The other side of early antimicrobial development

ANNLDO 3(9)63-72, 1986

ISSN 0738-1751

VOLUME 3, NUMBER 9, SEPTEMBER 1986

EDITORIAL BOARD

Editor

Associate Editors

DANIEL AMSTERDAM, PhD,

CLYDE THORNSBERRY, PhD,

RONALD N. JONES, MD,

State University of New York at Buffalo and Erie County Medical Center

Center for Infectious Diseases, Centers for Disease Control

Clinical Microbiology Institute

L O W E L L S. Y O U N G , M D , Kuzell Institute for Arthritis and Infectious Diseases Medical Research Institute of San Francisco Pacific Presbyterian Medical Center

College of Physicians and Surgeons, Columbia University

HAROLD C. NEU, MD,

THE OTHER SIDE OF EARLY ANTIMICROBIAL DEVELOPMENT EDITOR'S NOTE

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D. AMSTERDAM The Other Side of Early Antimicrobial

Development

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W. J. NOVICK, Jr.

N e w Drugs

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R. N. JONES Apocalypse s. BERGER

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W I L L I A M J. NOVICK, Jr. Hoechst-Roussel Pharmaceuticals Inc., Sommerville, New Jersey In the past 10 years we have seen a marked increase in the number and type of potential clinically effective antimicrobial agents in development. The reasons for this include the need for better antimicrobials, better chemical approaches and screening methods, or the desire of more companies to profitably participate in this market. Regardless of the reason, we now have many new entries in the field of cephalosporins, penicillins, monobactams, penems, macrolides, and quinolones, to mention

uation is currently recognized, Much of what Dr. Novick has This month, The A M N reports on written will be incorporated into a the current processes involved in National Committee for Clinical developing new antimicrobial corn- Laboratory Standards document, pounds. As the potential armaM23-P, a proposed guideline esmentarium of new drugs is burtablishing minimal data criteria for geoning, guidelines are needed for pharmaceutical and susceptibility their evaluation. While we all test reagent manufacturers. speak glibly of Phase I, II, and III The theme of drug development testing, Dr. Novick apprises us of is carried in Dr. Jones' ongoing other perspectives associated with section on "New Drugs."Dr. bringing new products to market, Jones details for us the "phase" such as the development of suscharacteristics of these compounds ceptibility test systems for both and informs u s o f recent dropouts. disk diffusion and dilution method"'Apocalypse completes the stoologies. A newly recognized ry and supposes where it all began phase, Phase IV, post-market eval- or.goes . . . EDITOR'S NOTE

ELSEVIER

only a few developments. In addition, there are several developments with combinations such as with beta-lactamase inhibitors. Generally, the antimicrobial literature concerning new drugs tends to concentrate on two areas--in vitro spectrum and clinical efficacy. What is often not appreciated is the vast amount of work necessary to bring a new compound to clinical use either as an investigative and subsequently marketed drug. The terms Phase I, Phase II, and Phase III clinical trials are familiar to most people in the medical fields. Briefly, Phase I is concerned with demonstrating safety in human subjects and for establishing the initial human pharmacokinetic parameters of a new agent (to be discussed in detail later). Phase II is the first entry into a patient population. This is the period when dose ranging and initial clinical efficacy are evaluated. In Phase II, safety is a primary objective and a natural extension from Phase I studies done in normal subjects. Phase III involves much broader clinical evaluation of a new agent and usually includes multi-investigator trials. This

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phase of study is directed toward getting an indication as to safety and efficacy in a situation mimicking the marketing interval. These developmental phases can often overlap. The studies generally constitute the major publications for each new or marketed drug. The major objective of these primary investigations for any new drug is to establish a profile of safety and efficacy in man. This, however, is not the whole story of drug development. This paper will attempt to describe "The Other Side of Early Antimicrobial Development," which is often not fully appreciated. It is a field where scientists of various disciplines and degrees of expertise must work in concert with the common goal of delivering a stable, standardized drug into the hands of the microbiologist and infectious disease physiclan. It is a field where many play a major role in realizing the ultimate goal of increasing the armamentarium of the physician treating patients. It is a field where success is often measured in small steps or, not too uncommonly, in negative data. SUPPLY The initial sample of a new antibiotic, as it comes from the chemist's bench or fermentor, is often the result of months of complex chemical alterations involving experimental fermentations and multiple complex synthetic steps. Using a simple activity screen with selected organisms, the microbiologist may recognize an "interesting" spectrum. At this point a major development process is set in motion that involves many investigators with differing specialized talents, From this embryonic beginning of milligram quantities of a drug, the ultimate goal is to produce

