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

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

Relation of Streptococcus Pyogenes tonsillitis isolate to antimicrobial agents and its infection treatment.

We reported the case of tonsillitis treatment in a 17-years-old boy with use of chemical non-antibiotic preparations, plant derived products and antibiotic benzathine phenoxymethylpenicillin. The antimicrobial agents for treatment were selected on the basis of their activity against a disease agent, the group A ß-hemolytic strain Streptococcus pyogenes BS1 isolated from a patient. The bacterium was susceptible in vitro to ß-lactams, with largest zones conditioned by penicillin G and benzathine phenoxymethylpenicillin discs, to fluoroquinolones and to cephems, with exception of cefazolin. Lincosamide clindamycin, macrolide spiramycin, aminoglycoside gentamicin, erythromycin, tetracycline and combination of sulfamethoxazole and trimethoprim were inactive against this bacterium. The Streptococcus pyogenes BS1 demonstrated intermediate susceptibility to the cephalosporin cephalexin, fluoroquinolone lomefloxacin and glycopeptide vancomycin. Non-antibiotic preparations were evaluated against Streptococcus pyogenes BS1 also. Among them "Stomatidin", "Chlorophyllipt", and phages of "Pyofag" were more effective than "Decatylen", "Decasan" and "Furadonin" in vitro. The antimicrobial applications of "Stomatidin", "Chlorophyllipt" and phages of "Pyofag" in the patient were less effective compared to the result of antibiotic benzathine phenoxymethylpenicillin treatment. Complete recovery of the patient was achieved with use of this antibiotic and Calendula flower extract as an local anti-inflammatory agent.

Clarithromycin, trimethoprim, and penicillin and oxidative nucleic acid modifications in humans: randomised, controlled trials.

AIMS: In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs. METHODS: This study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively. RESULTS: Clarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6-40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7-26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8-37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde. CONCLUSION: Clarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.

Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells.

Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides - which are the most frequent cause of adverse drug reactions - were co-incubated with THP-1, MUTZ-LC, or primary monocyte-derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1ß, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines.

Molecular drug-organiser: synthesis, characterization and biological evaluation of penicillin V and/or nalidixic acid calixarene-based podands.

Two well-known antibiotic heterocycles, the 'quinolone' nalidixic acid and the ß-lactam penicillin V, active at different levels of the bacterial growth process, have been attached via an ether-ester junction to the p-tert-butylcalix[4]arene lower rim, in alternate position. The resulting hydrophobic molecular drug-organisers were fully characterized, and evaluated over two Gram negative and three Gram positive reference strains, using disk diffusion assays with disks impregnated with solution of title compound in pure DMSO. An interesting activity was observed over Staphylococcus aureus ATCC 25923 with the dis-symmetrical podand incorporating one penicillin and one nalidixic ester moieties.

Recognition and binding of FEZ-1 from Legionella with penicillin V and cefoxitin by fluorescence spectra in combination with molecular dynamics simulation.

The recognition and interaction of FEZ-1 from Legionella (FEZ-1) with penicillin V(PV) and cefoxitin(CFX) were investigated using fluorescence spectra in combination with molecular dynamics simulation (MD). The results revealed that the CFX bind with FEZ-1 in stronger interaction and induced larger conformational change than PV, despite all being forced by the electrostatic interaction and along with the changing in an environment of amino acid residues as well as the polypeptide skeleton inside the FEZ-1. Moreover, only the loop1, loop2, and N-terminal were observed locating near the binding pocket of FEZ-1, consisting of a flexible "gate-like" zone with better adaptability that controlled the entrance of antibiotic into the pocket by allowing the newly introduced antibiotic to match the pocket better through the conformational changes of these three substructures in the binding procedure. The current study may provide some valuable information on the antibiotic hydrolytic process by metallo-beta-lactamase and thus the references for the development of new antibiotics for super bacteria.

Impact of narrow-spectrum penicillin V on the oral and faecal resistome in a young child treated for otitis media.

