[Review of oral cephalosporins. Basis for a rational choice]. / Revisión de cefalosporinas orales. Bases para una elección racional.

During the last 10 years, the emergence and spread of the most important and common resistant pathogens isolated from clinical infections led to the great release of new antibacterial agents. Many of new orally administered antibiotics introduced, such as newer fluoroquinolones or cephalosporins, showed a spectrum of activity and clinical efficacy for the most common clinical community infections. Therefore, therapeutic indication of a new cephalosporin is somewhat difficult to define, because the newer drugs must compete with improved properties over the previous ones. Therefore, choice of a first line antibiotic among apparently therapeutic equivalents could become questionable. The aim of this review was to compile the available data to offer help for a rational choice in confirmed infections of every particular patient condition and context based on microbiological activity, pharmacokinetic properties, clinical efficacy, safety and cost. Orally administered cephalosporins are beta-lactamic broad-spectrum antimicrobial agents that are often used empirically to treat community bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, in vitro antimicrobial potency, microbial resistance, pharmaco-kinetic properties and cost. These differences result from modifications of the cephalosporin molecule. The substitutions on the R1, R2, R3 or R4 side chains results in changes in antimicrobial spectrum, potency, bioavailability, half-life and profile of toxicity. In general, the first-generation agents are more active against gram-positive organisms, more susceptible to B-lactamases of gram-negative producers, shorter serum half-life and lower cost than the other agents. The second-generation cephalosporins present enhanced spectrum of activity due to increased resistance to beta-lactamase enzymes and have longer serum half-life. The third-generation agents are the most active against Entero-bacteriaceae, possess a superior beta-lactamase stability against selected enzymes of multiple resistant bacteria, improved pharmacokinetic properties with extended plasma half-life, that permit once or twice daily administration and are the most expensive compared with the previous drugs. Among these new oral cephems, the addition of an ester group enhances the oral absorption from the gastrointestinal tract and provides better bioavailability as well as antimicrobial activity. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action. Expertise in the choice and use of the cephalosporins will remain a challenge for the physician, as additional investigational cephalosporins will continue to be developed and introduced into clinical practice in the near future.

Revisión de cefalosporinas orales. Bases para una elección racional. / [Review of oral cephalosporins. Basis for a rational choice]

During the last 10 years, the emergence and spread of the most important and common resistant pathogens isolated from clinical infections led to the great release of new antibacterial agents. Many of new orally administered antibiotics introduced, such as newer fluoroquinolones or cephalosporins, showed a spectrum of activity and clinical efficacy for the most common clinical community infections. Therefore, therapeutic indication of a new cephalosporin is somewhat difficult to define, because the newer drugs must compete with improved properties over the previous ones. Therefore, choice of a first line antibiotic among apparently therapeutic equivalents could become questionable. The aim of this review was to compile the available data to offer help for a rational choice in confirmed infections of every particular patient condition and context based on microbiological activity, pharmacokinetic properties, clinical efficacy, safety and cost. Orally administered cephalosporins are beta-lactamic broad-spectrum antimicrobial agents that are often used empirically to treat community bacterial infections and also to treat culture-proven infections due to selected gram-positive and gram-negative microorganisms. Cephalosporins differ widely in their spectrum of activity, in vitro antimicrobial potency, microbial resistance, pharmaco-kinetic properties and cost. These differences result from modifications of the cephalosporin molecule. The substitutions on the R1, R2, R3 or R4 side chains results in changes in antimicrobial spectrum, potency, bioavailability, half-life and profile of toxicity. In general, the first-generation agents are more active against gram-positive organisms, more susceptible to B-lactamases of gram-negative producers, shorter serum half-life and lower cost than the other agents. The second-generation cephalosporins present enhanced spectrum of activity due to increased resistance to beta-lactamase enzymes and have longer serum half-life. The third-generation agents are the most active against Entero-bacteriaceae, possess a superior beta-lactamase stability against selected enzymes of multiple resistant bacteria, improved pharmacokinetic properties with extended plasma half-life, that permit once or twice daily administration and are the most expensive compared with the previous drugs. Among these new oral cephems, the addition of an ester group enhances the oral absorption from the gastrointestinal tract and provides better bioavailability as well as antimicrobial activity. The development of bacterial resistance has affected all steps of the cephalosporin mechanism of action. Expertise in the choice and use of the cephalosporins will remain a challenge for the physician, as additional investigational cephalosporins will continue to be developed and introduced into clinical practice in the near future.

[Audit of clinical trials in Argentina. Assessment of standardized operational procedures in 12 centers]. / Auditoría de ensayos clínicos en Argentina. Evaluación de procedimientos operacionales normatizados en 12 centros.