THE A N T I M I C R O B I C NEWSLETTER, VO[.UME 3, N U M B E R 9, SEPTEMBER 1986

thousands of kilos or often tons of pure therapeutic substance. For example, it is estimated that in the United States alone, annual consumption of erythromycin is 240,000 kg, penicillin G is 4000 billion U, and a large volume of cephalosporins such as cefoxitin is 25,800 kg. In each of these cases, major production scale-up problems had to be overcome. Taking the example of a cephalosporin, the usual starting point is 7-aminocephalosporanic acid (7ACA), which is isolated from highly developed fermentation processes. Tens of thousands of kilograms of 7-ACA are produced annually worldwide. There is a continuous research process to increase yield since each improvement can have a significant economic effect on a final drug product. Obtaining an ample supply of pure 7-ACA is just the first step. Many semisynthetic cephalosporins such as cefotaxime, cefoperazone, and ceftriaxone require multiple synthetic steps, each of which must be optimized for active end-product yield. In the end, each step must be scaled-up to achieve production quantities, Often the synthetic procedure is complex, as with the introduction of the beta-lactamase-stable methoximine sidechain of cefotaxime or cefuroxime. This sidechain must be in the syn-position since the antiform has a much reduced spectrum of activity.1 Therefore, stereochemical procedures had to be developed. This scale-up process requires the expertise of bench chemists working in gram quantitles, by batch chemists working in kilogram quantities, and finally, the production chemists, Totally synthetic antibiotics such as the quinolones also present major problems in converting from laboratory batches to production batches. Scale-up chemists and mi-

crobiologists represent a key group of scientists who often hold key positions in determining if a new antibiotic can be made in an efficient economical way. Their work is rarely published or recognized, but without their contributions, we would not have viable marketed antibiotics. PHARMACEUTICAL DEVELOPMENT During the process of antimicrobial development, a critical step is packaging the drug for use. Here, the research pharmacist has the responsibility to produce a stable product that can be prepared in tablets, capsules, or suspensions for oral administration or solubilized for parenteral administration. With tablets or capsules for oral administration, consideration must be given to the excipients used and, specifically, their flow properties in production-tableting machines or capsule-filling machines. It is not uncommon that active ingredients are not compatible with certain excipients and some excipients will impede oral absorption of active drug. There is also the problem of taste or light sensitivity, which would require film coating. As each of these problems are approached, the pharmaceutics researcher must use a combination of science and art to be successful. The vast amount of work done in this area usually appears only in internal company reports or in submissions to the Food and Drug Administration (FDA). Once a tablet or capsule formulation is developed, the quality control chemist must develop analytical methods to accurately measure the active drug in the presence of excipients, film coating, or the gelatin capsule. It is also the beginning of long-term stability studies at various temperatures, humidity, and light conditions. If

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there is degradation, it is necessary to develop analytical techniques to measure the degradation products in minute amounts. This process of stability and batch-tobatch control is an ongoing procedure covering many years, For intravenous preparations, the pharmaceutics research group must again be concerned with stability of the dry powder under various temperature, humidity, and light conditions, and also the short-term stability when dissolved in a variety of usual intravenous fluids. Here there is often a problem of foaming or gas formation in the mixing vial, or the ability to obtain a soluble salt with proper flow characteristics. In addition, compatibility with materials used for containers and stoppers sometimes present difficulties that must be addressed, Pediatric formulations pose a particular challenge to the pharmaceutical research group. Taste can be a major problem as with macrolides such as erythromycin. This is a complete science in itself and taste is so subjective that often what is acceptable to an adult may not be pleasing to a child. Also, a taste or flavor may be acceptable in one country but not in another, Satisfactory suspension in combination with good stability is sometimes difficult in pediatric formulation development, Packaging of intravenous antibiotics is always done with the convenience of the hospital pharmacist in mind. Recently this area has had a major improvement with the availability of premixed frozen supplies ready for use by the hospital pharmacist. In addition, piggy-back formulations were developed to reduce the labor necessary at the user level. In both cases, formulation and stability problems had to be solved prior to delivery of the finished product to the user. The delivery of a packaged antimicrobic to the pharmacist is taken as a given, but one should understand the large 0738-1751/86/$0.00 + 2.20

