The influence of pH and dissolved organic carbon on the ecotoxicity of ampicillin and clarithromycin.

The impacts of water chemistry properties including pH and dissolved organic carbon (DOC) on the ecotoxicity of active pharmaceutical ingredients (APIs) are increasingly evident. These impacts are a result of alterations in API bioavailability: pH regulates the bioavailability of many ionizable APIs via chemical speciation, whereas DOC interacts with several APIs to inhibit the APIs from traversing the membrane system of organisms. In this study, we examined the influences of pH and DOC on the bioavailability of ampicillin (AMP) and clarithromycin (CLA) with the help of a bioavailability model. The effects on bioavailability were quantified by ecotoxicity observed in cyanobacteria growth inhibition tests with Microcystis aeruginosa PCC7806. The median effect concentration (96 h-EC50total) of AMP increased by 5-fold when pH raised from 7.4 to 9.0, suggesting the zwitterionic AMP+/- species being higher in bioavailability than the negatively charged AMP- species. CLA ecotoxicity showed no significant pH-dependency, suggesting CLA+ and CLA0 species to be equally bioavailable, albeit it correlated significantly with M. aeruginosa growth rate in negative controls. In addition, DOC demonstrated no significant effects on the ecotoxicity of AMP or CLA. Overall, together with earlier results on ciprofloxacin, our data show that bioavailability relations with pH and DOC are variable among different antibiotics. Factors other than chemical speciation alone could play a role in their bioavailability, such as their molecular size and polarity.

Comparison of oxidative stress induced by clarithromycin in two freshwater microalgae Raphidocelis subcapitata and Chlorella vulgaris.

Clarithromycin (CLA), a macrolide antibiotic, has been frequently detected in the global surface waters. Concerns have been raised over the potential impacts of CLA on the non-target aquatic species, particularly algae acting as the primary producers in the ecosystem. This study therefore evaluated the toxicological effects of CLA at a range of concentration levels (0, 5, 20, 40, 80 µg L-1) on two green algae, Raphidocelis subcapitata (R. subcapitata) and Chlorella vulgaris (C. vulgaris). The algal growth, photosynthetic pigment contents, lipid peroxidation biomarker malondialdehyde (MDA), responses of antioxidants including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GP), and glutathione S-transferase (GST) were measured. After 7 d exposure, the growth of R. subcapitata was inhibited with the CLA exposure levels higher than 20 µg L-1, whereas the inhibition in C. vulgaris was detected at the concentration level of 80 µg L-1. The MDA contents in both species were elevated. To cope with the increased levels of ROS, the activities of enzymatic antioxidants (SOD, CAT, GP, and GST) and the content of non-enzymatic antioxidant (GSH) in R. subcapitata were all enhanced. However, in C. vulgaris, enhancement was detected only in the activities of antioxidant enzymes (SOD, CAT, and GP). In addition, chlorophyll a, b, and carotenoid contents were all significantly increased in R. subcapitata but decreased in C. vulgaris. The results suggested that R. subcapitata is more sensitive to CLA exposure than C. vulgaris. This study provides insights into the CLA - oxidative stress process in two algae.

Survival benefit associated with clarithromycin in severe community-acquired pneumonia: A matched comparator study.

Although analysis of retrospective studies has documented survival benefit from the addition of a macrolide to the treatment regimen for community-acquired pneumonia (CAP), no data are available to determine if there is differential efficacy between members of the macrolide family. In order to investigate this, an analysis was undertaken of data from 1174 patients with CAP who met the new Sepsis-3 definitions and were enrolled prospectively in the data registry of the Hellenic Sepsis Study Group. Four well-matched treatment groups were identified with 130 patients per group: clarithromycin and ß-lactam; azithromycin and ß-lactam; respiratory fluoroquinolone and ß-lactam monotherapy. The primary endpoint was comparison of the effects of clarithromycin with ß-lactam monotherapy on 28-day mortality. The secondary endpoint was resolution of CAP. Mortality rates for the clarithromycin, azithromycin, respiratory fluoroquinolone and ß-lactam groups were 20.8%, 33.8% (P=0.026 vs clarithromycin), 32.3% (P=0.049 vs clarithromycin) and 36.2% (P=0.009 vs clarithromycin), respectively. After stepwise Cox regression analysis among all groups, clarithromycin was the only treatment modality associated with a favourable outcome (hazard ratio 0.61; P=0.021). CAP resolved in 73.1%, 65.9% (P=0.226 vs clarithromycin), 58.5% (P=0.009 vs clarithromycin) and 61.5% (P=0.046 vs clarithromycin) of patients, respectively. It is concluded that the addition of clarithromycin to the treatment regimen of patients with severe CAP leads to better survival rates.

