(PMSB/ELD Notification No. 743 dated August 25, 1998) Regarding Guidelines for the Clinical Evaluation of Antibacterial Drugs To: Directors-General Health Department (Bureau) Prefectural Governments From: Director Evaluation and Licensing Division Pharmaceutical and Medical Safety Bureau Ministry of Health and Welfare Concerning the captioned subject, we request that you inform the industries concerned under your administrative control, regarding the standard evaluation method for clinical trials of antibacterial drugs to be carried out when planning to submit an application for approval of the manufacturing (or import) of those drugs as summarised in an attached paper. Furthermore, as a matter of course, you need not always abide by the standard evaluation method disclosed herein if you have developed and designed other methods based on rational grounds that reflect scientific progress. Guidelines for the Clinical Evaluation of Antibacterial Drugs 1 Introduction Unlike drugs used in other areas, antibacterial drugs operate mainly on general bacteria (excluding acid-fact bacteria, true fungi, and viruses) that may cause infections, rather than on hosts. Developed antibacterial drugs cannot always be easily clinically evaluated because relationships between those antibacterial drugs with target micro-organisms and hosts are complicated. The clinical trials of antibacterial drugs have been carried out according to the "Investigation into Standardising the Adaptability of Antibacterial Drugs" presented in May 1982. There was a revision to the document presented in 1987 to solve the problems with the execution of clinical trials. However, unfortunately, this revision from 1987 is still being used with no changes or modifications. In the USA and Europe, guidelines for the clinical evaluation of antibacterial drugs were announced (Beam T.R., Gilbert D.N. and Kunin C.M. (1992), General Guidelines for the Clinical Evaluation of Anti-Infective Drug Products. Clin. Infect. Dis. 15 (S-1), S 5-S32: European Society for Clinical Microbiology and Infectious Diseases (1993), European Guidelines for the Clinical Evaluation of Anti-Infective Drug Products). Furthermore, some people have been arguing recently that clinical evaluations should be harmonised. Under such circumstances, the problems accompanying the development of new drugs based on the past guideline should be solved so that antibacterial drugs may be developed and designed more smoothly in Japan. New "guidelines for the clinical evaluation of antibacterial drugs" are, therefore, proposed herein with a view towards harmonising such clinical evaluations with the guidelines in countries other than Japan. In Japan, a high-level insurance-based medical treatment system permeates, and basic concepts on how clinical trials should be carried out differ from those in the USA and Europe. Thus, the execution of clinical trials in Japan will be accompanied with many difficulties. In addition, unlike drugs used in other areas, antibacterial drugs can be predicted in terms of effectiveness from the antibacterial force and dynamic factors of target micro-organisms. This fact is known from the past antibacterial drug development process. In light of these elements, testing methods and case count applied to antibacterial drugs in Japan are partially different from those for drugs in other areas and from guidelines for antibacterial drugs adopted in the USA and Europe. The guidelines disclosed herein generally take into account a wide range of antibacterial drugs. Some antibacterial drugs cannot be readily tested comparatively because they do not target rare diseases, there are no control drugs, or the antibacterial spectrum is narrow. Moreover, some antibacterial drugs cannot be applied to local diseases. When such antibacterial drugs are developed, a clinical program should be created according to these guidelines so that target effectiveness and other effects may be evaluated objectively. Some of the contents of these guidelines may have to be revised and amended according to opinions and comments of those who deal with this subject. Standards focusing on the implementation of a suitable clinical evaluation of antibacterial drugs should, however, be developed as soon as possible. Some "items to be taken into account for the clinical evaluation of antibacterial drugs" and items on clinical trials of respiratory organs and children have been discussed separately. Those items are covered in the Schedule. Furthermore, since "antibacterial drugs for post-operation infections" are expected to be concretely developed, those drugs are covered in a separate proposal from these guidelines for future reference. 2 Testing Process The effectiveness and safety of an antibacterial drug to be developed must be in the end checked by clinical trial. Before a clinical trial, the effectiveness and safety of an antibacterial drug for humans must be inspected through a non-clinical trial. For this inspection, antibacterial resistance should be tested, as well as having a toxicity test, a pharmaceutical test and an anti-infective test performed using animals. Through a clinical trial, characteristics of an antibacterial drug to be developed as a medicine must be clearly understood, with the clinical trial designed according to those characteristics. For example, characteristics of the antibacterial drug may possibly be as follows. (a) It has wide antibacterial spectra, and can be applied to a cryptogenic heavy infection. (b) It has narrow antibacterial spectra, and operates selectively on causal bacteria, having little impact on a resident bacteria stock. (c) It shows high antibacterial effects on such special bacteria that are highly resistant to various medicines as MRSA and pyocyanic bacteria. (d) It produces few fast bacteria. (e) It has high safety, and can be applied readily to children and aged people. (f) It can be given readily. Its effects last for a long period despite a low administration count and dosage. (g) It is characterised by excellent pharmacokinetics. (h) It is excellent in terms of medical economy. A clinical trial must be performed in compliance with regulations related to GCP, along with other items. 1. Basic test (1) Bacteriological examination Bacteriological examination is important to determine the characteristics of an antibacterial drug to be developed, and to determine the diseases and bacteria to which the drug can be applied. For antibacterial drugs, the following items must be fully investigated. a Antibacterial effects in vitro As for causal bacteria separated frequently to which a drug will be applied under approval, measure the minimal inhibitory concentration (MIC) of the drug for the target bacteria (type strain and fresh separate strain). This measurement should conform to the standard method specified by the Chemical Treatment Association (Chemotherapy, 29, 76-79 (1981), ibid 38, 103-105 (1990)). In addition, examine the minimal biocidal concentration of the drug (MBC), if necessary. As a rule, the quantity of bacteria to be inoculated is 106 colony forming unit (CFU)/ml. For bacteria and drugs for which MIC reportedly varies empirically with the quantity of inoculated bacteria, however, measurement also should be made under the quantity of inoculated bacteria of 103 CFU/ml. Record the quantity of applied bacteria liquid used for testing. (For agar, the bacteria quantity per spot can also be used. For the fine liquid method, the bacteria quantity per well can also be used.) For bacteria types including Chlamydia and Legionella for which separate measurement methods are defined, follow those defined measurement methods. b Post-antibiotic effects (PAE) in vitro If PAEs observed in the drug to be developed are regarded as being clinically available, clarify those effects. c Function mechanism Examine the effects of an antibacterial drug on penicillin-linked proteins (PBPs), DNA gyrase, ribosome, etc.. d Resistance acquisition mechanism Perform a test on resistance acquisition, and, in addition, investigate into the resistance mechanism of any already existing fast bacteria. e Intracellular transition For antibacterial drugs that target cytozoic bacteria, examine intracellular transition. (2) Test using an animal Records on animal experiments preceding a clinical trial provide valuable data for predicting the effectiveness, safety and pharmacokinetics of an antibacterial drug to be developed. Carry out the following basic tests using various kinds of animals. a Toxicity test and general pharmacological test b Pharmacokinetic test c Pharmaceutically dynamic test (including PAE) d Anti-infective treatment (control) test e Drug interaction (when such interaction may be caused due to structure and drug metabolism) Clearly describe the method for measuring drug concentration. When declaring the characteristics of the intracorporeal dynamics of the drug to be developed, as a rule, carry out the same measurement on the control drug as well. Following these records, predict bacteria types and diseases to which the drug can be applied, clinical effectiveness, and side effects. If clear characteristics can be expected in comparison with existing antibacterial drugs, the following clinical trial can be undertaken. 2 Clinical trial The effectiveness of an antibacterial drug can possibly be analogised relatively readily from existing antibacterial drugs in terms of pharmacokinetics and antibacterial effects on the target micro-organism in comparison with other drugs. Naturally, a clinical trial must be carried out in compliance with GCP and according to a predefined clinical trial program. The clinical trial for a patient following Phase II is classified into: - test for examining and checking dosage (to fix a recommended clinical dosage for a typical infection); - comparative test for proving effectiveness and medical advantages; and - general clinical trial for determining diseases and bacteria to which the drug can be applied. Such type of clinical trial focuses on checking effectiveness and safety, on examining dosage, administration and the period of administration, and on verifying characteristics of the antibacterial drug to be developed. (Please see Schedule 1, "Items to be taken into account for clinical evaluation of antibacterial drugs.") (1) Phase I studies These studies aim at understanding the range of clinical safety quantity for a healthy person, pharmacokinetics such as absorption and excretion, and effects on resident bacteria stocks. As a rule, these studies target healthy persons and maintain safety as a basic element. As such, if the antibacterial drug to be developed may operate toxically on a healthy person, a patient to be given the antibacterial drug may be adopted as the subject instead. Because grounds for predicting pharmacokinetics and human safety from data on animal experiments have not been established, the data must be carefully inspected before proceeding to the next step. After having checked for safety on a single dose, carefully examine a repeat dose. It is advisable that the initial dosage in a single dose test be lower than, but near, a clinically estimated dosage. Normally, however, this initial dosage is set at 1/60 of non-toxic quantity for the most susceptible animal in a repeat toxicity test to provide for safety. The dosage is increased by double or geometrically. The measure for the highest dosage is twice the clinically estimated dosage if there are no problems with safety. The single dose test focuses on investigating into dosage, humoral drug concentration, side effects, and abnormal variations in laboratory values and their dose response relationships. The dosage for a repeat dose test is the clinically estimated maximum dosage. The period of administration should not be determined uniformly, and is, as a rule, the period in which the concentration of a drug in blood has reached a steady state and can be verified. Normally, this concentration reaches a steady state in five times the half-life. The repeat dose test is performed to examine humoral drug concentration, side effects and abnormal variations in laboratory values, as well as to investigate into effects on enterobacteria stocks. This investigation is carried out for a drug which considerably affects enterobacteria stocks. If the clinically estimated dosage is higher than the maximum dosage for Phase I studies as a result of the Phase II studies, an additional test may be performed in Phase I. The following provides the method for carrying out Phase I studies, as well as the conditions required for the tester responsible for these studies, and for those institutions. a Medical institution in which Phase I studies are carried out This institution must have equipment and staff members that can cope with emergency cases, such as shock. b Investigator and physician sharing clinical investigation The investigator and physician must be familiar with clinical pharmacology and clinical trials. c Items to be