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amount of unpublished work that is necessary to accomplish this end. TOXICOLOGY As with any drug, extensive toxicology studies are conducted and required to ensure patient safety. These studies range from acute administration investigations to repeated dosing in at least two animal species. Also included are studies for mutagenicity, reproduction, and teratology. For antibiotics, special studies are conducted to evaluate nephrotoxicity and ototoxicity. In some cases, a disulfiram-like reaction, hypoprothrombinemia, platelet aggregation inhibition, or testicular effects must be considered, Acute toxicity studies involve two animal species at least, using gradually increasing dosages to find the maximum tolerated dose. These are conducted using at least two routes of administration and an observation period of 14 days. Since most antimicrobial therapy is of short duration, the repeated dose toxicology studies (subacute) usually are limited to 3 to 6 months. A standard approach uses groups of 20 male and 20 female rats treated with placebo or low, mid, and high doses of drug. Treatment is by the route of administration to be used in clinical trials and is given daily, 7 days a week for the full 3 to 6 months of the trials. During this time, complete records of overt effects, mortality, food consumption, body weight, hematology, urinalysis, and serum clinical chemistry are kept. At the end of treatment, surviving animals are sacrificed and an autopsy is performed. Approximately 20 tissue samples are taken from each animal for histopathology evaluation. Assuming all animals survive, this amounts to over 3000 tissues that must be evaluated by veterinary pathologists. It is easy to see why a 3-month study requires 6 to 9 months to produce a final report,

A second nonrodent species, generally the dog or monkey, will usually be included in these studies. Here, the practice is to use four male and four female animals per group with the same parameters measured as listed for rats. A point often not realized is that the job of a toxicologist is to find toxicity and define the "target" organ. This information plays a key role in defining the highest "safe" human dose and the organ system that may be the most sensitive to the test agent. In both of the subacute studies described previously, current practice is to include additional animals at the mid and/or high dose. When the "in life" phase is completed, animals are kept for 1 to 3 months to see if toxicity observed is reversible. Of course, this adds to the time and number of observations needed to complete a study. Some antibiotics have been associated with nephrotoxicity (ie, cephaloradine and aminoglycosides) or ototoxicity (ie, aminoglycosides). Predicting the potential for these side effects requires special studies. For nephrotoxicity, measurement of alanine aminopeptidase excretion in rats or rabbits can be used. In addition, special studies using furosemide and/or gentamicin-primed animals are conducted. Detailed studies on kidney function and tissue histology are also possible. 2 Often, these approaches cannot accurately predict the dose in man that would produce nephrotoxicity. However, they permit a ranking of structurally similar agents for potential nephrotoxicity. Clinical experience with older agents can then place the potential seriousness of this side effect in perspective. Ototoxicity is often evaluated in the guinea pig where techniques to measure the function and pathology of auditory nerve function are available. Again, these studies result in a ranking among similar agents, and clinical experience with older agents helps to place

© 1986 BY ELSEVIER SCIENCE PUBLISHING CO., INC.

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the seriousness of side effect potential in a new agent, In recent years investigators have uncovered other unexpected adverse reactions with antimicrobics. Certain agents are capable of producing a disulfiram-like reaction following consumption of alc o h o l . 3 In addition, bleeding due to hypoprothrombinemia and/or platelet aggregation inhibition has been observed. 4 There is also some evidence that certain agents produce testicular atrophy in neonate animals. In each of these cases, there is strong evidence 5 that the 3-position thiomethyltetrazole sidechain on a cephalosporin structure is responsible. Moxalactam, cefotetan, cefoperazone, and cefamandole are agents with this sidechain. Understanding this particular interaction has lead to development of specific animal studies to evaluate potential problems with newer agents, The recent introduction of newer quinolones has presented the problem of central nervous system side effects and the theoretical problem of more widespread gyrase inhibition. In both cases, the toxicologist is faced with development of new animal or in vitro models to address the potential problem, In this short presentation, it is not possible to describe all of the contributions of the pharmaceutical toxicologist. However, with increasing emphasis being rightfully placed on clinical safety, the toxicologist is required to conduct more studies than before and to interpret the results in a more critical way for extrapolation to man. The study must be conducted according to the Good Laboratory Practice (GLP) regulation from the FDA. This is a good approach to insure proper execution of studies; it does, however, add considerable work, time, and expense in the normal approach to toxicology, Toxicologists are often the "forgotten" people in the development of a new drug. This is perhaps un-