Oxidative stress responses and cellular energy allocation changes in microalgae following exposure to widely used human antibiotics.

The individual effect of four human antibiotics on the microalgae Raphidocelis subcapitata was investigated following a 120-h exposure. The effects were assessed by analyzing growth, and biochemical parameters related with: 1) antioxidant capacity and oxidative damage by measuring superoxide dismutase (SOD) activity and lipid peroxidation (LPO) levels; and 2) cellular energy allocation (CEA) by quantifying the content in energy reserves, which represents the energy available (Ea), and the electron transport system activity that represents a measure of oxygen and cellular energy consumption (Ec). Growth yield inhibitory concentrations of sulfamethoxazole (18-30%), clarithromycin (28.7%), ciprofloxacin (28%) and erythromycin (17-39%) were found to elicit a considerable increase in Ec, thereby causing a significant decrease in the CEA. The elevated Ec can be a result of the need to respond to oxidative stress occurring under those conditions given the significant increase in SOD activity at these levels. For sulfamethoxazole, erythromycin and ciprofloxacin, the antioxidant responses do not seem to be enough to cope with the reactive oxygen species and prevent oxidative damage, given the elevated LPO levels observed. A stimulatory effect on growth yield was observed (up to 16%) at ciprofloxacin lowest concentration, which highly correlated with the increase in CEA. Based on the no observed effect concentration (NOECs) and/or effective concentration (EC10) results, Ec, SOD and CEA were more sensitive than the classical endpoint of growth rate for all the tested antibiotics. By revealing the antibiotic stress effects in R. subcapitata at the cellular level, this study suggests CEA as a more reliable indicator of the organisms' physiological status.

Sub-lethal pharmaceutical hazard tracking in adult zebrafish using untargeted LC-MS environmental metabolomics.

Antibiotics in the aquatic environment are dispersed through anthropogenic activities at low concentrations. Despite their sub lethal concentration, these biologically active compounds may still have adverse effects to non-target species. This study examined the response of adult zebrafish to 0.1mg/L concentration of clarithromycin, florfenicol, sulfamethazine, and their mixture using environmental metabolomics. Embryo and larvae of the fish were also used to assess fish embryo acute toxicity and behavior tests respectively. The fish embryo toxicity test did not show any inhibition of growth and development of the embryos after 96h of exposure to the antibiotics. Changes in swimming activity were seen in 5-dpf larvae which is believed to be correlated with the length of exposure to the compounds. Meanwhile, environmental metabolomics revealed diverse metabolites and pathways that were affected after 72h of exposure of the adult fish to sub-lethal concentration of the compounds. We found that even at low concentration of the antibiotics, behavioral and metabolic effects were still observed despite the lack of visible morphological changes. Further studies involving other aquatic organisms and bioactive compounds are encouraged to strengthen the findings presented in this novel research.

Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models.

The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water).

Toxicity of macrolide antibiotics on isolated heart mitochondria: a justification for their cardiotoxic adverse effect.