tested The items required for checking safety are examined in light of similar drugs and results of animal experiments. d Post-inspection Post-inspection is carried out 7 to 10 days after the end of administration. If any abnormalities are found, follow-up is performed until a normal state is reached. In addition, if the half-life is shorter or longer, a separate suitable period for examination should be set. e Others If pharmacokinetics may possibly be changed due to diet or antacid, a test for checking this change is conducted. (2) Phase II studies Phase II studies are broken down into early Phase II studies and late Phase II studies. a Early Phase II studies Early Phase II studies focus mainly on tentatively testing for safety, effectiveness and pharmacokinetics of an antibacterial drug to be applied to a patient who suffers from an infection. Since Phase II studies are performed with a view towards determining clinical characteristics of an antibacterial drug to be developed, the number of cases to be set varies with the purpose. Particularly, in early Phase II studies, it is important to set purposes for a small number of cases. When a specified number of cases are reached, evaluation should be done to go on to the following step. Early Phase II studies precede a test for examining dosage, targeting respiratory infections and urinary tract infections to be tested to check dosage. In this stage, exclude patients who suffer from a critical basic disease that may make it difficult to check safety and clinical effects or who take a number of other drugs. Pharmacological and pharmacokinetic inspection intends to identify some measures on a clinically estimated dosage and safety in comparison with test results on healthy adults. b Late Phase II studies The late Phase II studies focus mainly on: - examining the clinically recommended dosage tentatively fixed in the early Phase II studies; - check effectiveness and safety for diseases other than respiratory infections and urinary tract infections; and - investigate pharmacokinetics. Set blood collection time and other factors according to characteristics of dynamics in vivo of the drug. The late Phase II studies precede Phase III comparative studies, being carried out to fix a dose method and period of administration. In this stage as well, exclude, as a rule, patients who suffer from a critical basic disease that may make it difficult to check safety and clinical effects or who take a number of other drugs. In addition, it is important to understand in detail the clinical process after a patient has been given an antibacterial drug. This understanding enables the discovery of the end point on when what item is to be observed to prove features of an antibacterial drug to be developed. The following provides possible features of the antibacterial drug. (a) Period in which a case improves as a result of clinical inspection (b) Compliance (c) Effectiveness in terms of antibacterial force and spectra (Bacterial removal rate and speed, effects on an infection whose cause in unknown, resistance acquisition rate, effects on fast bacteria, characteristics of bacteria appearing after administration, and other factors) (d) Safety (e) Economic efficiency For a clinical trial that targets infections due to bacteria, it is not morally permitted to apply a placebo group. The antibacterial drug operates mainly on micro-organisms causing infections, and the clinical dosage can be estimated from antibacterial effects and pharmacokinetics in comparison with existing antibacterial drugs. A test for examining and checking dosage is, therefore, carried out instead of a test for setting three factors of a low dosage, a clinically estimated dosage and a high dosage that are required for other drug groups. The test for examining and checking dosage of an antibacterial drug aims mainly at identifying a clinically recommended dosage and at finding out the end point (items to be evaluated). One possible method for this test is to compare the potential clinically recommended dosage gained in the early Phase II studies with the clinically estimated maximum dosage (normally twice the clinically recommended dosage). The other possible method is to compare three groups which include the control drug with one another to find out characteristics of the antibacterial drug to be developed. In this case, not only effectiveness and safety but also bacteriological effects are important points. The target diseases suitable for the test for examining and checking dosage are: - urinary tract infection that is often encountered and whose causal bacteria can be detected relatively readily; and - respiratory infection that is often encountered in the clinical field although its causal bacteria cannot be detected readily. In this case, the possible control drug is an antibacterial drug regarded as being a standard drug in the field, or an antibacterial drug that can potentially be compared with an antibacterial drug to be developed in terms of characteristics. The general clinical trial in Phase II (test targeting patients other than those who suffer from a critical basic disease or who take a number of other drugs), and the test for examining and checking dosage are carried out to determine clinical advantages of an antibacterial drug to be developed. If the antibacterial drug is considered as possibly contributing to the treatment of an infection, Phase III studies can be undertaken. (3) Phase III studies Phase III studies are mainly classified into three elements. a Major comparative test on an infection This major comparative test on an infection is carried out to check that the antibacterial drug to be developed provides effects equal to or greater than those of existing antibacterial drug and that there are no safety problems. The potential target diseases are respiratory infection and complicated urinary tract infection. These two diseases have been selected due to the following reasons. (a) The patients suffer from organic or functional faults to some degree, and significant individual differences in humoral transition of an antibacterial drug are found. (b) Respiratory infection is due to bacteria resident in various kinds of Gram-positive and -negative epipharynx. On the other hand, urinary tract infection is often caused by bacteria resident in intestines, pyocyanic bacteria and other Gram-negative bacteria not fermented by grape sugar. The bacteria which cause these diseases include many of the clinically important bacteria. (c) Both diseases are subject to bacteria alternation phenomena. (d) A large number of clinical cases are encountered. As a rule, a randomised double blind experiment is adopted as the method for the comparative test. The following gives requirements for the institution responsible for performing the test. (a) Experts on the infection and chemical treatment work on a full-time basis. (b) Emergency measures can be taken. Care should be taken so that an imbalance between institutions in terms of case count are not generated. In order to minimise differences between institutions, objective diagnostic standards, clinical effect judgement standards, side effect judgement standards, and other required standards must be set wherever possible. Effectiveness and safety may be estimated from records of a general clinical trial without performing the comparative test on other diseases if: - it is proved by comparative test on the major two diseases that the effectiveness of the antibacterial drug is equal to or greater than that of the control drug; - it is checked that there are no safety problems; or - characteristics of the antibacterial drug to be developed are observed. b Major comparative test on a disease other than the infection The second comparative test aims at diseases other than the infection. This test is performed to check characteristics of the antibacterial drug to be developed, as well as to verify the effectiveness and safety of the drug when the target disease, bacteria and other items are limited, and when the major two comparative tests (covered in a) are not performed. c General clinical trial The third test is the general clinical trial for fixing the diseases and bacteria to which the drug is to be applied. This test focuses on obtaining additional information on effectiveness and safety through extending the target (host state and disease). (a) Examination of pharmacokinetics, and verification of effectiveness and safety on the patient who suffers from respiratory infection or urinary tract infection, as well as from a critical basic disease or complication not subject to the comparative test (excluding the patient who influences effect judgement). (b) Examination of pharmacokinetics, and inspection of effectiveness and safety on the disease for which the comparative test has not been carried out. (c) Examination of pharmacokinetics, and verification of effectiveness and safety on special groups including children and aged people. (Please see Chapter 3, Testing on Special Subject Groups.) Phase III studies also investigate into, wherever possible, pharmacokinetics on a patient who suffers from renal or liver trouble in addition to above a, b and c according to dehydration or the path of antibacterial drug excretion. In particular, to measure the concentration of the drug in blood and humour, MIC of causal bacteria is important to understand the characteristics of the antibacterial drug to be developed. (4) Survey after introduction into the market (Phase IV studies) A survey is carried out after approval and introduction into the market. This test intends to check safety and effectiveness on a wider range of patients. Should certain points not be clarified before approval, those points are also examined at this time (clinical trial after approval). Moreover, interactions due to parallel use of drugs are examined. Investigation on effectiveness after introduction into the market, on whether bacteria increase, and on safety are required in comparison with data and information recorded when the drug was approved. Therefore, effectiveness and safety should be checked in light of records of a clinical trial for development and of systematised judgement standards. In addition, the above investigation requires records based on enough bacteriological inspection that can be compared with those gained for development. For examination on drug susceptibility (fast bacteria), data measured in a medical institution having sufficient knowledge and skill provides reference for the typical appropriate bacteria separated from different regions. 3 Testing on Special Subject Groups Special subjects include women who can conceive, pregnant women, neonates, premature babies, children and aged people. 1 Women who can conceive Adult women, except those infertile due to surgical operation and those who closed menstruation more than one year prior, who can conceive. Women who can conceive may take part in a clinical trial after it is verified by a toxicity against procreation test that the antibacterial drug to be developed does not adversely affect procreation. For the clinical trial, women who wish to conceive during its period should be excluded. Furthermore, for women who would like to take part in a clinical trial, the time from the last menstruation should be calculated. In addition, a pregnancy test should be carried out if needed, with instructions for contraception taken into account. 