THE ANTIMICROBIC NEWSLETTER, VOLUME 3, NUMBER 9, SEPTEMBER 1986

derstandable since the objective is to have a safe agent. The extensive work in this field results in large volumes of data for submission to the FDA but often it is not published except for a short statement in the Summary Basis of Approval and/or the final package insert, SENSITIVITYTEST SYSTEMS In vitro tests for measuring susceptibility to antimicrobial agents have been carefully standardized. 6-11 The National Committee for Clinical Laboratory Standards (NCCLS) has been instrumental in developing the current level of test standardization. When a new antimicrobial agent is ready to be released for market in the United States, standards for in vitro testing of that agent must be incorporated into appropriate FDA and NCCLS documents. Prior to this time, certain types of data are collected in order to permit the selection of appropriate interpretive standards and quality control guidelines, In the case of simple paper disks, considerable work is needed to establish the appropriate disk mass to produce zones of inhibition of a range usable in a clinical laboratory. This is often initially done with hand-made disks, which then must be confirmed with commercially prepared disks.The usual practice is to construct regression lines of a zone of inhibition versus minimal inhibitory concentration (MIC) for about 500 separate isolates covering the complete spectrum of the new antimicrobial (sensitive, moderately sensitive, and resistant strains), These studies often include one or more control antimicrobials of the same class as the test agent. The bacterial strains used should be obtained from geographical areas throughout the United States and should represent the major routine clinical strains to be treated with the antimicrobial agent, Breakpoints are selected based upon the pharmacokinetics of the

© 1986 BY ELSEVIER SCIENCE PUBLISHING CO., INC.

agent in humans, the ability to separate resistant and susceptible bacterial species, and minimizing of major errors of interpretation (false-susceptible or false-resistant). In addition, disks must be evaluated for content (stability) over time under proper storage conditions. The type of antimicrobial agent usually dictates the selection of test strains or bacteria. If an agent is to be used only for gram-positive bacteria or gram-negative bac° teria, selection is restricted. Broad spectrum antimicrobials such as the "third-generation" cephalosporins require a broader selection of bacterial species. In all cases, there should be a good mixture of sensitive, moderately susceptible, and resistant strains. Appropriate breakpoint criteria are generally selected using modifications of the error-bound method of Metzler and DeHaan.12 After proper disk concentration and breakpoints are selected, extensive studies must be conducted to establish quality control (QC) ranges using the recommended standardized organisms (usually ATCC). This procedure involves the use of three batches of disks (at least two commercially made) and repeated evaluation in 5 to 9 laboratories. At least 50 separate assays are conducted in each laboratory and appropriate statistical methods used to establish the QC range for each ATCC organism. ~ The final result of this work is a single line in the package insert or an NCCLS document table. 6' ~"9 This hardly reflects the amount of work by various laboratories needed to select a valid QC range. The development of MIC breakpoints also reflects a major commitment of work in many laboratoties. Just as for disk test development, solid pharmacokinetic data are needed as a guide for MIC breakpoints. Distribution curves for hundreds and, more likely, thousands of clinical isolates are plotted. These are analyzed by 0738-1751/86/$0.00 + 2.20

THE ANTIMICROBIC NEWSLETFER, VOLUME 3, NUMBER 9, SEPTEMBER 1986

bacterial species and breakpoints are selected so that a major species is not divided and the breakpoints should reflect attainable blood levels. Determining QC limits for MICs follows a procedure similar to that done for disks. Several laboratories conduct repetitive assays on standard organisms (ie, ATCC). These data are then evaluated for mode and range MICs. 8"11 The major use of disk zones of inhibition or MIC determinations is to advise the clinician whether a clinical isolate is sensitive or resistant to a particular antimicrobial agent. However, in vitro effectiveness does not guarantee clinical success in treating a patient, Breakpoints for zone of inhibition and MIC are selected initially by strictly in vitro procedures. It is necessary to review the clinical and bacteriologic success versus the zone of inhibition or MIC of the isolated organism. For this reason, breakpoints are given a tentative status for a new antimicrobial agent and subsequent clinical use and effectiveness must be monitored over time. This procedure not only strengthens the selected breakpoints but can also indicate a change in bacterial susceptibility with long-term use of an agent, Thus, breakpoints for disks and for MICs are carefully selected by the FDA and NCCLS. There is a concerted effort to have the breakpoints and QC ranges in agreement between these two regulatory and advisory groups. To reach this stage, a set of guidelines are being developed for the data necessary for selection of appropriate breakpoints. 11 It is hoped that these guidelines will help to minimize different interpretations of data sets. PHARMACOKINETICS