OBJECTIVES: Antibiotic overuse has led to the global emergence of antimicrobial-resistant bacteria, and children are among the most frequent users of antibiotics. Most studies with broad-spectrum antibiotics show a severe impact on resistome development in patients. Although narrow-spectrum antibiotics are believed to have fewer side effects, their impact on the microbiome and resistome is mostly unknown. The aim of this study was to investigate the impact of the narrow-spectrum antibiotic phenoxymethylpenicillin (penicillin V) on the microbiome and resistome of a child treated for acute otitis media. METHODS: Oral and faecal samples were collected from a 1-year-old child before (Day 0) and after (Days 5 and 30) receiving penicillin V for otitis media. Metagenomic sequencing data were analysed to determine taxonomic profiling using Kraken and Bracken software, and resistance profiling using KMA in combination with the ResFinder database. RESULTS: In the oral samples, antimicrobial resistance genes (ARGs) belonging to four classes were identified at baseline. At Day 5, the abundance of some ARGs was increased, whereas some remained unchanged and others could no longer be detected. At Day 30, most ARGs had returned to baseline levels or lower. In the faecal samples, seven ARGs were observed at baseline and five at Day 5. At Day 30, the number of ARGs had increased to 21. CONCLUSIONS: Following penicillin V, we observed a remarkable enrichment of the aecal resistome, indicating that even narrow-spectrum antibiotics may have important consequences in selecting for a more resistant microbiome.

Ischemic Stroke and Systemic Embolism in Warfarin Users With Atrial Fibrillation or Heart Valve Replacement Exposed to Dicloxacillin or Flucloxacillin.

The antibiotics dicloxacillin and flucloxacillin induce cytochrome P450-dependent metabolism of warfarin. We explored the influence of these drug-drug interactions on the clinical effectiveness of warfarin therapy due to atrial fibrillation or heart valve replacement. Using the population-based Danish registers, we performed a propensity-score matched cohort study including around 50,000 episodes of dicloxacillin/flucloxacillin matched to phenoxymethylpenicillin and to no antibiotic, respectively. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) by comparing 21-day (days 7-28) risks of ischemic stroke/systemic embolism (SE) following initiation of each exposure. When compared with phenoxymethylpenicillin, dicloxacillin/flucloxacillin was associated with an HR of ischemic stroke/SE of 2.09 (95% CI 1.51-2.90; strongest for dicloxacillin (HR 2.17; 95% CI 1.56-3.02)). Use of an untreated comparator strengthened the association (HR 2.84; 95% CI 1.97-4.09). Dicloxacillin should be used with caution in patients receiving warfarin. This may also apply to flucloxacillin; however, more data on the risks associated with flucloxacillin exposure during warfarin therapy are needed.

Tunable antimicrobial polypropylene surfaces: simultaneous attachment of penicillin (Gram +) and gentamicin (Gram -).

Surface reactions were performed on polypropylene (PP) surfaces to retard the simultaneous growth of Staphylococcus aureus (S. aureus) and Pseudomonas putida (P. putida) bacteria. Microwave plasma reactions in the presence of maleic anhydride (MA) resulted in the formation of acid groups on the surface of PP. Such surfaces were further modified by conducting two parallel reactions: (1) poly(ethylene glycol) (PEG) was attached to COOH groups of the PP surface, followed by penicillin V (PEN) reactions to target S. aureus destruction and (2) diglycidyl PEG was attached, followed by gentamicin (GEN) reactions, to create antimicrobial surfaces targeted at P. putida . Simultaneous gram "+" and gram "-" resistance was obtained by varying the PEN/GEN ratios on such modified PP surfaces, thus providing the controllable degree of gram "+" and gram "-" antimicrobial strength. While spectroscopic analyses revealed chemical attachments of PEN and GEN, the effectiveness against proliferation of S. aureus (Gram +) and P. putida (Gram -) bacteria was determined using liquid culture tests. These studies show for the first time the formation of tunable antimicrobial polypropylene surfaces with controllable strength.