2 Paediatric area Children can be broken down into neonates, premature babies (less than four weeks after they were born), and children (from children four or more weeks after they were born to children aged less than 16). (1) Children (from children four or more weeks after they were born to children aged less than 16) As a rule, a paediatric drug is subjected to a paediatric test in light of safety after its application for adults has been approved. Moreover, test of the drug for safety on the part of children is started only after safety on adults has been verified. For the antibacterial drug, however, this procedure apparently delays the time when its development is completed. For antibacterial drugs that must be urgently developed (including drugs for MRSA and drugs for fast Klebsiella preumoniae), or for which safety is ensured using similar drugs (including β-lactam drugs and macrolide drugs), the test can be started before their safety is verified by a survey after introduction. The requirement on this start is that it is verified that different reactions from past similar drugs are not observed. (Please see Schedule 2, "Clinical Trial in the Paediatric Area.") (2) When a clinical trial on children is started The time when such clinical trial is started is classified into the following three groups, depending on the antibacterial drug. a Antibacterial drugs that should be developed rapidly in the paediatric area, as well as caused by an increase in fast bacteria. According to judgement by the company from test records on the adult area, clinical trials on these antibacterial drugs are started when effectiveness in the adult area is forecast in compliance with comments of a paediatric expert (for example, in the second half period of late Phase II studies for an adult). b Antibacterial drugs for which safety on children can be predicted from clinical experiences in the paediatric area using a past similar antibacterial drug, clinical trial records in the adult area, records of toxicity tests on young animals, and other records. Clinical trials on these antibacterial drugs are started after it is verified that reactions different from those to a past similar drug are not observed in terms of effectiveness and safety in the adult area (after the start of Phase III studies for an adult). c Antibacterial drugs for which safety on children is not established according to records of clinical trials on the adult area using a past similar antibacterial drug, records of young animal toxicity tests, and other records. As a rule, validity of clinical development on application to children is checked after use for an adult is approved according to the results of re-examination and study reports in countries other than Japan. (3) Neonates and premature babies (less than four weeks after birth) Neonates and premature babies are more often subject to fatal infections than older infants. In addition, additional chemical treatments are required, while their pharmacokinetics is different from that of children and drugs tend to accumulate due to delayed excretion. A separate subsequent test is, therefore, started, if needed, after effectiveness and safety on children are verified. 3 Aged people Aged people show various pathology because of a number of basic diseases and organic trouble due to age. Moreover, significant individual differences are found. Those people are subject to infections originating in various attenuated bacteria and fast bacteria, and have high expectation for new antibacterial drugs. Since these drugs will be given to a wide range of older people after their introduction into the market, effectiveness and safety on older people must be verified before such introduction. On the other hand, aged people are somewhat different from younger people in terms of acceptability of drugs. When agreement with a clinical trial is obtained, particular care should be taken in respect to safety and morality. (1) Classifications of aged people Aged people can be classified into the following three groups according to the pharmacokinetics of antibacterial drugs and pathology of infections. a People aged 65 to 74: Although the pathology of an infection, pharmacokinetics, and other factors are affected by age, their degree is relatively slight and, therefore, impacts of age need not be significantly taken into account concerning the dosage of an antibacterial drug. Or rather, cancer and other diseases have some significant impact. Thus, a testing plan should be designed in light of basic diseases. b People aged 75 to 79: Since these people more often suffer from organic trouble resulting from the impacts of age, and renal function may be lower than that of younger people, particular care should be taken. A decline in liver function due to age may not cause significant problems with the administration of an antibacterial drug for a short period. Because some of the operations of an antibacterial drug being developed on humans is unknown, however, careful measures should be taken. The present Japanese average life falls in this age group, which is regarded as being the standard aged people group. c People aged 80 or more: These people are significantly affected by age, and the pathology of an infection is considerably different from the pathology in younger people. (2) Clinical trials for aged people by age group The following rough standards are applied. a Phase II studies Early Phase II studies target people aged 65 to 74 who do not suffer from a critical basic disease and take few other drugs. If early Phase II studies indicate effectiveness and safety on aged people, late Phase II studies focus on people aged 65 to79 who do not suffer from a critical basic disease and take few other drugs. b Phase III studies The comparative test complies with the late Phase II studies. For the test in which a high dosage of a control drug is given to the subject, however, Phase III studies target people aged 65 to 74 in light of the hazard of excessive administration. The general clinical trial aims at all age groups including people aged 80 or more. In this case, a test on a relatively low dosage is first performed according to judgement by the principal investigator in light of records of the late Phase II studies and the pathology of the patient. Available records are stratified according to age to fix the standard dosage for each age group. On the basis of judgement by the principal investigator, the start dosage should be described in advance in a protocol in light of pathology. c Pharmacokinetic studies Although pharmacokinetic studies should be executed for each age group, this execution may be accompanied by some difficulties. In this case, records on people aged 65 to 74 cannot represent the pharmacokinetics of more aged people. Thus, records on people aged 75 to 79 must also be accumulated. Useful information can be gained by screening the pharmacokinetics of a population covered in guidelines for aged people even if a sufficient number of samples are not obtained from one subject. 4 Methods of Clinical Trials A clinical trial must be carried out in compliance with GCP, according to a protocol. 1 Uniform evaluation For the clinical trials following the Phase II in which many institutions take part, the following standards should be negotiated in advance for uniform evaluation wherever possible. Describe these standards in a protocol. (1) Diagnostic standards for a bacterial infection (2) Standards for judging the seriousness of an infection (3) Standards for judging clinical effects (4) Standards for fixing causal bacteria and judging bacteriological effects (5) Standards for handling side effects and abnormal laboratory values 2 Selection standards To clearly define a subject group to be tested, clearly describe selection standards for a target disease, the seriousness of an infection, age, sex, the state of pregnancy, records of hospitalisation and outpatients, and other items in a protocol. Check for correctness, then carry out the test. 3 Exclusion standards To develop exclusion standards and to fix standards for their handling, clearly fill out a protocol according to various assumed states for taking proper measures. It is important to preset standards for cases for which safety is to be examined. If a case to be excluded is encountered during execution of the test, administration must be immediately suspended to select another suitable antibacterial drug. The exclusion standards cover the following items, but should be fixed according to features of an antibacterial drug to be developed. Moreover, for each test, exclusion standards should be described in a protocol. (1) Patient who has suffered from critical side effects that possibly result from an antibacterial drug for the same system as an antibacterial drug to be developed (or the control drug used for a comparative test) (2) Patient who also takes a drug which reportedly adversely affects the pharmacokinetics of an antibacterial drug to be developed (control drug for a comparative test), or reportedly significantly amplifies the hazardousness caused by the toxicity of the antibacterial drug (3) Patient who apparently suffers from infection due to bacteria not susceptible to an antibacterial drug to be developed (control drug for the comparative test) and on whom no effects can possibly be brought out (4) Patient who may suffer from prognostic failure or who suffers from a critical or progressive basic disease or complicated disease and for whom the test cannot possibly be safely carried out or effect cannot possibly be judged readily (5) Patient who requires parallel administration of other antibacterial drugs (6) Patient whose case is improving by applying another antibacterial drug or whose case progress is unknown (excluding a patient having a switch treatment where an injection is followed by an oral drug to be tested) (7) Pregnant woman or possibly pregnant woman, and woman having a baby who requires lactation (8) Patient who has taken part in investigating the same antibacterial drug to be developed (9) Patient who took part in an investigation in the past half year 4 Administration of an antibacterial drug to be developed The following items must be clearly defined in a protocol. (1) Administration route (2) Type of a drug to be administered (3) Quantity of a drug to be administered, and administration program (4) Period of administration (5) Rules for suspending administration The minimum and maximum periods of administration must be specified. Administering an antibacterial drug for a long period may affect enteric bacteria stocks and generate side effects. Administering an antibacterial drug without a clear perspective after effects of treatment have been observed must, therefore, be avoided. 5 Final evaluation The antibacterial drug operates on micro-organisms that parasitize humans. To securely identify causal bacteria and to observe changes in the number of causal bacteria and in the accompanying clinical case are, therefore, important. The causal bacteria may, however, be fixed from the clinical case in some diseases for which it is difficult to identify such bacteria. It is crucial to design a clinical trial that enables the understanding of characteristics of an antibacterial drug to be developed, to come up with a method for judging those characteristics, and to prove that trial records are valid. 6 Safety It is vital to compare effects of an antibacterial drug to be developed with its risk. Therefore, to detect side effects in each test, a method for clinical evaluation or laboratory value evaluation must be clearly defined in each protocol. Such number of patients (total number of cases: 1,500) as is required for detecting side effects with an appearance rate of 0.2% should be examined to collect treatment records. Some drugs that provide narrower antibacterial spectra, and other drugs do not always require 1,500 cases. The clinical investigator must record all harmful events detected during investigation in a case report. It is difficult to detect side effects that rarely occur. The clinical investigator should, therefore, provide fully against unexpected side effects. (1) Observation of side effects by clinical inspection: Inspection such as standard haematological inspection, biochemical inspection (focusing on transaminase, urea nitrogen, creatinine, electrolyte and other compounds), and uroscopy (aiming at protein, sugar and other compounds) must be carried out. Other inspection may be included according to the results of a non-clinical toxicity test and the chemical analogy with similar antibacterial drugs having a known toxicity profile. (2) Levels of side effects: Three levels of slight, medium and serious side effects are used for judgement. Clearly define judgement standards for those levels in a protocol. (3) Causal relationships with a study drug: When causal relationships are judged, temporal relationships between administration and occurrence of symptom, a period until disappearance, the process of a side effect, the state of the patient, anamnesis, other drugs used together, and other factors must be taken into account. For example, the causal relationships are classified as follows. (a) Obvious relationship (b) Potential relationship (c) Possible relationship (d) No potential relationship (e) No relationship (4) Examination after introduction into the market (Phase IV studies): Less frequently side effects may not be defected in thousands of patients who are tested by a clinical trial. Even if a clinical trial indicates that some side effects may occur less frequently, more patients must be tested to the check characteristics of their seriousness, the frequency of occurrence, relationships with other drugs administered together, and other factors through examination after introduction into the market. 