The field of antimicrobial pharmacokinetics has evolved into a distinct science. Although it is imporrant in all fields of therapy, it is particularly important for antimi0738-1751/86/$0.00 + 2.20

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crobials where drug level (body fluids and tissues) often can be directly related to efficacy, Pharmacokinetic studies are traditionally conducted in healthy adults and it is becoming increasingly evident that the values obtained do not necessarily apply to seriously ill, infected patients. These early data should be taken as indicative but not absolute for all patient classes, As with quality control assays discussed previously, quantitative analytical methods must be developed to measure antimicrobial agent levels in blood, urine, bile, cerebrospinal fluid, and other tissues or fluids. This often presents difficult problems especially with the newer very potent agents. As an example, the MIC may be in the range of 0.05 to 0.1 ~g/mL while the high-pressure liquid chromatography detection limit is 0.7 to 1.0 ~g/mL. The usual approach for pharmacokinetics is to evaluate blood and urine levels after a single dose given by the route and procedure to be used in clinical trials. When the intravenous route is used, caution must be used to give the drug by slow infusion (20 to 30 minutes) rather than a bolus. Quite different results can be obtained, especially in the maximum serum concentration, and this can be misleading since the typical hospital practice is to administer slow infusions. The effect of repeated dosing is also measured to evaluate possible accumulation of drug or changes in pharmacokinetic parameters, Both the single dose and multidose studies are often run on 20 subjects taking multiple samples, It is not uncommon to have several thousand samples for assay to complete this minimal work. In addition to normal subjects, it is critical to evaluate pharmacokinetics in patients with varying degrees of renal failure, patients on hemodialysis, lactating women, etc. The volume of data generated

today in this area is beyond usable limits. Unfortunately, we often speak only of the half-life of an agent and base many decisions o n that parameter. What is probably of greater importance is the time that the MICgo* of a bacterial strain is surpassed by the blood level. This is particularly true for the potent beta-lactam agents introduced in recent years. More attention should also be applied to pharmacokinetics in various patient populations, protein binding, and tissue levels/pharmacokinetics. SUMMARY This presentation has attempted to describe some of the lesser recognized expertise needed to bring an antimicrobial agent to the hands of the physician. It should be remembered that the scale-up chemist, microbiologist, toxicologist, research pharmacist, and pharmacokinetic expert all contribute in an indispensable way in this process. In addition, we should appreciate the time and cost for this development. The scaling-up from milligram quantities to thousands of kilograms often requires investment in new chemical microbiology and production facilities. Preparation for marketing the new agent must begin years in advance. As mentioned previously, a 3month toxicity study can take 6 to 9 months to complete. The cost of a 3-month rat toxicity study is approximately $60,000. If one adds a dog or monkey study, or extends the "in-life" phase to 6 months or 1 year, the costs increase accordingly. Carcinogenicity studies in mice or rats can have dosing periods of 18 months to 2 years and require close to 3 years to finish. The cost of these studies can reach $400,000 each. Development of sensitivity test systems (disks or MICs) is an ongoing procedure that is often com*The concentration(l~g/mL) at which 90% of isolates tested are inhibited.

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THE ANTIMICROBIC NEWSLETTER, VOLUME 3, NUMBER 9, SEPTEMBER 1986

pleted about the time clinical trials are completed. After the basic paper disks and microdilution proce-

Early Antimicrobial D e v e l o p m e n t " and those w h o m a d e it possible.

dures are established, it m a y be necessary for d e v e l o p m e n t of the a u t o m a t e d systems for the new agent. In most cases, these more elaborate systems are not ready at the time of market introduction

