Class of 2015 Abstract / Objectives: The goals of this study were to determine how frequently azithromycin and moxifloxacin were used in combination with other drugs that cause QTc prolongation, describe the effects these combinations have on QTc interval length, determine the incidence of QTc prolongation in patients on these medication combinations, and identify risk factors associated with QTc interval prolongations in patients on these medication combinations. Methods: A retrospective chart review was performed on patients who received at least two doses of azithromycin or moxifloxacin. It was noted whether these patients received other medications that prolonged the QTc interval. ECG information was grouped into daily phases depending on whether the patient was at baseline, receiving antibiotic therapy, QTc prolonging medication therapy, or concomitant therapy. These data were compared using a repeated measures ANOVA. Results: Patients received concomitant antibiotic-QTc prolong medication therapy in 70% of cases analyzed. In all patients on concomitant therapy there was no significant difference in any measured ECG data (all p-values > 0.26). In those who were on azithromycin and experienced QTc prolongation there was a significant difference in RR interval length (p=0.034). In those that experienced QTc prolongation on moxifloxacin there was a significant difference in QT (p=0.0033) and QTcF (p=0.0089) length. Conclusions: These medication combinations are used frequently in the hospital. These medications may not increase the QTc interval length in the general population but more research is warranted in this area to confirm this finding.

Azithromycin, an azalide and member of the macrolide group, is a broad spectrum antimicrobial, representing one of the bestselling antimicrobials worldwide. It is derived from erythromycin and exhibits improved acidic stability as a result of its structural modifications. The stable solid form of azithromycin is its dihydrate, although it also naturally occurs in its metastable forms, i.e. the monohydrate and anhydrate. Because azithromycin is poorly soluble in water, its absorption from the gastro-intestinal tract is negatively influenced, which ultimately affects its bioavailability following oral administration (37 %). Polymorphic (monohydrates and dihydrates) and anhydrous forms of azithromycin were screened and investigated. One anhydrous form also proved to be amorphous, which shifted the focus of this study from polymorphism to amorphism. An amorphous glassy azithromycin was subsequently prepared and fully characterised to present its solid state profile. The stability of this amorphous glassy form was established at a high temperature and relative humidity over a period of four weeks. Exposure to increased relative humidity (up to 95 %) and increased water content (up to 50 %) also served as stability indicating tests. Its solubility in various aqueous media was determined. A solid dosage form (tablet), containing the azithromycin glass, was prepared, whereafter these tablets were subjected to dissolution studies in different aqueous media. The stability of azithromycin glass in tablet form was determined over a period of three months. The permeability of azithromycin glass across excised pig intestinal tissue was further established at various pH values. This amorphous glassy form of azithromycin (AZM-G) proved to be very stable at high temperature and relative humidity, whilst also remaining stable after prolonged exposure to 95 % of relative humidity, as it only adsorbed moisture onto its surface. Water content (up to 50 %) had no plasticising effect on azithromycin glass. It demonstrated a significantly higher water solubility (339 % improvement) in comparison with the commercially available azithromycin dihydrate and was it also 39 % more soluble in phosphate buffer (pH 6.8) than its dihydrate counterpart. The prepared azithromycin glass tablets showed a promising dissolution profile in water, due to the improved water solubility of this glass form. The transport of azithromycin glass at higher pH values (6.8 and 7.2) across the membrane proved to be significantly higher than that of azithromycin dihydrate, thus also illustrating its pH dependence for its transport across pig intestinal tissue. The improved water solubility of the azithromycin glass, together with its faster dissolution rate, its superior stability and its increased permeability, may ultimately result in a higher azithromycin bioavailability following oral administration. These research outcomes hence give rise to the need for investigating the effect of administering lower dosages of azithromycin and to determine whether the same antimicrobial efficacy would possibly be achieved, due to maintaining the same tissue concentration levels at these lower dosages. / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Azithromycin, an azalide and member of the macrolide group, is a broad spectrum antimicrobial, representing one of the bestselling antimicrobials worldwide. It is derived from erythromycin and exhibits improved acidic stability as a result of its structural modifications. The stable solid form of azithromycin is its dihydrate, although it also naturally occurs in its metastable forms, i.e. the monohydrate and anhydrate. Because azithromycin is poorly soluble in water, its absorption from the gastro-intestinal tract is negatively influenced, which ultimately affects its bioavailability following oral administration (37 %). Polymorphic (monohydrates and dihydrates) and anhydrous forms of azithromycin were screened and investigated. One anhydrous form also proved to be amorphous, which shifted the focus of this study from polymorphism to amorphism. An amorphous glassy azithromycin was subsequently prepared and fully characterised to present its solid state profile. The stability of this amorphous glassy form was established at a high temperature and relative humidity over a period of four weeks. Exposure to increased relative humidity (up to 95 %) and increased water content (up to 50 %) also served as stability indicating tests. Its solubility in various aqueous media was determined. A solid dosage form (tablet), containing the azithromycin glass, was prepared, whereafter these tablets were subjected to dissolution studies in different aqueous media. The stability of azithromycin glass in tablet form was determined over a period of three months. The permeability of azithromycin glass across excised pig intestinal tissue was further established at various pH values. This amorphous glassy form of azithromycin (AZM-G) proved to be very stable at high temperature and relative humidity, whilst also remaining stable after prolonged exposure to 95 % of relative humidity, as it only adsorbed moisture onto its surface. Water content (up to 50 %) had no plasticising effect on azithromycin glass. It demonstrated a significantly higher water solubility (339 % improvement) in comparison with the commercially available azithromycin dihydrate and was it also 39 % more soluble in phosphate buffer (pH 6.8) than its dihydrate counterpart. The prepared azithromycin glass tablets showed a promising dissolution profile in water, due to the improved water solubility of this glass form. The transport of azithromycin glass at higher pH values (6.8 and 7.2) across the membrane proved to be significantly higher than that of azithromycin dihydrate, thus also illustrating its pH dependence for its transport across pig intestinal tissue. The improved water solubility of the azithromycin glass, together with its faster dissolution rate, its superior stability and its increased permeability, may ultimately result in a higher azithromycin bioavailability following oral administration. These research outcomes hence give rise to the need for investigating the effect of administering lower dosages of azithromycin and to determine whether the same antimicrobial efficacy would possibly be achieved, due to maintaining the same tissue concentration levels at these lower dosages. / Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2006.