Photolysis of four ß­lactam antibiotics under simulated environmental conditions: Degradation, transformation products and antibacterial activity.

߭Lactam antibiotics are among the most widely used antibiotics in human medicine and their effects on the aquatic environment - concerning bacterial resistance - are controversially discussed. This study focused on the photolysis of the four ߭lactam antibiotics - amoxicillin, ampicillin, penicillin V and piperacillin - under simulated environmental conditions. It was observed that all investigated ߭lactam antibiotics are photolytically degradable by simulated sunlight (1 kW/m2) with half-lives between 3.2 and 7.0 h. Structure elucidation of transformation products performed with liquid chromatography coupled to high resolution mass spectrometry showed that the hydrolysis of the ߭lactam ring is the primary transformation reaction, followed by the elimination of carboxylic and dimethyl thiazolidine carboxylic acid. Growth inhibition tests on Bacillus subtilis showed the loss of bactericide activity of irradiated solutions of amoxicillin, ampicillin and piperacillin, suggesting the transformation of the ߭lactam ring is responsible for the antibiotic effect. In contrast, the solutions of penicillin V did not show any decline of the antibacterial activity after photolytic degradation, probably due to the formation of still active epimers.

2-aminoimidazoles potentiate ß-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing ß-lactamase secretion and increasing cell envelope permeability.

There is an urgent need to develop new drug treatment strategies to control the global spread of drug-sensitive and multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). The ß-lactam class of antibiotics is among the safest and most widely prescribed antibiotics, but they are not effective against M. tuberculosis due to intrinsic resistance. This study shows that 2-aminoimidazole (2-AI)-based small molecules potentiate ß-lactam antibiotics against M. tuberculosis. Active 2-AI compounds significantly reduced the minimal inhibitory and bactericidal concentrations of ß-lactams by increasing M. tuberculosis cell envelope permeability and decreasing protein secretion including ß-lactamase. Metabolic labeling and transcriptional profiling experiments revealed that 2-AI compounds impair mycolic acid biosynthesis, export and linkage to the mycobacterial envelope, counteracting an important defense mechanism reducing permeability to external agents. Additionally, other important constituents of the M. tuberculosis outer membrane including sulfolipid-1 and polyacyltrehalose were also less abundant in 2-AI treated bacilli. As a consequence of 2-AI treatment, M. tuberculosis displayed increased sensitivity to SDS, increased permeability to nucleic acid staining dyes, and rapid binding of cell wall targeting antibiotics. Transcriptional profiling analysis further confirmed that 2-AI induces transcriptional regulators associated with cell envelope stress. 2-AI based small molecules potentiate the antimicrobial activity of ß-lactams by a mechanism that is distinct from specific inhibitors of ß-lactamase activity and therefore may have value as an adjunctive anti-TB treatment.

Reduced ability of penicillin to eradicate ingested group A streptococci from epithelial cells: clinical and pathogenetic implications.

BACKGROUND: Group A streptococci (Streptococcus pyogenes; GAS) invades human epithelial cell lines. Failure of penicillin to eradicate GAS from the throats of patients, especially those who are GAS "carriers," has been increasingly reported. However, there has been no comprehensive evaluation of how effectively antibiotics that are used to treat GAS enter upper respiratory tract epithelial cells and kill internalized GAS. We examined the viability of ingested, intracellular GAS after epithelial cell exposure to antibiotics commonly recommended for therapy of GAS infections. METHODS: A human laryngeal epithelial cell line (HEp-2) was used. Three techniques were used to study antibiotic (penicillin V, erythromycin, azithromycin, cephalothin, and clindamycin) killing of ingested GAS: examination by electron microscopy of ultrathin sections of ingested GAS, qualitative determination of intra-epithelial cell antibiotic, and special stain evaluation of intracellular GAS viability after epithelial cell exposure to antibiotics. RESULTS: GAS survived intracellularly despite exposure of the GAS-containing epithelial cells to penicillin. In contrast, there was killing of ingested GAS after exposure of epithelial cells to either erythromycin or azithromycin. Electron microscopy confirmed a lack of intracellular GAS fragmentation (cell death) after exposure of epithelial cells to penicillin in contrast to obvious GAS fragmentation after epithelial cell exposure to erythromycin or azithromycin. Cephalothin, a cephalosporin, and clindamycin were more effective in killing ingested GAS than was penicillin, but they were less effective than erythromycin or azithromycin. CONCLUSIONS: These observations strongly suggest that if the GAS upper respiratory tract carrier state results from intra-epithelial cell GAS survival, the failure of penicillin to kill ingested GAS may be related to a lack of effective penicillin entry into epithelial cells. These unique observations may have clinical implications for understanding GAS respiratory tract carriers and managing GAS infections.

