. pneumoniae (amoxicillin MICs, 2 microg/ml [one strain], 4 microg/ml [two strains], and 8 microg/ml [one strain]) were instilled into the bronchi of rats. Amoxicillin-clavulanate was given by computer-controlled intravenous infusion to approximate the concentrations achieved in the plasma of children following the administration of oral doses of 45/6.4 mg/kg/day or 90/6.4 mg/kg/g/day divided every 12 h or saline as a control for a total of 3 days. Infusions continued for 3 days, and 2 h after the cessation of infusion, bacterial numbers in the lungs were significantly reduced by the 90/6.4-mg/kg/day equivalent dosage for strains for which amoxicillin MICs were 2 or 4 microg/ml. The 45/6.4-mg/kg/day equivalent dosage was fully effective only against the strain for which the amoxicillin MIC was 2 microg/ml and had marginal efficacy against one of the two strains for which amoxicillin MICs were 4 microg/ml. The bacterial load for the strain for which the amoxicillin MIC was 8 microg/ml was not reduced with either dosage. These data demonstrate that regimens which achieved concentrations in plasma above the MIC for at least 34% of a 24-h dosing period resulted in significant reductions in the number of viable bacteria, indicating that the efficacy of amoxicillin-clavulanate can be extended to include efficacy against less susceptible strains of S. pneumoniae by increasing the amoxicillin dose.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed2001

[Escherichia coli eradication from the blader urine by amoxicillin-sulbactam. Intrinsic activity of the inhibitor].

RATIONALE: At urine concentrations obtained after the oral administration of amoxicillin-sulbactam (500/500 mg) this combination inhibits roughly 90% of Escherichia coli and Proteus mirabilis strains. AIMS: To administer amoxicilin-sulbactam 875/125 mg and to determine: a) minimum inhibitory concentration (MIC) of sulbactam for E. coli and P. mirabilis; b) urine inhibitory titres power (UIT) against amoxicillin-resistant E. coli or P. mirabilis; c) urine concentrations of sulbactam; and to verify whether sulbactam 125 mg as single drug, attains a high enough UIT to support the intrinsic action of the inhibitor; and to compare the activity of amoxicillin-sulbactam and amoxicillin-clavulanate and that of sulbactam and clavulanate. METHODS: Twelve healthy volunteers received a single oral dose of amoxicillin-sulbactam 875/125 mg or amoxicillin-clavulanate 875/125 mg, according to a randomized cross-over design. Urine samples were drawn at: 0 (basal), 2, 4, and 6 hours after dosing. Urine pH, specific gravidity and UIP were assessed. Thirty nine strains isolated from urine samples were used: 30 TEM-1 producing E. coli strains and 3 extended spectrum CTX-M-2 betalactamase-producing E. coli; and 6 P. mirabilis resistant to both combinations. In 6 healthy volunteers, sulbactam 125 mg was administered orally and UIT against E. coli (MIC amoxicillin > 2048 mg/l) was assessed. RESULTS AND DISCUSSION: MIC-90 for amoxicillin plus sulbactam or clavulanate were similar to those for sulbactam or clavulanate alone, without any difference attributable to the chemical composition of the urine. The activity of amoxicillin plus the inhibitors could be due, not only to the inhibition of betalactamase but also to the intrinsic effect of the inhibitor. Both combinations showed an equivalent inhibitory activity. Two-hour UIT remained high for the entire 6-h evaluation period. Sulbactam concentration far exceed sulbactam MIC for the 6h-period, inhibiting urine E. coli. We disagree with the cut-off limit proposed for intermediate values of NCCLS, which, for these antimicrobial are 16/8, a value lower than those obtained in urine samples after the administration of betalactamase inhibitors. This may be an explanation for the beneficial effect of amoxicillin-sulbactam in the recovery of uncomplicated lower urinary tract infections in women when the involved strains were considered resistant by diffusional methods.

Adult↗