This thesis investigated the physical properties of the macrolide antibiotics: Erythromycin dihydrate (EM-DH), Roxithromycin monohydrate (RM-MH) and Azithromycin dihydrate (AZM-DH). The abovementioned hydrate compounds were investigated in terms of the hydrate-anhydrate crystal structure stability, dehydration and observed polymorphism under controlled temperature heating programs. Identified hydrate and anhydrate polymorphs were subjected to physical stability testing during controlled storage. EM-DH was characterized by thermal analysis (DSC, TGA), X-ray diffraction, FTIR and microscopy. Dehydration of EM-DH at temperatures of 100, 157 and 200°C (followed by supercooling to 25°C) produced the form (I) anhydrate (Tm =142.9°C), form (II) anhydrate (Tm = 184.7°C ) and amorph (II) (Tg = 118°C) respectively. The attempts to produce amorph (I) from melting (in vicinity of form (I) melt over temperature range 133°C to 144°C) and supercooling was unsuccessful due to the high crystallization tendency of the form (I) melt. Brief humidity exposure and controlled temperature (40°C)/ humidity storage for 4 days (0-96% RH) revealed hygroscopic behaviour for the anhydrate crystal (forms (I) and (II)) and amorph (II) forms. Form (II) converted to a nonstoichiometric hydrate where extent of water vapour absorption increased with increased storage humidity (2.1% absorbed moisture from recorded TGA at 96% RH). Amorph (II) exhibited similar trends but with greater water absorption of 4.7% (recorded with TGA) at 96% RH. The pulverization and sieving process of amorph (II) (at normal environmental conditions) was accompanied by some water vapour absorption (1.1%). A slightly lower absorbed moisture content of 3.3% (from TGA) after controlled 4 days storage at 40°C/ 96% RH was recorded. This suggested some physical instability (crystallization tendency) of amorph (II) after pulverization. The thermally induced dehydration of RM-MH by DSC-TG was evaluated structurally (SCXRD), morphologically (microscopy) and by kinetic analysis. Various kinetic analysis approaches were employed (advanced, approximation based integral and differential kinetic analysis methods) in order to obtain reliable dehydration kinetic parameters. The crystal structure was little affected by dehydration as most H-bonds were intramolecular and not integral to the crystal structure stability. Kinetic parameters from thermally stimulated dehydration indicated a multidimensional diffusion based mechanism, due to the escape of water from interlinked voids in crystal. The hygroscopicity of the forms RM-MH, Roxithromycin-anhydrate and amorph glass (Tg = 81.4°C) were investigated. Roxithromycinanhydrate (crystalline) converted readily to RM-MH which were found to be compositionally stable over the humidity range 43-96%RH. Amorphous glass exhibited increased water vapour absorption with increasing storage humidity (40°C/ 0-96% RH). TG analysis suggested a moisture content of 3.5% at 96% RH after 4 storage days. DSC and powder XRD analysis of stored pulverised amorphous glass indicated some physical instability due to water induced crystallization. Commercial AZM-DH and its modifications were characterized by thermal analysis (DSC, TGA), SC-XRD and microscopy. Thermally stimulated dehydration of AZM-DH occurred in a two-step process over different temperature ranges. This was attributed to different bonding environments for coordinated waters which were also verified from the crystal structure. Dehydration activation energies for thermally stimulated dehydration were however similar for both loss steps. This was attributed to similarities in the mode of H- bonding. Different forms of AZM were prepared by programmed temperature heating and cooling of AZM-DH. The prepared forms included amorphous glass (melt supercooling), amorphous powder (prepared below crystalline melting temperature), crystalline anhydrate and crystalline partial dehydrate. Humidity exposure indicated hygroscopic behaviour for the amorphous, crystalline anhydrate and crystalline partial dehydrate modifications. Both the crystalline anhydrate and partial dehydrate modifications converted to the stoichiometric dihydrate form (AZM-DH) at normal environmental conditions at ambient temperature. Both the amorph glass and amorph powder exhibited increased moisture absorption with increased humidity exposure. TG analysis of the pulverised amorph glass indicated a moisture content of 5.1% at 96% RH after 4 storage days. The absence of crystalline melt in DSC and presence of Tg (106.9°C) indicated the sample remained amorphous after pulverisation and storage for 4 days at 40°C/ 96% RH.