1. Macrolides belong to the polyketide class of natural products. These products are a group of drugs (typically antibiotics) which their activity stems from the presence of a macrolide ring. Antibiotic macrolides are used to treat infections caused by Gram-positive bacteria and Haemophilus influenzae infections such as respiratory tract and soft-tissue infections. Macrolides, mainly erythromycin and clarithromycin, rarely show QT prolongation, as their infamous adverse reaction which can lead to torsades de pointes. Electrophysiological studies showed that macrolides prolonging the QT interval inhibit the rapid component of the delayed rectifier K(+) current (IKr) through the block of potassium channels encoded by the human ether-a-go-go-related gene (HERG). Other studies suggest that increased ROS generation alters the kinetics of hERG K(+) conductance. 2. In our study, rat cardiomyocytes were isolated with collagen perfusion technique. Finally, mitochondria isolated from cardiomyocytes were exposed to erythromycin, azithromycin and clarithromycin for their probable toxicity effects. 3. Our results demonstrated that macrolides induced reactive oxygen species formation, mitochondrial membrane permeabilization and mitochondrial swelling and finally cytochrome c release in cardiomyocyte mitochondria. 4. These findings suggested that the toxicity of heart mitochondria is a starting point for cardiotoxic effects of macrolides including QT prolongation, torsades de pointes and arrhythmia.

The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides.

As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity.

In vitro approach to study the synergistic effects of tobramycin and clarithromycin against Pseudomonas aeruginosa biofilms using prokaryotic or eukaryotic culture media.

Recurrent Pseudomonas aeruginosa infections involving biofilm formation are frequent in cystic fibrosis, aggravating the respiratory distress. Co-administration of clarithromycin and classical tobramycin could improve the health status of patients. Antibiotic toxicity was assessed on epithelial (CFBE41o(-)) and macrophagic (THP-1) cell lines. Non-toxic concentrations of antibiotics alone or in combination were applied twice daily for 12 days on mature (12-day-old) biofilms of three P. aeruginosa strains, developed either in prokaryotic culture broth [tryptic soy broth (TSB)] or in a eukaryotic cell culture medium (RPMI-FCS) more similar to an in vivo environment. The antibiofilm and bactericidal effects of antibiotics were assessed. No toxicity of tobramycin was observed on eukaryotic cell lines at concentrations up to 500µg/mL, whilst 100µg/mL was selected as the clarithromycin upper safe limit. The amount of biofilm was strongly reduced by 100µg/mL and 500µg/mL tobramycin for each strain in both media, whilst clarithromycin was only effective in RPMI-FBS, with synergistic (PAO1 strain) and additive (PYO2 strain) effects detected when combining tobramycin 4µg/mL and clarithromycin 100µg/mL. Finally, tobramycin at ≥100µg/mL exerted strong bactericidal effects on each strain in both media. Clarithromycin also exerted bactericidal effects on each strain in both media; its effect was weaker than tobramycin in TSB but was similar in RPMI-FBS. Synergistic effects were observed on PAO1 and MUCO biofilms, e.g. when combining tobramycin 4µg/mL and clarithromycin 100µg/mL. These in vitro data show that co-administration of clarithromycin and tobramycin acts synergistically against in vitro P. aeruginosa biofilms.

Aquatic toxicity of the macrolide antibiotic clarithromycin and its metabolites.

The human macrolide antibiotic clarithromycin is widespread in surface waters. Our study shows that its major metabolite 14-hydroxy(R)-clarithromycin is found in surface waters in comparable amounts. This metabolite is known to be pharmacologically active. Additionally, clarithromycin is partly metabolised to N-desmethyl-clarithromycin, which has no antimicrobial activity. For clarithromycin, some ecotoxicological studies on aquatic organisms have been published. However, many of them are not conform with the scientific principles as given in the "Technical guidance for deriving environmental quality standards" (TGD-EQS), because numerous studies were poorly documented and the methods did not contain analytical measurements confirming that the exposure concentrations were in the range of ± 20% of the nominal concentrations. Ecotoxicological effects of clarithromycin and its two metabolites on the zebrafish Danio rerio (embryo test), the microcrustacean Daphnia magna, the aquatic monocotyledonous macrophyte Lemna minor, the freshwater green alga Desmodesmus subspicatus (Chlorophyta) and the cyanobacterium Anabaena flosaquae were investigated in compliance with the TGD-EQS. Environmental risk assessment was performed using ErC10 values of Anabaena, the species most sensitive to clarithromycin and 14-hydroxy(R)-clarithromycin in our testing. Based oncomparable toxicity and similar concentrations of clarithromycin and its active metabolite 14-hydroxy(R)-clarithromycin in surface waters, an additional multiplication factor of 2 to the assessment factor of 10 on the ErC10 of clarithromycin should be used. Consequently, a freshwater quality standard of 0.130 µg L(-1) is proposed for clarithromycin as the "lead substance". Taking this additional multiplication factor of 2 into account, single monitoring of clarithromycin may be sufficient, in order to reduce the number of substances listed for routine monitoring programs.