5 Determination of Bacteria Types, Groups and Genera to which a Drug Can Be Applied It is well known that the main causal bacteria of an infection may change with age and that a new bacteria type becomes clinically important. The target bacteria type for examining antibacterial spectra must be selected according to age trends in light of a new bacteria name. The order in which bacteria names are displayed is as shown in Table 1 to maintain uniformity. Bacteria types, groups and genera should be totally determined according to the following records and other elements. (1) Antibacterial spectra based on a MIC distribution on the standard bacteria stock and various bacteria stocks separated for five years from the start of the test (2) Records of infection treatment (control) on an infection experiment model (3) Pharmacokinetics of an antibacterial drug to be developed in humans (4) Antibacterial force for causal bacteria identified by an executed clinical trial, and bacteria removal effects and clinical effects Even if the control drug for a comparative test cannot be applied to a bacteria type, the drug sample is regarded as being applicable to the bacteria type when effectiveness can be predicted from antibacterial force, general clinical trial records, and bacteriological effects. For bacteria types separated less frequently (2 to 3 percent) through a clinical trial, the drug sample is judged to be applicable to those bacterial types according to a small number of clinical records if effectiveness can be predicted from antibacterial force and pharmacokinetics. For bacterial types described in Table 2, it is very difficult to acquire clinical cases. Whether the drug sample is applicable to those bacteria types is, therefore, judged from antibacterial force, pharmacokinetics and effectiveness on similar diseases. It is advisable to cover some clinical examples. 6 Determination of Applicability to Various Types of Infections Some antibacterial drugs have been proven by comparative tests to be at least equally effective on a major infection in comparison with the control drug, and to be accompanied by no safety problems. Some other antibacterial drugs have been proven to be particular applicable to a major infection. For those antibacterial drugs, diseases to which they can be applied should be determined from antibacterial force for frequently causal bacteria, pharmacokinetics, and general clinical trial records. Antibacterial drugs for which no comparative tests are carried out or that do not meet the above requirements require comparative tests for each of the infection areas to be covered, except for special cases. Antibacterial drugs of the same type that provide the same effectiveness are classified according to the purposes of use as follows. (1) Injection antibacterial drugs that have wide antibacterial spectra and may also be effectively applied to infections of patients who suffer from complicated basic diseases (2) Oral antibacterial drugs that may be effectively applied to slight or medium infections from pharmacokinetics such as concentration in blood In the past, only antibacterial drugs that had been proven to be applicable in the range of investigation by development applicants have been approved. Such approval method is, however, accompanied by the difficulty that some antibacterial drugs have not been approved due to an insufficient number of cases although effect is theoretically expected. This has resulted in the imbalance among antibacterial drugs of the same type and effectiveness in terms of diseases to which they can be applied, and troubled the site of medical treatment. Concerning antibacterial drugs that are classified into (1) and (2) above, therefore, the diseases to which those drugs must be able to apply to have been defined for integrity in terms of applicability. Those diseases must be examined on the basis of the number of cases covered at least in Table 3, which provides the number of cases and the diseases to which antibacterial drugs in wide sense must be able to apply to. When an application for approval is made on the basis of investigational records that do not satisfy the above requirements, the availability of the drug must be proved separately. The diseases to which the antibacterial drugs of the same type and effectiveness are expected to be applied according to basic examination but may not be applied in terms of MIC and pharmacokinetics are excluded. If a clinical trial has been carried out on a specific disease other than the essential disease, the diseases to which the antibacterial drug can be applied may be added according to examination records covering the number of cases shown in the remarks column in Table 3. The number of cases given here is such that the development of isolates (regarded as being causal bacteria) has been examined. Since cases for which causal bacteria have not been actually detected are also included, examination is required according to two to five times the number of cases. Although major records are concerned with ordinary dosage, a separate dosage should be determined in light of safety if many records deal with a large dosage like pyogenic meningitis. 1 Sepsis and infectious endocarditis If effectiveness and safety have been proved through a major comparative test, indications should be fixed according to general clinical trial records that cover a specified number or more number of cases. For an effective case for which the causal bacteria have been detected, the indication may be determined in light of MIC (MBC) of detected bacteria, an antibacterial drug dosage, concentration in blood, side effects, and other factors. Because the period of administration for this disease may exceed four weeks, side effects and abnormal laboratory values must be checked on the basis of examples of long-term administration. While injections are applicable to these diseases, those injections may be replaced by oral drugs after the case has moderated. Whether such oral drugs are applicable should be determined in light of antibacterial force and pharmacokinetics. (In this case as well, the major comparative test must provide equivalent or higher records in comparison with the control drug.) 2 Infections in the dermatological area If effectiveness and safety are proved through the major comparative test, whether the drug is applicable can be determined according to antibacterial force, pharmacokinetics, and a specified number or more number of cases for the general clinical trial. For some of antibacterial drugs that are applicable to this disease group, it may be difficult to carry out the above comparative test because they focus only on Gram-positive bacteria or specific bacteria. In this case, a comparative test is carried out on infections in the dermatological area to determine whether those drugs are applicable in light of antibacterial force and pharmacokinetics. Acne is not an infection, but the antibacterial drug is expected to reduce the number of propionibacteria acnes, contributing to medical treatment. When the antibacterial drug is applied to propionibacteria acnes, a clinical trial should be carried out to fix the applicability. 3 Infections in the surgical area The first requirement is that effectiveness and safety must be proved through a major comparative test. Then, whether the drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. The indications include (1) cholecystitis, (2) cholangitis, and (3) endoceliac tumours classified in groups 7 and 11. They also include so called catheter sepsis in an example of central venous catheter insertion to be classified into sepsis in group 1. In some cases, a major comparative test may have not been carried out, or effectiveness or safety may have not been verified. In those cases, effectiveness and safety must be checked for through a comparative test on peritonitis or periproctitis as an infection in the surgical area. Then, whether the drug is applicable should be determined according to antibacterial force on bacteria with a high frequency as causal bacteria, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. (Please see Schedule 3, "Surgical Infections.") Issues with applicability to so called postoperative infection prevention are under examination, and new requirements will be added after the end of the examination. Policies for those issues are attached as a proposal separate from these guidelines for future reference. (Please see "Antibacterial drugs for preventing postoperative and perioperative infections.") 4 Infections in the orthopaedic area The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, whether the drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. Issues with applicability to so called postoperative infection prevention are under examination, and new requirements will be added after the end of the examination. Policies for those issues are attached as a proposal separate from these guidelines for future reference. (Please see "Antibacterial drugs for preventing postoperative and perioperative infections.") 5 Infections in respiratory organs The first requirement is that effectiveness and safety must be checked for through a comparative test on infections in respiratory organs. Then, whether the drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the indications include the acute upper airway infection, peritonsillar abscess, laryngopharyngitis, laryngopharynx tumours (including retropharyngeal abscess), pneumonia, lung pyopoiesis, empyema, and secondary infections (or acute exacerbation) of chronic respiratory diseases (such as chronic bronchitis, diffuse panbronchiolitis, bronchiectasis, lung emphysema, fibroid lung, and bronchitic asthma). If a comparative test only on pneumonia has been carried out from the antibacterial spectra of an antibacterial drug to be developed, the above disease group other than the secondary infections of the chronic respiratory disease is also considered as being indications. Whether the drug is applicable should be determined according to antibacterial force on the major causal bacteria in each disease group, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. A test for pneumonia due to mycoplasma, Chlamydia or other specific causal bacteria should also be based on the above criteria. In this case, however, only specific lung infections should be taken into account in light of antibacterial spectra. If a comparative test only on tonsillitis is carried out, effectiveness and safety must be checked for through the comparative test. In this case, indications should be fixed according to antibacterial force on causal bacteria with a high frequency of tonsillitis, pharynx, laryngopharyngitis or acute bronchitis, pharmacokinetics, a specified number or more number of causes, and other general clinical trial records. For pneumonia among infections of the respiratory organs, it is often difficult to identify the causal bacteria. Various types of approaches must be made to make every effort to determine or identify the causal bacteria. For chronic airway infection, airway discharges are sampled relatively readily. A smear should, therefore, be prepared to identify the significant causal bacteria by using an incubation method together. Lately, with the development of antibacterial drugs, the ratio of aged patients among all patients who suffer from respiratory infections has been increasing, with diversified causal bacteria. For investigation, care should be taken according to the Schedule. (Please see "Infections of respiratory organs.") 6 Urinary tract infection The first requirement is that effectiveness and safety must be checked for through a comparative test for the complicated urinary tract infection. Then, determine whether the drug is applicable according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. Analysing causal bacteria on the basis of infected body parts, pathology and detected bacteria, and examining bacteria alternation, the bacterial appearance rate after the end of administration, and the types of detected bacteria will contribute to understanding the features of the antibacterial drug. For a comparative test on a simple urinary tract infection, the antibacterial drug can be considered as applying to the simple urinary tract infection (including nephritis and cystitis) if effectiveness and safety are observed. Urethritis should be classified into gonorrheal urethritis and nongonococcal urethritis for examination. For gonorrheal urethritis, examine antibacterial force on gonococcim and carry out a general clinical trial. Because nongonococcal urethritis often comes from chlamydia trachomatis, determine whether the antibacterial drug is applicable according to antibacterial force on chlamydia, pharmacokinetics, and other general clinical trial records on the chlamydia infection and other infections. Prostatitis often originates in causal bacteria common to the urinary tract infection. Thus, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacterial with a high frequency of the urinary tract infection, pharmacokinetics, and other general clinical trial records based on a specified number or more number of cases. Although epididymitis often results from chlamydia trachomatis or causal bacterial common to urinary tract infection, the causal bacteria may not often be fixed. But, bacteria detected from urine can be used for prediction. Whether the antibacterial drug is applicable should be determined according to antibacterial force on chlamydia, and other general clinical trial records on the chlamydia infection, etc. For the above tests, refer to UTI Drug Effectiveness Evaluation Standards issued in December 1996 by the Urinary Organ Subcommittee of the Clinical Evaluation Committee in the Japanese Chemical Treatment Association (UTI Drug Effectiveness Evaluation Standards, the fourth tentative version, the Journal of the Japanese Chemical Treatment Association, 45(5), 203-247(1997)). 