REFERENCES 1. Bucourt R, Bormann D, Heymes R, et al: Chemistry of cefotaxime, J Antimicrob Chemother 6 (Suppl. A):63-67, 1980. 2. Silverblatt F: Pathogeneis of nephrotoxicity of cephalosporins and aminoglycosides: A review of current concepts. Rev Infect Dis 4(Suppl):S360-S365, 1982. 3. Platt R: Adverse effects of thirdgeneration cephalosporins. J Antimicrob Chemother 10(Suppl. C):135-140, 19XX. 4. Weitekamp MR, Aber RC: Prolonged bleeding times and bleeding diathesis associated with moxalactam administration. JAMA 249(1):69-71, 1983. 5. Lipsky J: Testicular atrophy in animals--an effect of methylthiotetrazole-containing antibiotics. J Antimicrob Chemother 17:267-268, 1986. 6. National Committee for Clinical Laboratory Standards: Performance standards for the antimicrobial disk susceptibility tests. Third edition Approved standard. NCCLS publication M2-A3. Villanova, PA, NCCLS, 1984. 7. National Committee for Clinical Laboratory Standards: Evaluation

and m a y follow by 1 year or more. We have all heard or viewed the papers at the Interscience Conference on Antimicrobial Agents and C h e m o t h e r a p y and American Society for Microbiology on comp o u n d s that seem to then disappear. In m a n y cases, it is because of unexpected toxicity, uneconomical scale-up costs, or a poor pharmacokinetic profile. In each case, considerable effort was e x p e n d e d before the decision to discontinue development, In the final analysis the value of an antimicrobial rests in its ability to be effective and safe in the clinical situation. W h e n we listen to presentations of clinical results or read articles of clinical efficacy or see the attractive advertisement for a new antimicrobial, we need also to r e m e m b e r the " O t h e r Side of

NEW DRUGS R O N A L D N. J O N E S ORAL CEPHALOSPORINS The antibiotic literature in the last year continues to be d o m i n a t e d by the same few drugs, cefixime (FK027), cefuroxime axetil ester, RO 15-8074, and RO 19-5247 (T2525). Cefuroxime is a well-know parenteral cephalosporin with a second-generation spectrum of activity,~, 2 but as an axetil ester has more c o m p r o m i s e d serum levels. 3 The other three c o m p o u n d s are ester or structural modifications of aminothiazolyl-methoxyimino cephalosporins possessing a spectrum and potency most similar to cefotaxime. ~-6 These drugs also

have lower serum peaks c o m p a r e d with earlier cephalosporins such as cephalexin, cephradine, or even cefaclor.5, 7 Formulation or dosing alterations may produce higher serum concentrations that could allow the incorporations of staphylococci and most streptococci into their clinical spectrum. Acceptable clinical care rates have been reported for u p p e r respiratory infection and uncomplicated urinary tract infections generally caused by gram-negative organisms. ~' ~ LY164846 was a unique oral cephalosporin structure also having a unique spectrum limited to methicillin-susceptible Staphylococcus spp, non-enteric Streptococcus spp, Haemophilus influenzae, Branhamella catarrhalis, and some anaer-

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8.

9.

10.

11.

12.

of Production Lots of Dehydrated Mueller-Hinton Agar. Proposed standard. NCCLS publication M6-P. Villanova, PA, NCCLS, 1986. National Committee for Clinical Laboratory Standards: Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard. NCCLS publication M7-A. Villanova, PA, NCCLS, 1985. National Committee for Clinical Laboratory Standards: Reference agar dilution procedures for antimicrobial susceptibility testing of anaerobic bacteria. Approved standard. NCCLS publication Mll-A. Villanova, PA, NCCLS, 1985. National Committee for Clinical Laboratory Standards: Alternative methods for antimicrobiat testing of anaerobic bacteria. Proposed guideline. NCCLS publication M17-P. Villanova, PA, NCCLS, 1985. National Committee for Clinical Laboratory Standards: Proposed guideline for pharmaceutical and susceptibility test reagent manufacturer. Proposed guideline, NCCLS publication M23-P. Villanova, PA, NCCLS, 1986. Metzler DM, DeHaan RM: Susceptibility tests of anaerobic bacteria: Statistical and clinical considerations. J Infect Dis 130:588-594, 1974.

obes. 1° Unforeseen in vitro and in vivo results forced the withdrawal of this c o m p o u n d . BMY 28100 is a drug having structural features closest to cefadroxil (7' position) and cefixime (3' position), but a spectrum very similar to cefaclor.H Phase II and III studies of this oral agent are currently pending. CGP 19,359 and FK089 are still in very early d e v e l o p m e n t with little published data as to applicable spectrums of activity or results of human pharmacokinetics. PARENTERAL CEPHALOSPORINS The n e w e r parenteral cephalosporins have a wide variety of spectra ranging from the second-generation true cephalosporins and cephamycins to those 3' pyridine0738-1751/86/$0.00 + 2.20