Characteristics and evaluation of an injectable clarithromycin lipid-based complex in vitro and in vivo.

The purpose of this paper is to prepare a less-irritating and lipid-based clarithromycin complex (LCC) by the route of intravenous administration qualified with high drug-loading and fine particle size. The LCC was prepared by the injection of organic solvent phase (containing clarithromycin, sodium cholesterol sulfate and phospholipid at a molar ratio of 1:1:1.5) into the Tris buffer solution (0.05 M, pH 7.2) at 40 °C, and then was concentrated by ultrafiltration to remove the organic solvent. The technique of lyophilization was applied to obtain the LCC lyophilized products. Evaluation of the injectable LCC was performed by particle sizes analysis, transmission electron microscope, entrapment efficiency, stability and irritation tests. The LCC possessed a log-normal size distribution with an average size of 75.4 nm. The drug entrapment efficiency was above 97.0%, which was influenced by the amount of phospholipid, pH value of the media and ionic strength of aqueous suspension. The results of stability and irritation tests proved that LCC had more stability and less irritation. This unique LCC formulation may be applied to the human by the route of injection with less or no irritation. LCC could be an appropriate candidate for intravenous preparation and has a great potential for clinical and industrial-scale production.

Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro.

Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors expressed on human TE671 cells. Telithromycin decreased the twitch contraction force of the rat diaphragm muscle in response to phrenic nerve stimulation in a concentration-dependent manner with an IC(50) of 22.3 microM and a maximal inhibition of approximately 70%. The trans-membrane current from the ACh receptors expressed in the TE671 neuromedulloblastoma cells was recorded in the whole-cell patch-clamp configuration. When applied to the TE671 cells, telithromycin caused a dose-dependent inhibition of the nicotinic ACh current with an IC(50) of 3.5 microM and maximal inhibition of nearly 100%. These results indicate that telithromycin inhibits postsynaptic nicotinic ACh receptors in vitro and partially blocks neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Based on these findings, we propose that exacerbation of myasthenia gravis reported in some patients taking telithromycin results in part from postsynaptic neuromuscular transmission block.

Macrolide antibiotics aggravate experimental autoimmune encephalomyelitis and inhibit inducible nitric oxide synthase.

Recent studies have implicated Chlamydia pneumoniae (C. pneumoniae) is present in a subset of patients with multiple sclerosis (MS) in which C. pneumoniae could act as a cofactor in the development of the disease. Macrolide antibiotics are most widely used anti-chlamydial agents and have immunomodulatory effect independently of their anti-bacterial activity. To investigate their effects on experimental autoimmune encephalomyelitis (EAE), EAE was induced by immunization with MBP68-86 peptide emulsified in complete Freund's adjuvant (CFA). Clarithromycin (CM) or azithromycin (AM, 50 mg/100 g body weight) was administrated daily from day 2 before immunization. All rats developed and survived EAE, but the groups administrated CM or AM had more severe symptoms. On day 11 post-immunization, mononuclear cells (MNCs) were prepared from the spleen of control group and cultured with or without macrolide antibiotics (10mug/ml). We evaluated nitric oxide (NO) production in the serum and culture supernatant. Inducible nitric oxide synthase (iNOS) mRNA and protein expression in the spinal cords and cultured MNCs were measured. The results showed that CM and AM similarly inhibited NO production and iNOS mRNA and protein expression in vivo and in vitro. Macrolide antibiotics may aggravate EAE by inhibiting iNOS mRNA and protein expression. Further studies are needed to investigate the effect of macrolide antibiotics on MS and to compare the effect of different anti-chlamydial antibiotics on MS.