7 Biliary infection The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. 8 Infectious enteritis For this disease group, it has become difficult to carry out a comparative test with a reduction in the number of cases. Examination should, therefore, be based on a general clinical trial. Whether the antibacterial drug is applicable should be determined according to records of clinical effects, bacteriological effects and safety. That enteral bacteria stocks have not been significantly changed must, however, be checked on a few patients who suffer from diarrhea. The target bacteria include dysentery bacillus (five or more cases), Salmonella (ten or more cases) and Canpirobacter (ten or more cases). Cases due to causal bacteria of infectious enteritis (three or more cases), as well as cases diagnosed clinically as infectious enteritis despite negative reactions may be additionally included as needed. For salmonellosis and specific enteritis, a comparative test should be carried out on an antibacterial drug whose similar drugs are not applicable to fix indications according to records of clinical effects, bacteria removal effects and safety. 9 Scarlatina If the antibacterial drug is considered as being applicable to an upper airway disease on the basis of a comparative test on the respiratory infection, whether that drug is applicable should be determined according to antibacterial force on group A streptococcus. 10 Pertussis If effectiveness and safety are observed through a comparative test on the respiratory infection, whether the antibacterial drug is applicable should be determined according to antibacterial force in pertussis bacteria, bacteria removal effects and other general clinical trial records. Although it is difficult to detect the causal bacteria of this disease, it is desirable that three or more cases for which the causal bacteria can be detected should be gained. 11 Peritonitis The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacterial with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. If a major comparative test has not been carried out or if effectiveness and safety have not been checked for, a comparative test on peritonitis can be carried out as if peritonitis were a surgical infection. Peritonitis due to a VP shunt or CAPD should, however, be analysed separately. 12 Infection in the obstetric and gynecologic area The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the indications include: (1) intrauterine infection, muliebria infection (such as metria, lochiometritis, endometritis, infectious abortion, pyometra and myometritis), adnexitis, and parametritis; (2) cervicitis; (3) bartholinitis and Bartholin's abscess; and (4) pelvioperitonitis and Douglas abscess. If a major comparative test has not been carried out or if effectiveness and safety have not been checked for, whether the antibacterial drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the requirement is that effectiveness and safety be observed through a comparative test on the surgical infection, or the obstetric and gynecologic infection. For adnexitis, the causal bacteria cannot be often fixed. In light of the fact that adnexitis often originates in intrauterin infection, the causal bacteria may be estimated by bacteria detected from a womb. Cervicitis should be classified into gonorrheal and nongonococcal cervicites for examination. Because nongonococcal cervicitis often comes from Chlamydia trachomatis, determine whether the antibacterial drug is applicable according to antibacterial force on chlamydia, pharmacokinetics, and other general clinical trial records of chlamydiosis and other infections. Bartholinitis and Bartholin's abscess should be handled as edea infections. For pelvic peritonitis and Douglas abscess, whether the antibacterial drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, and other general clinical trial records. 13 Pyogenic pachymeningitis The first requirement is that effectiveness and safety must be checked for through the major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force (MIC and MBC) on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. For pyogenic pachymeningitis, the dosage may be different from that for other infections. 14 Infection in the ophthalmologic area The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. The possibility that nearly all external eye infections may be cured completely only by local treatment (instillation) must, however, be taken into account. If a major comparative test has not been carried out or if effectiveness and safety have not been checked for, whether the antibacterial drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the requirement is that effectiveness and safety be checked for through a comparative test on the infection in the ophthalmologic or dermatologic area. Diseases which require systemic drugs are a sty, dacryocystitis, bacterial interstitial keratitis, eye socket infections, blepharadenitis, and whole eye ball infections. Instillation can provide sufficiently against conjunctivitis and blepharitis. For bacterial interstitial keratitis, administer an antibacterial drug to be developed for one or two days. If no effect is observed, another drug (including instillation drug) should be immediately administered. For treatment of an infection in the ophthalmologic area, an instillation drug of the same type, or an instillation drug and salve of another antibacterial drug must not be administered locally as a rule. 15 Infection in the otolaryngological area The first requirement is that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. If a major comparative test has not been carried out or if effectiveness and safety have not been checked for, whether the antibacterial drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the requirement is that effectiveness and safety be checked for through a comparative test on the infection in the otolaryngological or dermatologic area. For sinusitis, an X-ray test should be carried out to estimate effect. 16 Infections in the dental and oral surgical areas For some diseases such as pericoronitis and other open abscesses, it is difficult to identify causal bacteria. The first requirement is, however, that effectiveness and safety must be checked for through a major comparative test. Then, determine whether the antibacterial drug is applicable according to antibacterial force on causal bacteria with a high frequency in the oral surgical area, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. If a major comparative test has not been carried out or if effectiveness and safety have not been checked for, whether the antibacterial drug is applicable should be determined according to antibacterial force on causal bacteria with a high frequency, pharmacokinetics, a specified number or more number of cases, and other general clinical trial records. In this case, the requirement is that effectiveness and safety be checked for through a comparative test on the infection in the oral surgical area. 7 Evaluation of Clinical Trial Records To evaluate the records of a clinical trial, characteristics of an antibacterial drug to be developed must be identified. Moreover, the important points consist in whether a clinical trial has been carried out according to the purposes of the development, whether the clinical trial has abided by GCP, and whether the trial has been carried out according to a protocol. The records of a clinical trial to be evaluated include the following points. 1 Execution of a clinical trial When a clinical trial is executed, GCP must be observed, and related guidelines including these guidelines must be fully taken into account. 2 Evaluation of effectiveness Effects of an antibacterial drug depend on the case of a host, the susceptibility of causal bacteria to the antibacterial drug, drugs used together, and other factors. It is, therefore, difficult to identify those effects. The records of a comparative test with the control drug are, however, very important, and the verification that the antibacterial drug provides effects equal to or higher than those of the control drug offers objective grounds of effectiveness. If effectiveness has not been verified, evaluation should focus on the necessity of the antibacterial drug to be developed according to its characteristics. Frankly speaking, nearly all new antibacterial drugs are not applicable to diseases with rare clinical cases. The evaluation of those antibacterial drugs should be based on antibacterial force on causal bacteria, pharmacokinetics, and a few clinical cases. 3 Evaluation of bacteriological effects Naturally, the antibacterial drug targets causal bacteria. For some diseases, however, it is difficult to detect causal bacteria. In bacteriological effects, bacteria removal is the final target. But, information about the presence or absence of bacteria alternation, and about bacteria alternately appearing is also important. Thus, the presence or absence of bacteria alternation during the administration of an antibacterial drug to be developed, and bacterial readily appearing should also be examined to determine the bacteriological characteristics of the drug. The evaluation of bacteria with a low detection frequency should based on antibacterial force, pharmacokinetics, and a few clinical cases. 4 Evaluation of safety For safety, a general clinical trial and a comparative test must be carried out to provide against side effects and abnormal laboratory values. The evaluation of safety should be based on not only manifestation but also the types and degree of side effects and abnormal laboratory values, and their transformation. Also required is an analysis of a patient's case on side effect manifestation, relationships with drugs used together, the number of days until manifestation, relationships with allergy, and support by an animal experiment. 8 Handling of Missing and Exclusion Cases The selection and exclusion standards covered in a protocol must be strictly abided by. For a case which does not follow a protocol, another suitable antibacterial drug must be selected when this fact is found out. To carry out a high-quality test, the process of the test must be so fully monitored that the protocol is observed. Furthermore, illegal cases should be excluded from the bottom line as missing and exclusion cases for PC analysis. In addition, perform analysis on all cases for which treatment has been made (so called ITT) to support the validity of test results from both types of analysis. 9 Statistical Processing of Clinical Trial Records The statistical processing of clinical trial records must follow "Statistical Principles for Clinical Trials" under examination, and "Guidelines of the Configuration and Contents of Total Investigational Reports." Data material for high-quality reliable drug effectiveness evaluation should be developed. Examination group for developing guidelines for the clinical evaluation of antibacterial drugs Keisuke Sunagawa (group leader): Director of the department of pediatrics in the National Tokyo Treatment Center Shohichi Onodera: Associate professor of the department of urology in Jikei University School of Medicine Hiroshi Chiba: Processor of the pharmacological department in the faculty of pharmacology in Chiba University Yuhji Hanaya: Instructor of the first surgical department in the faculty of medicine in Teikyo University Keizoh Yamaguchi: Professor of the department for micro-organisms in the faculty of medicine in Toho University (Arbitrary order) Table 1 Sample names of bacteria stocks and groups (excluding viruses) [Aerobic Gram-positive micrococci] Staphylococci: Yellow staphylococcus, staphylococcus epidermidis (or coagraze-negagtive staphylococcus) Streptococci: Group A streptococcus (streptococcus pyogenes), group B streptococcus (agalactia bacteria), oral streptpcoccus (pyridanse group), and mutance bacteria Klebsiella pneumoniae Enterococci: Certain Enterococci [Aerobic Gram-negative micrococci] Neisseriae: Gonococcus and meningococcus Moraxella: Moraxella (Branhamella) catalaris, and Moraxella lactana (Moraxella lacunata) [Aerobic Gram-positive bacteria] Listeria: Listeria monositegenes Erysipelothrix: Fire bacteria Corynebacterium: Corynebacterium diphtheriae Bacillus: Anthracic bacteria Nocardia [Enteral bacteria] Colibacilli: Colibacillus Dysentery bacillus Salmonella: Salmonella typhi, paratyphoid bacillus, and other Salmonellae Citrobacter Klebsiella: Klebsiella pneumoniae Enterobacter Serratia: Serratia marcescens Proteeae: Certain proteeae Morganella: Morgan bacillus (Morganella morgany) Providencia Yersinia: Yersinia pestis [Vibrio] Vibrio: Vibrio cholerae and enteritis vibrio Eromoni: Certain eromoni [Pasteurella] Pasteurella: Certain pasteurellae Haemophilus: Haemophilus influenzae, soft sore bacillus, and Hoch's bacillus [Grape sugar non-fermentation Gram-negative aerobic bacilli] Pseudomonas: Certain pseudomonases and pseudomonas aeruginosa Bergphorderiae: Certain berphorderiae Acinetobacter: Some acinetobacters Flavobacterium: Certain flavobacteria Alcaligenes: Certain alcaligenes [Legionella] Legionella: Some legionellae [Aerobic Gram-negative bacilli] Brucella: Certain brucella Bordetella: Bordetella pertussis and bordetella parapertussis Francisella: Certain francisellae [Slightly aerobic Gram-negative bacilli] Canpirobacter Helicobacter: Certain helicohacters [Anaerobic Gram-negative bacilli] Veillonella [Anaerobic Gram-positive bacilli] Peptostreptococcus: Certain peptostreptococci Peptococcus [Anaerobic Gram-negative bacilli] Bacteroides: Certain bacteroides Prevotella Porphyromonas Fusobacterium [Anaerobic Gram-positive bacilli] Clostridium: Clostridium perfringens, clostridium tetani, and gas gangren bacillus group Actinomyces: Certain actinomyces Propionibacterium: Acne Eubacterium: Certain eubacteria Mobiruncus [Other] Gardnella: Certain gardnellae [Spirochete] Treponeme: Treponema pallidum Borrelia: Certain borreliae [Leptospira] Leptospira: Certain leptospirae [Rickettsia] Rickettsia: Rickettsia prowazekii and rickettsia typhi Coxiella: Q-fever rickettsia Bartonella: Certain bartonellae [Chlamydiaceae] Chlamydia: Chlamydia pneumoniae, chlamydia psittaci, and chlamydia trachomatis [Mycoplasma] Mycoplasma: Mycoplasma pneumoniae Ureaplasma: Ureaplasma ureariticum Table 2 Bacteria type and stocks in which few clinical cases have been found Neisseria meningitidis, bordetella pertussis, bordetella parapertussis, legionella, vibrio cholerae, salmonella typhi, paratyphoid bacillus, pasteurella pestis, corynebacterium diphtheriae, clostridium tetani, listeria, treponema, borrelia, leptospira, rickettsia, chlamydia pneumoniae, etc. Table 3 Diseases and the minimum number of cases required for fixing indications As a rule, this Table covers the number of cases for which the development of separated bacteria has been examined. (1) Antibacterial drugs as injections No Disease Required minimum number of investigational cases (for examining bacterial development) Remarks [Disease not necessary]. Required number of investigational cases for other diseases 1 Systemic infection Sepsis Total 5 Total 5 including one case for infectious endocarditis depending on the bacteria to which the drug is applicable 2 Infection in the dermatologic area Latent skin infection (Cellulitis, fire, lymphangitis, and lymphadenitis) 5 Thrombophlebtis: 5 Infectious abscess: 10 3 Infection in the surgical area Wound, thermal burn infection, and operation infection 3 10, if infections due to wounds or thermal wounds are included depending on the bacteria to which the drug is applicable 4 Infection in the orthopaedic area 3 each Myelitis and arthritis: 5 each depending on the bacteria to which the drug is applicable Pyogenic pachymeningitis: 3 Pyomyositis: 3 5 Respiratory infection ・ Peritonsillar abscess (including critical lacunar tonsillitis and peritonsillitis), ・ Retropharyngeal abscess, and secondary infection of a chronic respiratory disease (including chronic bronchitis, diffuse panbronchiolitis, bronchiectasis, lung emphysema, fibroid lung, and bronchial asthma) 3 Total: 30 (including Chronic bronchitis: 5 Bronchiectasis: 3 each) 10 Any disease: Total 3 Cases for lung pyopoiesis should be included. 6 Urinary tract infection Nephritis, Complex cystitis, Prostatitis 20 30 3 Gonorrheal urethritis: 3 depending on the bacteria to which the drug is applicable Orchiepididymitis: 3 7 Biliary infection Cholecystitis and choledochitis 3 each Liver abscess: 5 depending on the bacteria to which the drug is applicable Acute pancreatitis: 5 11 Celiac infection Celiac abscess and peritonitis (*) 5 each 12 Infection in the obstetric and gynecologic area Intra-genital infection (Intrauterine infection, adnexitis, and parametritis) Total 15 Pelvic peritonitis and Douglas abscess: 3 depending on the bacteria to which the drug is applicable 13 Pyogenic pachymeningitis 5 The target is only the drug that rapidly permeates lymph. (Infants are also available.) 14 Infection in the ophthalmic area Keratitis, eye socket infection, and eyeball infection (including endophthalmitis) Total 5 including 1 from each 15 Infection in the otolaryngologic area Tympanitis (including mastoid process and petrosa disease) 5 each Limited to medium or more serious diseases. 16 Infection in the dental and oral surgical area Cellulitis around basal bone 5 each 17 Others Syphilis: 5 * Includes pores in the small and large bowels. (2) Oral antibacterial drugs No Disease Required minimum number of investigational cases (for examining bacterial development) Remarks [Disease not necessary]. Required number of investigational cases for other diseases 2 Infection in the dermatologic area ・Sublimis skin infection (Acute sublimis folliculitis and vulgaris abscess) ・Latent skin infection (Cellulitis, fire, lymphangitis, lymphadenitis, boil, boil abscess, abscess, vulgaris sycosis, and pyogenic abscess around nails) ・Chronic skin disease (Pyogenic hidradenitis and subcutaneous abscess) ・Secondary skin infection (Latent thermal wound, eczema, cut, and operation wound) 10 including 2 each 20 including 2 each 10 including 2 each 10 including 2 each (Infants may be examined for infections.) 3 cases of acne depending on the bacteria to which the drug is applicable 3 Infection in the surgical area Mastitis and periproctitis 10 including 2 each 10 including 3 cases of each of wounds, thermal wound infections, and operation infections depending on the bacteria to which the drug is applicable 5 Respiratory infection Acute upper airway infections (including tonsillitis, pharyngitis, sore throat, and acute bronchitis) 20 including 5 cases of tonsillitis Definitions for injections are applied when oral indications are acquired on secondary infections of pneumonia or chronic respiratory disease. Mycoplasma pneumonia: 10 depending on the bacteria to which the drug is applicable Chlamydia pneumonia: 5 6 Urinary tract infection Pyelonephritis Cystitis Prostatitis 20 30 3 Gonorrheal urethritis: 10 depending on the bacteria to which the drug is applicable Nongonococcal urethritis: 10 (including 5 or more for chlamydia urethritis) Epididymitis: 5 8 Infectious enteritis Dysentery: 5 depending on the bacteria to which the drug is applicable Salmonellosis: 10 9 Scarlatina Upper airway disease (Acute upper airway disease in 5'): The drug should be applicable to group A streptococcus 10 Pertussis Pertussis: 3 depending on the bacteria to which the drug is applicable 12 Infection in the obstetric and gynecologic area Bartholin's abscess (Bartholinitis) Total 3 for any of the diseases Cervicitis: 5 depending on the bacterial to which the drug is applicable 14 Infection in the ophthalmic area Eyelid abscess, dacryocystitis, sty, tarsitis, and keratitis (including cornea abscess) 15 including 2 each 15 Infection in the otolaryngologic area Otitis externa, otitis media, pyogenic sialadenitis, and sinusiitis 3 each 3 5 Infectious stomatitis (including glossitis): 5 16 Infection in the dental and oral surgical area Periodonitis, operculitis, and cavitas infection Total 10 For these diseases, the above Table offers the required number of cases to be covered to provide for the integrity of application among same-system drugs. Features of the appropriate drug must be separately described if the indications cannot be acquired from the bacteria to which the drug is applicable and from intracorporeal characteristics. For the other diseases, a separate clinical trial should be carried out to fix indications according to its records. Schedule 1 Items to be taken into account for the clinical evaluation of antibacterial drugs The following sets out the items to be taken into account when a clinical trial is carried out according to the "guidelines for the clinical evaluation of antibacterial drugs." For details of postmarketing investigation, please see the "guidelines for appropriate postmarketing investigations." 1 Execution of investigation complying with the purposes of development Naturally, the infection to which an antibacterial drug is to be applied varies with the method of its administration. Reflecting how to use such antibacterial drug for actual clinical investigation in a clinical trial will require a clinical trial method based on the items described below. (1) If a bacteria alternation disease and side effects are taken into account for an injection, the same drug need not be administered for a certain specified period. You should investigate into whether, after the start of the administration of the injection, when can an oral antibacterial drug that provides more moderate effects begin administration. (2) If the case has remitted by administering an injection, you should next investigate into whether an oral drug to be administered can bring out the effect. 2 Principles for administering an antibacterial drug in a clinical trial The following three principles are applied to administering an antibacterial drug in a clinical trial. (1) The target diseases are mild or medium diseases. For these diseases, check effects of the antibacterial drug, and effects on a more serious disease, if required. (2) Causal bacteria to which an antibacterial drug to be developed is to be applied must be identified in advance through basic examination. If the disease is judged to have been cured even during the period of administration, this administration should be suspended, or another suitable drug to be administered should be selected. If the disease may recur or be recrudescent by suspending the administration of the investigational drug, however, the administration can be continued for a certain period. In such a case, the reason for this continuation must be clarified. Investigational drugs that must be administered beyond a specified period should be defined separately. (3) Administration is suspended when expected effects are brought out, as well as when selection criteria are not met or when expected clinical effects are not observed. In such cases, another commercially available drug should be selected as soon as possible. 3 Period of antibacterial drug administration in a clinical trial Various arguments are made concerning the period of antibacterial drug administration. The principle for judging clinical effects of an antibacterial drug consists in curing the infection. For a powerful wide-range antibacterial drug, however, whether the drug should continue to be administered until the cure of the infection must be examined from aspects of a bacterial alternation disease, the patient's pain, and medical economics. For setting the period of administration, the shortest and longest periods are often described. In this case as well, you should predefine handling to be applied when the case is remitted before the fixed shortest period and when administration is considered as being needed beyond the longest period. Furthermore, criteria for suspension must be clearly defined. If the number of cases for which an antibacterial drug is administered for a short period is increased, the number of cases which enable examination of safety against a bacteria alternation disease and allergy may be decreased, with the frequency of occurrence reduced. Safety must, therefore, be examined through basic inquiry and Phase III studied. 4 Primary end point For an oral drug, important points are when the patient or the physician determines the suspension of antibacterial drug administration and how he/she determines the suspension of injection administration or a change to oral drug. This may be a primary end point. The primary end point should cover clinical manifestation, as well as the results of the appropriate clinical inspection and bacteriological inspection. In addition, however, the presence or absence of recrudescence, and whether bacteria can be removed and discharged again must be examined. For the observation of these factors, a necessary period should be predetermined. 5 Observation from time to time of clinical case and laboratory value According to the primary end point described above, changes in clinical cases and laboratory values after the start of administration of an antibacterial drug to be developed should be essentially examined along with the period of administration when administration is suspended. However, because examination only of records upon the suspension of administration may result in dispersion depending on the case, those changes should be observed from time to time according to a specified program. Observation from time to time should cover items which enable the most significant verification of characteristics of an antibacterial drug to be developed. Grounds for item and time settings should be determined in Phase II studies. 