Epidemiological factors associated with ESBL- and non ESBL-producing E. coli causing urinary tract infection in general practice.

The purpose of the study was to evaluate how use of antibiotics precedes the presence of ESBL-producing E.coli in general practice. The authors performed a triple-case-control study where three case groups were individually compared to a single control group of uninfected individuals. Urine samples were prospectively collected and retrospective statistical analyses were done. This study included 98 cases with urinary tract infection (UTI) caused by ESBL-producing E. coli, 174 with antibiotic-resistant (non-ESBL) E. coli, 177 with susceptible E. coli and 200 with culture negative urine samples. Case groups had significantly higher use of antibiotics than the control group within 30 days before infection (p < 0.0001). The ESBL group had significantly more hospital admissions than the other case groups (p < 0.05). Hospital admission was an independent risk factor for community onset UTI by ESBL-producing E. coli. Exposure to antibiotics was a risk factor for UTI with E. coli, while prior antibiotic usage was not an indisputable predictor for infection with ESBL-producing E.coli in general practice.

Phenoxymethylpenicillin amidohydrolases from Penicillium chrysogenum.

A phenoxymethylpenicillin amidohydrolase which hydrolyses phenoxymethylpenicillin to 6-aminopenicillanic acid (6-APA) has been isolated from two species of Penicillium chrysogenum. The amidohydrolase had a molecular mass of approx. 42 kDa. Its activity with benzylpenicillin as substrate was only 1.5% of that with phenoxymethylpenicillin and it was inhibited by its products. No penicillin formation from 6-APA and phenoxyacetyl or phenylacetyl coenzyme A was observed. The enzyme is thus distinct from the phenylacetyl coenzyme A:6-APA acyltransferase, which also has amidohydrolase activity and is involved in the final stages of the biosynthesis of penicillins.

Preparation and properties of 5-phenylphenoxymethylpenicillin.

Cycloaddition of azidoacetyl chloride to benzyl D-5,5-dimethyl-5-phenyl-2-thiazoline-4-carboxylate (1a) gave 5-phenyl-6alpha-azidopenicillanate (2a). By catalytic reduction of 2a and reaction with phenoxyacetyl chloride, 5-phenyl-6-epiphenoxymethylpenicillin benzyl ester (4a) was obtained. Oxidation of 4a gave the sulfoxide 6, which was isomerized in the presence of DBN. The sulfoxide 7 with the normal configuration could be isolated but deoxygenation of the sulfoxide was not successful. Isomerization of 4a with DBN, either with or without silylation of the side chain, gave a mixture from which 5-phenylphenoxymethylpenicillin benzyl ester (5) was isolated. Compound 5 was debenzylated to 5-phenylphenoxymethylpenicillin potassium salt (8). The antibacterial activity of 8 was low, whereas the 6-epimer 9 was inactive. Contary to published information, the 5-phenylpenam derivative 4c could be prepared by the same method.

Coupling products of amino acids to penicillin V and cephalothin: synthesis and susceptibility to carboxypeptidases and lysosomal enzymes.