Hepatotoxicidad por claritromicina: recordatorio de farmacovigilancia / Clarithromycin hepatotoxicity: pharmacovigilance reminder

En nuestra práctica clínica diaria en la consulta dePediatría es frecuente la prescripción de antibióticospara el tratamiento de infecciones bacterianas devariada etiología, pero no tenemos la impresión deque exista una importante toxicidad de los mismosen niños, lo que nos puede llevar a olvidar que, aunqueno sean frecuentes, existen reacciones adversas,algunas graves, y que tenemos la obligación denotificarlas a nuestras Autoridades Sanitarias. Presentamosel caso clínico de un niño de 4 años conhepatitis en posible relación con la ingesta previa declaritromicina, con total reversibilidad clínico-analíticade las manifestaciones presentadas, tal como serefleja en la ficha técnica del fármaco entre los posiblesefectos adversos poco frecuentes. El caso nosha parecido de interés en la medida que nos sirvacomo recordatorio de nuestra obligación como profesionalessanitarios de declarar las sospechas deposibles reacciones adversas a fármacos a los Sistemasde Farmacovigilancia de nuestras ComunidadesAutónomas, con objeto de mejorar su seguridad,intentando mantener en todo momento una relaciónbeneficio-riesgo favorable para la población

In our daily clinical practice in the pediatric consultingroom, prescribing antibiotics for the treatment ofbacterial infections of diverse etiology it is very common.We do not have the impression that there existany important toxicity of these antibiotics in children,what can lead us to forget that, although uncommon,there are adverse reactions, some of themquite serious, and that we have the obligation of reportingthem to our Health Authorities. We presentthe clinical case of a 4 –year-old boy with hepatitis,possibly related to the previous intake of clarithromycin,with a complete clinical and analytical reversalof the observed clinical manifestations. The notedreversal of the symptoms matches the possible butinfrequent adverse effects which appear in the summaryof product´s characteristics. We find this casevery interesting, since it can be useful as a reminderof our obligations as health professionals. Theseobligations would include reporting to the PharmacovigilanceSystems of our Autonomous Communitiesany suspected possible adverse reactions to drugswith the objective of improving their safety, as wellas trying to maintain at all times a benefit-risk relationshipin favour of the population

Effects of eight antibacterial agents on cell survival and expression of epithelial-cell- or cell-adhesion-related genes in human gingival epithelial cells.

OBJECTIVE AND BACKGROUND: Our previous studies suggest that little adverse effect on the growth of the periodontal ligament would be expected, if tetracycline, minocycline, ofloxacin, roxithromycin, clarithromycin, and azithromycin were topically administered to the periodontal pocket at their MIC90 doses required to inhibit the growth of 90% of periodontopathic bacteria, including Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans. In the present study, we investigated the cytocidal effects of eight antibacterial agents on the human gingival epithelial cell line NDUSD-1. We also used NDUSD-1 cells to examine the effects of these agents on the mRNA and protein expressions of genes associated with the proliferation, differentiation, or cellular adhesion important to the epithelial regeneration of the periodontal attachment. METHODS: The cytocidal effect of the test agents was measured as a decrease in cell survival. To obtain a quantitative measure of the cytocidal effect, the LD50, i.e. the concentration which results in a 50% decrease in cell survival relative to the controls, was extrapolated from the concentration-response curves. The effects of the agents on the mRNA and protein expressions in NDUSD-1 cells were studied by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analyses, respectively. RESULTS: The cytocidal effect increased in a concentration-dependent manner as the concentration of each of the eight test agents increased. The order of the agents according to their cytocidal effects (LD50) was minocycline > tetracycline > enoxacin > clarithromycin > roxythromycin approximately ofloxacin > azithromycin > erythromycin. The cytocidal effects of minocycline, tetracycline, enoxacin, clarithromycin, roxythromycin, ofloxacin, and azithromycin ranged from 1.2 to 23.2 times greater than that of erythromycin. The maximum non-cytocidal concentrations (MNCCs) of these agents for NDUSD-1 cells were: 0.3 microm for minocycline, 1 microm for tetracycline, 3 microm for ofloxacin and erythromycin, 10 microm for enoxacin, clarithromycin, and azithromycin, and 100 microm for roxythromycin. The MNCCs of ofloxacin, azithromycin, clarithromycin, and roxythromycin were greater than their MIC90 concentrations for periodontopathic bacteria described above. The effects on the mRNA and protein expressions of epithelial-cell- or cell-adhesion-related genes were examined in NDUSD-1 cells exposed to clarithromycin, roxythromycin, ofloxacin, and azithromycin at their MNCCs. None of the agents affected the mRNA expressions of five genes: keratinocyte growth factor receptor, keratin 18, integrin beta1, integrin beta4, and laminin 5gamma2. Clarithromycin and ofloxacin slightly decreased the protein expression of integrin beta4. Roxythromycin markedly decreased the protein expressions of integrin beta4 and laminin 5gamma2. Azithromycin had little inhibitory effects on the protein expressions of any of the five genes. CONCLUSIONS: These results suggest that little, if any, adverse effects on growth, differentiation, and adhesion of basal epithelial cells would be expected with topical administration of clarithromycin, ofloxacin or azithromycin to the periodontal pocket at a dose equivalent to the MIC90. It is important to note, however, that the extrapolation of these findings to in vivo conditions has yet to be undertaken.