6 Notes on bacteriological inspection Although bacteriological inspection should focus on bacteria removal and bacteria removal repetition, the diseases for which detected bacteria can be immediately judged to be causal bacteria are limited. For a respiratory infection as well, causal bacteria can be estimated from inspection manifestation of expectations and from laboratory values, but may not be identified. This is because the results of inspection based on cultivation are affected by a specimen sampling method, the period from sampling to cultivation, and a processing method. In the future, sampling and processing should be performed according to a standardised level. In the present stage, however, the principal or clinical investigator must make judgement on the following items. (1) Detected bacteria are regarded as being causal bacteria. (2) Detected bacteria are assumed to be causal bacteria. (3) Detected bacteria are not judged to be causal bacteria. 7 Notes on pharmacokinetic measurement Now that there is no one constant clear method on drug effectiveness evaluation, determining a drug dosage requires the measurement of pharmacokinetics. On the other hand, currently, it has been pointed out that execution of a clinical trial covering pharmacokinetics grows increasingly difficult. A potential method is such that pharmacokinetics is estimated from animal data and that dynamic values are predicted from concentration in blood measured from a few points as polulationkinetics. But, the former method is restricted by the fact that a drug of a type of excretion though a kidney can be applied only to an adult. The latter method, although it does not highly load each patient, requires a much greater number of patients for computing dynamic values. These methods are, therefore, accompanied by a number of problems. Pharmacokinetics should be inspected very carefully for each case lest valuable data is not evaluated because GCP is not abided by. Schedule 2 Clinical trial in the paediatric area Introduction It has become very difficult to clinically evaluate antibacterial drugs for the paediatric area. On the other hand, serious infections have increased due to a reduction in the function of the immune system. The reduction apparently results from an increase in resistant bacteria, an increase in the number of premature or light-weight babies, an increase in the number of patients who suffer from leukaemia, and more frequent organ transplants. Many people desire that newly developed antibacterial drugs should be applied to the paediatric area as well as aged people and adults. Executing a suitable clinical evaluation and collecting more valuable clinical records under such circumstances require that the following measures be taken. 1 General principles A growing infant is different from an adult in terms of pharmacokinetics, including reactions to drugs and of the frequency of side effect manifestations. Moreover, the infant may suffer from particular diseases, and may also be different from an adult in terms of the frequencies of causal bacteria and of significance. Basic tests and clinical trials for infants should be performed separately from those for adults, except those common to the adult area. (1) Development of antibacterial drugs for an infant a Injection Since an injection directly enters the body through blood vessels in all people including infants and adults, significant differences in pharmacokinetics are not found between infant and adult. As a rule, the injection should be proposed according to indications and bacteria types common to the adult area. b Oral drug While tablets and capsule drugs are applied mainly to adults, grain drugs are often applied to infants. Furthermore, because differences in absorption are found depending on the drug, records of pharmacokinetics on infants may be different from those on adults. Indications and bacteria types may be different between infants and adults. For some drugs, differences in absorption through intestines are found between infants and adults. Those drugs should be proposed separately from drugs for adults. Concerning the biological homogeneity between drugs for infants and adults, pharmacokinetics has been examined by particular methods on infants as well to evaluate the effectiveness and safety of clinical trials. For verifying biological homogeneity, such important factors on applicability to infants as the taste may be ignored. The biological homogeneity between drugs for infants and adults need not, therefore, always be required. (2) Classification of children according to age In the paediatric area, children are classified according to age as follows. a Low-weight neonate: Neonate born without sufficient pregnancy (37 weeks) or whose weight is less than 2,500 g when born b Neonate: Baby within 28 days after birth c Baby: Baby 29 or more days to less than 24 months after birth d Infant: Child 24 or more months to six years after birth e Child: Child aged six or more to less than 16 An antibacterial drug may be judged to be applicable to a neonate and a low-weight neonate. In such a case, clinical trials of low-weight neonates and neonates should be started after verification of effectiveness and safety through a paediatric clinical trial covering infants and children. (3) When a clinical trial for an infant is started As a rule, a clinical trial for a drug for an infant should be started after approval of the drug for an adult in terms of safety. In this case, the requirement is that safety be checked for through postmarketing investigations (Phase IV studies). Since the antibacterial drug is accompanied by problems with the advent of resistant bacteria, however, this procedure may result in a delay of development for some antibacterial drugs. The antibacterial drugs are, therefore, classified into the following three groups to start clinical trials according to the time limit of development. a Antibacterial drugs to be developed rapidly (Drugs for MRSA and resistant klebsiellae pneumoniae) New resistant bacteria appear, and known resistant bacteria increase. In addition, since only a limited number of antibacterial drugs can be used, these antibacterial drugs for the paediatric area are required to be rapidly developed. Moreover, some antibacterial drugs are expected to bring out effects on popular causal bacteria, and few other antibacterial drugs can provide effects on those bacteria. Clinical trials for these antibacterial drugs should be started when effectiveness and safety are estimated in the adult area. (Late Phase II studies) b Antibacterial drugs that are estimated to be safe for an infant (β-lactam drug, macrolide drug, and other drugs) These drugs are similar to past antibacterial drugs. The requirement on application is that safety for an infant be estimated according to clinical experiences in the paediatric area, clinical trial records in the adult area, records of toxicity tests with young animals, and other records. Clinical trials of antibacterial drugs belonging to this group should be started after effectiveness and safety have been verified in the adult area. (Phase III studies) For the antibacterial drug that has wide antibacterial spectra and provides strong antibacterial force, variations in enteral bacteria stocks must be examined to investigate into measures against bacteria alternation and diarrhea. In particular, for a drug which has been estimated through a clinical trial in the adult area to frequently bring about diarrhea, measures to be taken against this must be examined. c Antibacterial drugs in which safety must be checked for first These antibacterial drugs should be carefully examined further in terms of safety from records of clinical trials in the adult area in comparison with past similar antibacterial drugs and from records of toxicity tests with young animals. For an antibacterial drug of the same system as a past antibacterial drug that is restricted in terms of application to an infant, a clinical trial for an infant must be started after approval of its use for an adult, after safety has been verified through re-examination or when the applicant ensures safety as a rule. 2 Non-clinical study For an antibacterial drug for an infant, the following tests are required in addition to non-clinical studies in the adult area. (1) In-vitro antibacterial force a Antibacterial force on such bacteria with a high detection frequency in the paediatric area as bordetella pertussis and group B streptococcus b For an antibacterial drug that may be administered to a noenate, tests on protein linkage and competition with bilirubin using human serum albumin (2) Animal experiment a Test using mature animals Generative toxicity test and genetic toxicity test including perinatal/lactational tests, and cancer test depending on the period of administration and the presence or absence of a cancer hazard b Investigation into safety using young animals (a) Toxicity test (b) Inspection of pharmacokinetics (c) Examination of problems if such side chains as ester may affect an infant on account of the structure of the antibacterial drug c Comparison of pharmacokinetics between young and mature animals According to the above data material, the necessity of the antibacterial drug, and effectiveness on and safety for an infant are examined by experts of infant infections and chemical treatment, then the start of a clinical trial is determined. In a clinical trial, examination of effectiveness and safety as well as at least requiring investigation into pharmacokinetics, in particular, metabolism on an infant, must be carried out. In this case, a required minimum number of specimens should be sampled. 3 Clinical trial (1) Procedure before a clinical trial, and notes a Determination of whether a clinical trial is to be started When a clinical trial on an infant is carried out, the sponsor must discuss with two or more qualified physicians on: - effectiveness and safety of the antibacterial drug to be developed; - necessity in the paediatric area; - records of non-clinical studies on protocol; and - records of clinical trials in the adult area. Then, the sponsor should determine whether a clinical trial for the antibacterial drug is to be started. b Development of a protocol Develop a protocol by noting the items below to examine effectiveness, safety, and a suitable dosage for an infant. (a) When carrying out a clinical trial, abide by GCP. (b) As a rule, clearly distinguish between target inpatients and outpatients. (c) A clinical trial must be carried out by a specialist of chemical treatment for infant infections. (d) Facilities in which a clinical trial is to be carried out must provide the capability to carry out clinical diagnostic inspections and be provided with equipment for dealing with side effects. After the determination of the execution of a clinical trial, explain its purposes to all facilities that will take part in the clinical trial to gain full understanding and support. (2) Clinical trial As a rule, for an infant whose representative (parent) has agreed to a clinical trial in writing, start the clinical trial according to a protocol. During this period, fix a dosage, and examine the method and period of administration to clarify characteristics (including effectiveness, safety and dosing nature) of an antibacterial drug to be developed. Start a clinical trial for infants first from school children to check for effectiveness and safety, then examine the execution of the clinical trial in descending age order. For a clinical trial in the paediatric area, it is unnecessary to carry out a comparative test from an ethical standpoint. Certain standards should be set to carry out a clinical trial so that the antibacterial drug may be compared with other antibacterial drugs. For those standards, references or details must be clearly described in a protocol. (3) Test on absorption, excretion and drug interactions For treatment, carry out this test on a case which requires drug administration. For absorption and excretion as well, carry out this test using a separately predetermined method on an infant whose representative has agreed to this test. Furthermore, examine effects of food and milk if possible and, in addition, investigate into characteristics of accumulation. Efforts should be made to sample a minimum number of specimens. (4) Explanation and agreement Comply with GCP. 4 Determination of a dosage Carry out a total clinical trial in light of records on adults, antibacterial force, pharmacokinetics on infants, and past experiences to fix a clinical dosage according to obtained test records. In general, set a dosage per body weight unit, and the upper limit for older children. The above notes concern the execution of a clinical trial on infections in the paediatric area. Schedule 3 Infections in the surgical area Target diseases Considerations for selecting a target disease according to the administration route of an antibacterial