The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.

Auditoría de ensayos clínicos en Argentina. Evaluación de procedimientos operacionales normatizados en 12 centros. / [Audit of clinical trials in Argentina. Assessment of standardized operational procedures in 12 centers]

The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.

Auditoría de ensayos clínicos en Argentina. Evaluación de procedimientos operacionales normatizados en 12 centros. / [Audit of clinical trials in Argentina. Assessment of standardized operational procedures in 12 centers]

The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.

Auditoría de ensayos clínicos en Argentina. Evaluación de procedimientos operacionales normatizados en 12 centros / [Audit of clinical trials in Argentina. Assessment of standardized operational procedures in 12 centers]

The purpose of these audits was to ensure the quality, integrity and validity of investigational data. Audits were performed by control of compliance to standard operational procedures (SOPs) for Good Clinical Practice (GCP). Guidelines were proposed and established by the Food and Drug Administration (FDA) in 1977-1979 and adopted by several countries of the European Community in 1987-1989 and 1990. In Argentina, 12 on site audits of clinical trials performed between 1987 and 1990, were carried out. Basic data of GCP, audited in 58 out of 153 patients included in 12 different centers, were: protection of individual rights, compliance to standard operational procedures, adverse event reports, access to original investigational data and source document archives. The analysis of all audited data showed that patient case reports form recorded findings are credible and reliable and that researchers and monitors had conducted the study with an acceptable level in accordance to SOPs of good clinical practice. Otherwise, several in need of change to obtain better clinical data were identified: ethical committees, written informed consent, protocol adherence, data record, drug accountability, document source archives and the necessity of a thorough theorical and practical training on SOPs for GCP for researchers and monitors of clinical trials.

[Comparison of empirical treatment with antibiotics in community acquired lung diseases]. / Comparación de tratamientos empíricos con antibióticos en neumopatías extrahospitalarias.

From December 1984 to June 1986, a prospective clinical trial was carried out in 48 patients with acute community-acquired pneumonia, comparing 2 possible therapeutic schemes: one, using only one antibiotic (roxithromycin: RXT) presumptively active on most of the germs usually involved. In a second group, the identification of the germs involved was attempted on the basis of clinical, epidemiological and radiological data, followed by treatment with the antibiotic/s (ATB) known to be more active against the suspected organisms. The dosage of RXT was 300 mg/day, orally during an average of 9 days. The mean duration of treatment in ATB group was 12 days. In both groups, the following microorganisms were identified: RXT group: St. pneumoniae (13 cases), H. influenzae (1), B. catarrhalis (1); mixed infections: St. pneumoniae + H. influenzae (2); Mycoplasma pneumoniae (3) and 4 patients with unidentified germ; in ATB group: St. aureus (3), St. pneumoniae (5), H. influenzae (2), B. catarrhalis (1); mixed infections: St. aureus + Enterobacter + E. coli (1); Mycoplasma pneumoniae (2) and 10 patients with unidentified germ. The therapeutic results were satisfactory (curation rate: 92%) and similar for both groups of treatment, concluding that both schemes are comparable. Therefore, the choice for one or the other scheme should be based on other reasons, such as easy administration and cost of the treatment.

Comparación de tratamientos empíricos con antibióticos en neumopatías extrahospitalarias. / [Comparison of empirical treatment with antibiotics in community acquired lung diseases]

From December 1984 to June 1986, a prospective clinical trial was carried out in 48 patients with acute community-acquired pneumonia, comparing 2 possible therapeutic schemes: one, using only one antibiotic (roxithromycin: RXT) presumptively active on most of the germs usually involved. In a second group, the identification of the germs involved was attempted on the basis of clinical, epidemiological and radiological data, followed by treatment with the antibiotic/s (ATB) known to be more active against the suspected organisms. The dosage of RXT was 300 mg/day, orally during an average of 9 days. The mean duration of treatment in ATB group was 12 days. In both groups, the following microorganisms were identified: RXT group: St. pneumoniae (13 cases), H. influenzae (1), B. catarrhalis (1); mixed infections: St. pneumoniae + H. influenzae (2); Mycoplasma pneumoniae (3) and 4 patients with unidentified germ; in ATB group: St. aureus (3), St. pneumoniae (5), H. influenzae (2), B. catarrhalis (1); mixed infections: St. aureus + Enterobacter + E. coli (1); Mycoplasma pneumoniae (2) and 10 patients with unidentified germ. The therapeutic results were satisfactory (curation rate: 92

) and similar for both groups of treatment, concluding that both schemes are comparable. Therefore, the choice for one or the other scheme should be based on other reasons, such as easy administration and cost of the treatment.