Prophylactic clarithromycin to treat mycobacterium avium in HIV patients receiving zidovudine may significantly increase mortality by suppressing lymphopoiesis and hematopoiesis.

The increased mortality observed when human immunodeficiency virus (HIV)-infected individuals are treated with clarithromycin (CLA) as prophylaxis for disseminated infection with organisms of the Mycobacterium avium complex (MAC) suggests that CLA might possess immunosuppressive activities. To test this possibility, we assessed the immunological response of BALB/c mice following subchronic (28 days) oral administration of CLA alone or in combination with zidovudine (ZDV). Because normal hematopoiesis is needed to maintain the immune system, we also examined the effect of these drugs given individually or in combination on several hematological parameters. The major effect of administration of 500 mg/kg CLA was a marked decrease in the lymphocyte/neutrophil ratio, and the only evidence of hematotoxicity in mice treated with 240 mg/kg ZDV alone was mild macrocytic anemia. However, treatment with a combination of CLA and ZDV resulted in severe hematotoxicity, evidenced by a significant (p < 0.01) decrease in the number of circulating erythrocytes, neutrophils, and lymphocytes and a 67% drop in splenic cellularity (p < 0.01). Treatment with CLA or ZDV alone or both drugs in combination had no effect on lymphocyte function, determined by measuring the ex vivo proliferative activity of splenocytes in response to alloantigens or a B cell mitogen, lipopolysaccharide (LPS). However, because of the cellular depletion in the spleen, overall immune responses in this organ decreased significantly (p < 0.05) in mice treated with CLA plus ZDV. These data suggest that interactions between CLA and ZDV warrant further evaluation because these drugs are given in combination to persons with advanced HIV infection.

Reversible ototoxic effect of azithromycin and clarithromycin on transiently evoked otoacoustic emissions in guinea pigs.

The possible cochlear toxicity of systemically applied macrolides--erythromycin (ER), azithromycin (AZ) and clarithromycin(CL)--was investigated in guinea pigs by measuring transiently evoked otoacoustic emissions (TEOAEs). A single dose of 125 mg/kg intravenous (i.v.) ER caused no change in TEOAEs in guinea pigs (p>0.05), whereas AZ (45 mg/kg orally) and CL (75 mg/kg i.v.) reversibly reduced the emission response (p<0.05). The reversible reduction of TEOAE responses due to AZ and CL, which is in accordance with the clinical picture of AZ and CL ototoxicity, could likely be attributable to the transient dysfunction of outer hair cells. The present study reveals that at least one ototoxic effect of AZ and CL is on the inner ear. The results may also encourage planning clinical researches on TEOAE monitoring in patients receiving high doses of AZ or CL.