Amino acids have been coupled to the carboxyl group of penicillin V and cephalothin by methods that keep the beta-lactam ring intact. Derivatives were successfully obtained with both neutral (Leu, Val, Ala, Ile, Trp, Tyr, Gly) and one acidic (Glu) amino acids. The new compounds were inactive in vitro against Staphylococcus aureus or Micrococcus luteus. Incubation in the presence of purified carboxypeptidases (A, B), soluble lysosomal fractions from liver, or cellular homogenates from liver, kidney, fibroblasts, and macrophages did not allow recovery of the antibacterial activity. Injection in mice also failed to cause liberation of microbiologically active compounds. HPLC studies confirmed that the amide linkage between the antibiotic and the amino acid was not hydrolyzed in the presence of soluble lysosomal fractions from liver. However, conversion of cephalothin and cephalothin-leucine to desacetyl derivatives was observed in the presence of soluble lysosomal fractions and extracts from liver and semipurified orange peel acetylesterase(s). It is concluded that amino acid derivatives of beta-lactam antibiotics do not offer potential chemotherapeutic use as prodrugs.

Effect of tetracyclines and 4-epiderivatives on the ureter.

1. The effect of tetracyclines on the isolated dog ureter is dependent on: (a) the tetracyclines used-mepicycline and doxycycline antagonizing, and tetracycline and rolitetracycline increasing the contractor action of barium chloride; (b) the percentage of 4-epiderivatives in the tetracyclines used-the higher the epiderivative concentration, the smaller the effect of mepicycline or doxycycline, and the greater the action of tetracycline or rolitetracycline.2. In vivo the addition of the antibiotics into the renal pelvis shows no significant differences between the various tetracyclines or different 4-epiderivative concentrations on the intra-ureteral flow of the dog or guinea-pig.3. Intravenous injection of mepicycline or doxycycline does not induce a significant change in the intra-ureteral flow, while intravenous administration of tetracycline or rolitetracycline produces a triphasic response: (a) a marked decrease of the intra-ureteral flow for a few minutes; (b) a return to the control condition for 30-60 min; and (c) a lesser but persistent decrease in flow for 60-120 minutes. In the first phase the ureteral smooth muscle is directly affected by the antibiotics circulating in the blood, while in the third phase the tetracyclines act via the intra-ureteral mucosa.4. Neurogenic effects on the ureter-bladder junction in vivo are not affected by the tetracyclines tested.

Azithromycin versus penicillin V for treatment of acute group A streptococcal pharyngitis.

OBJECTIVE: To compare a 3-day azithromycin vs. a 10-day penicillin V regimen for treatment of acute group A streptococcal (GAS) pharyngitis in children and to determine whether viral infection and/or pharyngeal GAS carriage in patients and adult contacts affect clinical and bacteriologic efficacy. METHODS: This multicenter, randomized, comparative, open label study compared 3-day, once daily 10 mg/kg azithromycin oral suspension with a 10-day regimen of 100,000 IU/kg/day penicillin V oral suspension in three divided doses in children with acute GAS pharyngitis. Clinical and bacteriologic efficacy and tolerability of the antibiotics were evaluated. Recurrence of symptoms and infection was monitored for 6 months. RESULTS: In total, 292 children (age range, 2 to 12 years) received at least one dose of study medication. Clinical success (cure/improvement) with either antibiotic was similar at the end of therapy (Day 14; azithromycin, 95%; penicillin V, 97%) and at Day 28 (azithromycin, 94%; penicillin V, 95%). Bacteriologic eradication was significantly less with azithromycin than with penicillin V at Day 14 (azithromycin, 38%; penicillin V, 81%; P < 0.001) and at Day 28 (azithromycin, 31%; penicillin V, 68%; P < 0.001). There was no associated increase in GAS-related sequelae. The lower incidence of bacteriologic eradication with azithromycin was not the result of possible concomitant viral infections in the patients, GAS carriage in one parent/guardian or any reduced susceptibility in pretreatment GAS isolates. Both antibiotics were equally well-tolerated. CONCLUSIONS: Treatment with 3-day, once daily 10 mg/kg azithromycin for GAS pharyngitis is associated with similar high levels of clinical efficacy, but lower levels of bacteriologic eradication, than with 10-day 100,000 IU/kg/day penicillin V.

