# Patent

## Title
Therapeutic application of N-substituted

## Abstract

This is a continuation-in-part of U.S. patent application Ser. No. 787,609 filed Oct. 15, 1985, now abandoned.

## Background
The present invention relates to a novel composition comprising a penem or carbapenem antibiotic in association with an amino acid derivative. The invention also provides a method of treating bacterial infections by administering to the patient, simultaneously or sequentially, a penem or carbapenem antibiotic and at least one amino acid derivative selected from a class of acylated amino acids.

The class of compounds known as "penem and carbapenem antibiotics" is, of course, very well known and is potentially of great value for the treatment of bacterial infections. Although, as a group, these penem and carbapenem antibiotics exhibit excellent anti-bacterial activity and a variety of other properties which render them highly suitable for pharmaceutical use, they do have a number of disadvantages. One of the problems of these antibiotics is that, in general, they exhibit a degree of renal toxicity, and some degree of kidney damage is a frequent side effect of their use; accordingly, such penem and carbapenem antibiotics should not be used for the treatment of patients with actual or suspected impaired renal function. As a result, the penem and carbapenem antibiotics cannot be used for many patients for whom otherwise they would be the antibiotic of choice. The problem of renal toxicity is particularly acute when the antibiotics are administered by intravenous or intrasmuscular injection in a high dose.

We have now surprisingly discovered that the concurrent, or effectively concurrent, administration, with the penem or carbapenem antibiotic, of one or more of a certain class of acylated amino acid derivatives significanty reduces this renal toxicity.

EP Publication No. 7614 discloses the use of a dipeptidase inhibitor in association with antibiotics similar to those to which the present invention relates. However, the dipeptidase inhibitors employed are structurally different from the amino acid derivatives of the present invention and are employed for a totally different purpose. The amino acid derivatives employed in the present invention possess little or no dipeptidase inhibitory activity.

It is, therefore, an object of the present invention to provide a composition comprising a penem or carbapenem antibiotic having lower renal toxicity than does the antibiotic on its own.

It is a further object of the invention to provide a method of treating a bacterial infection in a mammal by administering to said mammal, simultaneously or sequentially, a penem or carbapenem antibiotic and an acylated amino acid derivative.

Accordingly, in one aspect, the present invention provides a composition comprising:

(a) an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics; and

(b) a pharmaceutically acceptable N-acylated derivative of an amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof.

In another aspect, the invention provides a method of treating a mammal suffering from a bacterial infection by administering to said mammal:

(a) an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics; and

(b) a pharmaceutically acceptable N-acylated derivative as defined above.

There is no particular limitation on the nature of the penem or carbapenem antibiotic to which the present invention can be applied and it is believed that the beneficial effects of the concurrent administration of an N-acylated amino acid derivative will be achieved regardless of the particular antibiotic chosen. However, the penem and carbapenem antibiotics which are currently of most actual or potential interest may be represented by the general formula (I): ##STR1## in which: Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii): selected from the group consisting of substituents (iii), C.sub.1 -C.sub.4 alkylideneamino groups, C.sub.1 -C.sub.4 aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alkoxyalkyl groups where the alkoxy and alkyl parts are each C.sub.1 -C.sub.4, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups. C.sub.1 -C.sub.4 haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C.sub.1 -C.sub.6 alkanoyl groups, C.sub.1 -C.sub.6 alkanesulfonyl groups, C.sub.1 -C.sub.6 alkanesulfinyl groups, hydroximino groups, C.sub.1 -C.sub.4 alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub. 1 -C.sub.4 alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C.sub.1 -C.sub.4 and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups and C.sub.1 -C.sub.4 iminoalkyl groups; -C.sub.6 alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups.

Preferably Y represents a sulfur atom, a methylene group, or the group CH.sub.3 --CH<, CH.sub.3 O--CH< or (CH.sub.3).sub.2 C<.

Preferred examples of groups which may be represented by R.sup.1 include the ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N.sup.1 -(2-carbamoyloxyethyl)-N.sup.1 -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1 -iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl and 1-acetyl-3-pyrrolidinyl groups.

The invention may also be applied to pharmaceutically acceptable salts and esters of such antibiotics, such as are well known in the art.