drug Injection antibacterial drug: An injection antibacterial drug should be applied to complex perirectal abscesses such as ischiorectal fossa instead of an oral antibacterial drug. For a perioperative infection, it may be impossible to orally administer an antibacterial drug for a certain period and, therefore, an injection antibacterial drug should be applied. Currently, however, oral antibacterial drugs are applied mainly except for such special diseases. Oral antibacterial drug: Some oral antibacterial drugs are applied to cholecystitis and cholangitis. Also, lately, conservative treatment using oral antibacterial drugs may be applied to appendicitis. For evaluation, however, image diagnosis by CT and supersonic inspection should be added on the perirectal abscess as well. The above notes concern the execution of a clinical trial on surgical infections. Reference: Antibacterial drugs for providing against perioperative infections as well as postoperative infections The requirements on an antibacterial drug to be applied are as follows. - Many of the contamination bacteria show susceptibility to the antibacterial drug. - The target part to be operated on can be accessed readily. - Even under postoperative circumstances, few side effects are brought about. In Japan, no antibacterial drugs are applicable to this area and, therefore, the introduction of standard antibacterial drugs should be examined in light of the points below. Then, through comparison with those antibacterial drugs (or drugs whose effectiveness and safety have been verified through a test for comparison with the standard drug), whether the antibacterial drug is effective will be determined. To evaluate effects of providing against postoperative infections offered by an antibacterial drug administered during or after operation, several points must be taken into account. First, a perioperative infection must be clearly defined for proper diagnosis. The preventive antibacterial drug for providing against postoperative infection has been considered as focusing on wound infection caused on the skin and soft tissue subjected to operation. In the past, operations (Table 4) classified according to the number of bacteria have correlated with the rate of wound infection. For a dry cleaned wound, the rate of wound infection at 105 CFU of bacteria/ml is 50 percent. If an antibacterial drug is used effectively, infection rate at the same bacteria count is reduced to 10 percent. With the bacteria count always maintained below the number of bacteria bringing about infection, no infection is caused. Lately, however, wound infection has been reduced to a certain level. The rate of infection resulting from clean-contaminated, contaminated, and dirty/infected operations varies with the case and the organ subject to an operation. And, intrinsic bacteria play a more crucial role than extrinsic bacteria. We should, therefore, introduce the viewpoint that an antibacterial drug to be developed should provide against infection of not only a section but also all regions of the patient (please see Table 5). This concept provides a global target for control over infection resulting from surgical operations. Lately, in America and Europe, definitions have been revised to use surgical site infection, which is classified into the following categories. 1 Infection of a surficial section including skin and subcutaneous tissue 2 Infection of a deep section including deep soft tissue 3 Infection of organs, endoceliac space and other spaces other than a section opened and operated on This new wider concept indicates that all factors not related to bacteria but to perioperative infection must be taken into account. Currently, however, a clinical trial should focus on bacterial infection that may be brought about during an operation and on the organ operated on. The presence or absence of a postoperative infection should be estimated according to bacteria detected from a wound operated on and ecthyma as diagnostic grounds. Second, the target investigational cases should be unified in terms of background factors for suitable stratification. In addition, we should aim at the clean-contaminated operation as medium bacteria contamination according to the frequency of an infection manifestation. In this case as well, the wound operated on should be searched for bacteria in an appropriate case, and the actual presence or absence of an infection should be fully examined. Third, when selecting a patient in which a preventive antibacterial drug is to be administered, conditions of the host must be taken into account in addition to the possibility of bacterial infection resulting from an operation. In the past, nearly all surgeons have argued that a preventive antibacterial drug need and should not be administered in a clean case. The necessity of a preventive antibacterial drug has been proved for: - patients who may suffer a risk on a wound resulting from the use of an artificial article; - aged patients; - critical patients; and - patients who may suffer a high risk of an increase in perioperative infections including immuno-compromised hosts. For example, also, in such clean operations that require no antibacterial drug as herniotomy and mamma operations, risk should be evaluated to select a patient for whom an operation takes two or more hours or who suffer from three or more types of disease. A patient who has undergone a clean-contaminated or contaminated abdominal operation or an operation over two or more hours is highly subject to perioperative infection. In Japan, an aged patient who suffers from a complicated disease is highly subject to perioperative infection. These factors must be pre-evaluated to use a preventive antibacterial drug. Criteria on definitions on a high risk will, however, be improved in the future as well. Fourth, when an antibacterial drug is administered, dosage, route, and the time of administration must be taken into account. A dosage before an operation must be made equal to the maximum dosage of the antibacterial drug. Administer an antibacterial drug via a vein immediately before the skin section. The period of an operation apparently significantly affects the rate of infection. If the period of an operation reaches three or more hours or becomes two times longer than the half-life of the antibacterial drug, a second administration is required. Also, if a large volume of blood flows out (for example, the volume of blood loss is equal to or greater than the volume of circulating blood), a second administration is required. The period of administration depends on whether the antibacterial drug is administered for prevention (only for one day) according to clinical findings or for endoceliac infection control for treatment during an operation (a second or more administrations are required). It is important to distinguish between prevention and treatment, and it is not fitting to administer the same antibacterial drug for prevention three to five days after an operation. The fifth problem consists in prevention by preoperative bowel processing with an antibacterial drug or prevention by preoperative bowel processing with an antibacterial drug by a palliative large bowel operation. This problem is concerned with what antibacterial drug is the best and how the best antibacterial drug is to be administered. The argument of oral administration is based on the importance of reducing the number of bacteria in the bowel before its opening. To the contrary, the argument of administering an antibacterial drug via a vein is based on the importance of the suitable level of the antibacterial drug in the bowel. The administration of an antibacterial drug from the previous day should be reviewed. Table I Indications of an antibacterial drug for controlling perioperative infection 1 Clean case (1) Patient for whom artificial things such as an artificial cardiac valve, an artificial blood vessel, orthopaedic metal items, or an artificial eye lens are used (2) High-risk patient due to a host factor a Patient who suffers from three or more types of complicated disease b Operation taking two or more hours 2 Clean-contaminated case (1) Abdominal operation a Only a high-risk patient who has undergone an operation of the cholecyst Patient aged 70 or more who has suffered from cholepathia, biliary atresia or choledocholith, or undergone a biliary re-operation or an operation for opening choledoch b Operation of liver or lien c Operation of stomach or duodenum Patient who suffers from blood loss, cancer, tumour or blockade (2) Operation of head, throat or esophagus Including operations of mouth, pharnx or esophagus (3) Obstetric and gynecologic operations a Caesarian section b Abortion c Abdominal operation (4) Urologic operation Positive cultivated urine 3 Contaminated case (1) Operation of colon or rectum a With ileus b Without ileus (2) Appendix removal (3) Laparotomy without definite diagnosis Holed stomach or duodenum, or disrupted liver or pancreas (4) Wound (within 24 hours) Laparotomy providing against wound not holed by a solid means Abdominal wound holed (5) Fracture recovery operation (6) Open fracture (7) Soft tissue trouble in wide sense Table II Definitions of postoperative infection 1 Wound infection Operative wound for which the discharge or presence of pus or puriform liquid is observed by naked eyes after an operation. Also includes a drain insertion wound, but excludes a bowel wound. These are accompanied by obvious operative infection, and general inflammatory reactions such as heat, an increase in the number of white blood cells, and an increase in CRP. 2 Postoperative abdominal infection This is accompanied by clinical abdominal infections such as heat generation and peritonitis. Or, there is possibly an abdominal infection source according to abdominal physical findings, blood inspection (number of white blood cells, CRP, and erythrocyte sedimentation rate, discharged puriform drained liquid, chest X-ray data (including contrast data), supersonic inspection, CT, MR, scintigraphy, and other image diagnostic data. Infections resulting from improper closure or puriform pancreatic juice must be clearly described. 3 Postoperative pneumonia A patient suffers possibly from a respiratory infection according to heat generation, an increase in the respiration rate and other general symptoms, as well as physical findings (hypophonsis and La-tone), chest X-ray findings, arterial gas analysis, and findings on sputa (increase in the number of neutrophilic leukocytes or bacteria detected by dyeing, and detection of significant causal bacteria through cultivation). This case originates in mechanical trachea damage due to anaesthesia, airway blockade, atelectasis, a swallowing error, lung emphysema, or other causes. This infection results from bacteria or fungi in the bronchia or lung. A preoperative respiratory infection may contribute to this case. Although it is difficult to distinguish between pneumonia and ARDS not accompanied by bacterial infection, however, only the case for which causal bacterial have been identified by sputum cultivation is the object for judging effects of an antibacterial drug, 4 Urinary tract infection Identification requires that an increase in the number of while blood cells be observed through urine inspection (five or more white blood cells in one sight) or that the number of bacteria of 104 CFU/ml or more is observed through quantitative urine cultivation. In catheterization, however, these inspection results may be obtained even if the patient does not suffer from an infection. The patient should, therefore, be observed in terms of urine discharge pain, frequency of urine discharge, number of while blood cells, CRP, and other factors for clinical urinary tract infection identification. 5 Postoperative biliary infection (1) Postoperative acute cholecystitis Carry out abdominal inspection and supersonic inspection (to find out cholecystis extension, thick wall and the presence of debris in cholecystis that suggest cholecystitis), and CT. Whether cholecystitis exists can be determined from these types of inspection. (2) Postoperative cholangitis Carry out abdominal inspection, liver function inspection, bile inspection (for detecting bacterial and symptom), CT inspection, supersonic inspection, and other types of inspection. Whether cholangitis exists can be determined from these type of image diagnosis. The patient is not regarded as suffering from cholecystitis, only by the fact that bacteria have been found in bile by T-tube and PTCD. (3) A postoperative liver abscess is also included. 6 Sepsis (1) Sepsis identification requires the presence of a general infection case and that the presence of bacteria in blood be proved. (2) Catheter sepsis is handled separately. (3) Some people argue that an endotoxin blood disease, and high cytokine blood diseases such as IL-1, IL-6 and TNF cytokine be considered as sepsis. The present definitions do not cover this argument.