Comparison of two dosages of azithromycin for three days versus penicillin V for ten days in acute group A streptococcal tonsillopharyngitis.

BACKGROUND: Three-day, 10 mg/kg/day azithromycin (AZM) studies in pediatric acute group A streptococcal tonsillopharyngitis have shown contradictory bacteriologic results. This study investigates the efficacy and tolerability of two dosages of 3-day azithromycin (20 mg/kg/day and 10 mg/kg/day) compared with 10-day penicillin V. METHODS: This was a prospective, comparative, randomized, multicenter trial. Children were scheduled to return for visits at 14 days (main end point) and 1 month after the onset of treatment for clinical and bacteriologic assessment. Molecular tools were used to compare pre- and posttreatment group A beta-hemolytic Streptococcus (GABHS) isolates. RESULTS: Between November, 1997, and July, 1998, 501 patients (169 AZM 10 mg, 165 AZM 20 mg, 167 penicillin V) between 2 and 12 years old were enrolled; 500 were assessable for safety, 469 for intent to treat analysis and 420 for efficacy in the per protocol analysis. Before treatment 25 (7.9%) of 315 GABHS stains isolated from patients receiving AZM were resistant to this compound. On Day 14 pretreatment GABHS were eradicated from 78 (57.8%) of the 135 children receiving the AZM 10 mg regimen, 131 (94.2%) of the 139 receiving AZM 20 mg and 123 (84.2%) of the 146 taking penicillin. One month after the outset of treatment, bacteriologic relapses were observed in 40.5% (n = 30) of the children receiving AZM 10 mg, 14.8% (n = 18) of children taking AZM 20 mg and 13.2% (n = 15) of those treated with penicillin V. AZM 20 mg/kg/day was statistically superior to AZM 10 mg/kg/day microbiologically on Day 14 (P = 0.0001) and Day 30 (P = 0.0001) and clinically on Day 14 (P = 0.0035). AZM 20 mg/kg/day was statistically equivalent both microbiologically and clinically to standard therapy with penicillin V at all endpoints. The incidence of treatment-related adverse events was similar in the two azithromycin groups [AZM 10 mg, 31 of 169 (18.3%); AZM 20 mg, 37 of 164 (23%)] but significantly higher than those observed in the penicillin V group [5 of 166 (3%); P < 0.0001]. Most treatment-related adverse events were gastrointestinal and of mild-to-moderate severity. Fourteen patients withdrew from the trial because of adverse events (1 in the penicillin V group, 7 in the AZM 10 mg group and 6 in the AZM 20 mg group). CONCLUSION: This is the first study to demonstrate a daily dose-dependent difference in microbiologic efficacy of a regimen; 3-day AZM 20 mg/kg/day is a more effective regimen than 3-day AZM 10 mg/kg/day for pediatric GABHS tonsillopharyngitis.

Candida in the faeces of children receiving oral tetracycline and phenoxymethyl penicillin.

The faeces from 100 children under 14 years receiving no antibiotic or steroid therapy were examined for Candida spp. The proportion (8%) of positive isolates is compared with the number of Candida spp. isolated from the faces of 50 children receiving oral tetracycline (14%) and 59 children on phenoxymethyl penicillin (10%) for complaints other than gastrointestinal infections. The use of selective media is described and the significance of the greatly increased numbers of Candida spp. found by these methods is discussed. In this series no clinical manifestations of candidiasis were observed, although slightly more Candida spp. were recovered from the two groups of children on oral antibiotics than from those not on such therapy. It is suggested that, in children at least, there is a need to re-assess the significance of the presence of Candida in the bowel during the administration of oral antibiotics. The almost complete absence of active tetracycline from the faeces and the small proportion of tetracycline-sensitive bowl organisms, coupled with the low incidence of change in bowel flora in these patients, suggest that this is not the reason for proliferation of Candida in the cases that do occasionally occur.