No description available.

No description available.

Mycobacterium avium isolates resistant to clarithromycin and azithromycin have been recovered from patients undergoing antibiotic therapy. Comparison of DNA fingerprints of sensitive and resistant isolates showed that resistance resulted from mutation of the original, sensitive isolate in five of seven patients. In the other two patients, the clarithromycin-resistant isolates were unrelated to the sensitive isolate, suggesting that the resistant isolate resulted from either superinfection or selection of a resistant strain from a polyclonal population. Investigation of the mechanisms of clarithromycin and azithromycin resistance in M. avium showed that high-level resistance resulted from a point mutation at position A-2058 in the 23S rRNA. Based on this finding, a rapid screen for clarithromycin-resistance in M. avium was developed based on PCR. Twenty-three clinical isolates were analyzed, seven of which were clarithromycin-resistant. The target product was amplified only in clarithromycin-resistant strains, all of which had mutations at position 2058. A polyuridylic acid (poly U)-dependent in vitro translation system from M. avium was developed to investigate the effect of antibiotics on protein synthesis. Clarithromycin was an effective inhibitor of protein synthesis in cell-free extracts of a susceptible M. avium strain, whereas a high-level resistant strain was less susceptible to clarithromycin in vitro. Mixtures of extracts from sensitive and resistant strains showed a pattern of clarithromycin inhibition similar to the resistant strain, suggesting that resistance may be dominant in partial diploids. Three M. avium strains exhibiting step-wise, intermediate resistance to azithromycin were characterized in comparison to the sensitive parent. All strains were similar in hydrophobicity, growth medium requirements, and growth response to temperature. The azithromycin-resistant strains were resistant to several unrelated agents, including ciprofloxacin, rifabutin, and ethidium bromide. Addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP) did not lower minimal inhibitory concentrations (MICs) for ciprofloxacin or ethidium bromide. Cell-free extracts of the strains were as sensitive to azithromycin in vitro as the parent strain. The results rule out inactivation, efflux, and mutations in the target as resistance mechanisms, and suggest intermediate resistance may be due to altered permeability of the cell wall or membrane. / Ph. D.

Thesis (M.S.)--University of Michigan, 2004. / Includes bibliographical references.

It is a well-known fact that drugs can exist in different solid-state forms. These solid-state forms can be either crystalline or amorphous. Furthermore, significant differences are identified between the different solid-state forms of the same drug. Physico-chemical properties that are affected by the solid-state include: melting point, solubility, dissolution rate, stability, compressibility, processability, to name but a few. During the last two decades a significant amount of attention was directed towards the amorphous solid-state forms of drugs. The amorphous form is the direct opposite of the crystalline solid-state. While crystalline forms are constituted by unit cells arranged in a repetitive and structured nature, amorphous forms do not have a long-range order. This lack of order leads to an increase in the Gibbs free energy of such compounds which in turn leads to increased dissolution and solubility. The advantage of improved aqueous solubility and dissolution is a sought after characteristic within the pharmaceutical industry. Improved solubility ultimately could lead to improved bioavailability of a drug. In this study the amorphous nature and stability of amorphous azithromycin was studied. Although previous studies reported that amorphous azithromycin can be easily prepared, there is not a significant amount of data available on the stability of the amorphous form. Furthermore, the effect of milling, mixing, compression, handling and storage on the amorphous form was also investigated. This study showed that amorphous azithromycin remains stable during milling, mixing and compression. A compatibility study on azithromycin when mixed with tableting excipients showed some incompatibilities and this was helpful information to assist with the choice of excipients to be included in the tablet formulation. During the formulation study it became evident that good formulation strategies can greatly improve the flow properties of a drug. The stability of amorphous azithromycin was also studied. During this phase of the study an atypical stability indicating method was used in order to determine and demonstrate the stability of amorphous azithromycin. Dissolution studies were used to illustrate the stability of amorphous azithromycin due to the fact that dissolution is the only method that indicates the phenomena of solution-mediated phase transformation of an amorphous form to a stable crystalline form. During the stability study of six months at 40°C ± 75% RH no recrystallisation of the amorphous form to the crystalline form occurred. It was concluded that amorphous azithromycin will remain stable during processing steps, product formulation and manufacturing as well as during storage for a period of six months at elevated temperature and humidity. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2015