Specific examples of compounds of formula (I) which may be employed in the present invention are those in which R.sup.1 and Y are as defined below: Comp. No. R.sup.1               Y ______________________________________ 1. ##STR2##             CH.sub.2 2. ##STR3##             CH.sub.2 3. ##STR4## ##STR5## 4. ##STR6##             CH.sub.2 5. ##STR7##             S 6. ##STR8##             CH.sub.2 7. ##STR9##             CH.sub.2 8. ##STR10##            CH.sub.2 9. ##STR11##            CH.sub.2 10. ##STR12##            CH.sub.2 ##STR13##            CH.sub.2 ##STR14##            CH.sub.2 ##STR15##            CH.sub.2 ##STR16##            CH.sub.2 ##STR17##            CH.sub.2 ##STR18##            CH.sub.2 ##STR19##            CH.sub.2 ##STR20##            CH.sub.2 ##STR21##            CH.sub.2 20. ##STR22## ##STR23## ##STR24## ##STR25## ##STR26## ##STR27## ##STR28## ##STR29## ##STR30## ##STR31## ##STR32## ##STR33## ##STR34##            CH.sub.2 ##STR35## ##STR36## ##STR37##            CH.sub.2 ##STR38##            CH.sub.2 30. ##STR39##            CH.sub.2 ##STR40##            CH.sub.2 ##STR41## ##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48## 36.     CH.sub.2 CH.sub.3     S 37.     CH.sub.2 CH.sub.2 F   S ##STR49##            S 39.     CH.sub.2 CN           S 40. ##STR50##            S ##STR51##            S 42.     CH.sub.2 CH.sub.2 NH.sub.2 S ##STR52##            CH.sub.2 ##STR53##            S 45.     CH.sub.2 CH.sub.2 CN  CH.sub.2 ##STR54##            CH.sub.2 ##STR55##            CH.sub.2 ##STR56## ##STR57## ##STR58## ##STR59## 50. ##STR60## ##STR61## ##STR62##            CH.sub.2 ##STR63##            CH.sub.2 ##STR64## ##STR65## ##STR66##            CH.sub.2 ##STR67## ##STR68## ##STR69##            CH.sub.2 ##STR70## ##STR71## ##STR72##            CH.sub.2 ##STR73## ##STR74## 60. ##STR75##            CH.sub.2 ##STR76## ##STR77## ##STR78##            CH.sub.2 ##STR79## ##STR80## ##STR81##            CH.sub.2 ##STR82## ##STR83## ##STR84##            CH.sub.2 ##STR85## ##STR86## ##STR87## ##STR88## ##STR89##            CH.sub.2 70. ##STR90##            CH.sub.2 ##STR91##            CH.sub.2 ##STR92## ##STR93## ##STR94##            CH.sub.2 ##STR95## ##STR96## ##STR97##            CH.sub.2 ##STR98##            CH.sub.2 ##STR99##            CH.sub.2 ##STR100##           CH.sub.2 ##STR101##           CH.sub.2 ______________________________________

Of the compounds listed above, we particularly prefer those which have the same configuration as thienamycin, i.e. (5R,6S)-6-[1(R)-hydroxyethyl]. In particular, the following compounds are preferred: apenem-3-carboxylic acid (isomer of Compound No. 1) arbapenem-3-carboxylic acid (isomer of Compound No. 6) arbapenem-3-carboxylic acid (isomer of Compound No. 7) )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 23) )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 24) )-methyl-2-carbapenem-3-carboxylic acid (isomer of Compound No. 27) droxyethyl]-2-carbapenem-3-carboxylic acid (isomer of Compound No. 28)

The above compounds may likewise be employed in the form of their pharmaceutically acceptable salts or esters, examples of which are well-known to those skilled in the art and which are given, for example, in U.S. Pat. No. 4,552,873, the disclosure of which is incorporated herein by reference.

The protective effect against renal toxicity appears to be exhibited by the whole range of amino acids wherein the amino and carboxylic acid groups are attached to a saturated aliphatic carbon chain or carbon atom. However, we have found that best results are achieved when employing N-acylated derivatives of those amino acids which may be represented by the formula (II):

wherein X represents a C.sub.1 -C.sub.10 alkylene group or a C.sub.1 -C.sub.10 alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, C.sub.6 -C.sub.14 aryloxy groups, substituted C.sub.6 -C.sub.14 aryloxy groups, C.sub.7 -C.sub.9 aralkyloxy groups, substituted C.sub.7 -C.sub.9 aralkyloxy groups, mercapto groups, C.sub.1 -C.sub.4 alkylthio groups, C.sub.6 -C.sub.14 arylthio groups, substituted C.sub.6 -C.sub.14 arylthio groups, C.sub.7 -C.sub.9 aralkylthio groups, substituted C.sub.7 -C.sub.9 aralkylthio groups, C.sub.2 -C.sub.5 carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting of C.sub.6 -C.sub.14 aryl groups, C.sub.7 -C.sub.9 aralkyl groups, substituted C.sub.7 -C.sub.9 aralkyl groups and carboxylic acyl groups,

C.sub.6 -C.sub.14 aryl groups, substituted C.sub.6 -C.sub.14 aryl groups, carboxy groups, amidino groups, sulfo groups, C.sub.1 -C.sub.4 alkylsulfinyl groups, C.sub.1 -C.sub.4 alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups.

In general terms, the N-acylated derivatives of these amino acids may be represented by the formula (III):

wherein R.sup.2 represents a carboxylic acyl group and X is as defined above.

N-acylated derivatives of ornithine and lysine may be represented by the general formula (IV):

and phenylalanine and phenylglycine derivatives may be represented by the general formula (V):

In the above formulae, n represents the integer 3 or 4, whilst m represents the cypher 0 or the integer 1.

Ph represents the phenyl group.

R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen atoms and carboxylic acyl groups, provided that R.sup.3 and R.sup.4 are not simultaneously hydrogen atoms.

Examples of carboxylic acyl groups which may be represented by R.sup.2, R.sup.3 and R.sup.4 include:

alkanoyl groups, and preferably alkanoyl groups having from 1 to 18, more preferably from 1 to 10 and still more preferably from 1 to 8, e.g. from 2 to 5 or from 5 to 8, carbon atoms, for example the acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl and decanoyl groups; in the case of those amino acids (e.g. ornithine, lysine, phenylglycine and phenylalanine) which have relatively bulky and lipophilic groups, lower (e.g. C.sub.2 -C.sub.5) alkanoyl groups are preferred; for others (e.g. glycine), higher (e.g. C.sub.5 -C.sub.8) groups are preferred;

alkenoyl and alkynoyl groups, and more preferably such groups having from 3 to 8, more preferably 3 or 4, carbon atoms, for example the acryloyl, methacryloyl, crotonoyl or propioloyl groups;

aromatic acyl groups in which the aryl ring is a carbocyclic ring having from 6 to 14, preferably 6 to 10, carbon atoms and optionally having from 1 to 5, more preferably from 1 to 3, substituents preferably selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups, sulfo groups and halogen atoms, for example the benzoyl and naphthoyl (1- or 2-naphthoyl) groups and the benzoyl and naphthoyl (1- or 2-naphthoyl) groups having one or more of the above substituents, for example the p-toluoyl, m-toluoyl, o-toluoyl, 4-butylbenzoyl, 4-hydroxybenzoyl, 3-hydroxybenzoyl, 2-hydroxybenzoyl, 4-methoxybenzoyl, 3-methoxybenzoyl, 2-methoxybenzoyl, 4-butoxybenzoyl, 4-aminobenzoyl, 3-aminobenzoyl, 2-aminobenzoyl, 3-sulfobenzoyl, 4-chlorobenzoyl, 3-fluorobenzoyl, 2-bromobenzoyl, 3-hydroxy-2-naphthoyl and 1-hydroxy-2-naphthoyl groups;

alicyclic acyl groups in which the carbocyclic ring has from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms, and in which the cycloalkane ring is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and phenyl groups, for example the cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, 1-phenyl-1-cyclopropanecarbonyl, 1-phenyl-1-cyclopentanecarbonyl, 1-methyl-1-cyclohexanecarbonyl and 1-phenyl-1-cyclohexanecarbonyl groups;

araliphatic acyl groups in which the aryl ring is a carbocyclic ring having from 6 to 14, preferably 6 to 10, carbon atoms and optionally having from 1 to 5, more preferably from 1 to 3, substituents preferably selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups, sulfo groups and halogen atoms, and in which the alkyl moiety has from 1 to 4 carbon atoms, such as the phenylacetyl, .alpha.-phenyl-.alpha.-methylacetyl, .alpha.-phenyl-.alpha.-ethylacetyl, .alpha.,.alpha.-diphenylacetyl, .alpha.-phenyl-.alpha.-cyclopentylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 4-tolylacetyl, 4-hydroxyphenylacetyl, 4-aminophenylacetyl, 4-methoxyphenylacetyl, 3-sulfophenylacetyl and 4-chlorophenylacetyl groups;

heterocyclic acyl groups which may have saturated or unsaturated ring systems, the rings having 5 to 6 ring atoms, of which from 1 to 3 are hetero-atoms independently selected fronm the group consisting of nitrogen, sulfur and oxygen atoms and the ring being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and hydroxy groups, for example the nicotinoyl, 2-thiophenecarbonyl, 2-furoyl, 2-pyrazinecarbonyl, 2-piperidinecarbonyl, N-methylnicotinoyl and 6-hydroxynicotinoyl groups;

alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms, for example the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and pentyloxycarbonyl groups; and

aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups, for example the benzyloxycarbonyl, .alpha.-methylbenzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-hydroxybenzyloxycarbonyl, p-tolyloxycarbonyl and 4-aminobenzyloxycarbonyl groups.

In addition to the acyl groups listed above, R.sup.2, R.sup.3 or R.sup.4 can also represent an acyl group derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups. Hence, R.sup.2, R.sup.3 and R.sup.4 can also represent such an acyl group connected to the parent amino acid via one or more amino acid residues, preferably from 0 to 5, more preferably from 0 to 3 and most preferably from 0 to 2, such residues. Hence, R.sup.2, R.sup.3 or R.sup.4 could represent a group derived from an N-acylated amino acid, for example the N-benzoylglycyl or N-benzoylglycylglycyl group. Hence, compounds of formula (I) also include such oligopeptide compounds as N-benzoylglycylglycine, N-benzoylglycylglycylglycine and similar compounds.

Preferred examples of groups which may be represented by R.sup.2, R.sup.3 and R.sup.4 include: saturated aliphatic acyl groups having from 1 to 8 carbon atoms; aromatic acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms; araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or  6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom; alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms; and aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups.

Particularly preferred groups which may be represented by R.sup.2, R.sup.3 and R.sup.4 include: aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, hydroxy groups and amino groups; alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms; phenylaliphatic acyl groups in which the phenyl groups is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms; and aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 or 1 substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups.

In addition, such acyl groups linked to the amino acid via at least one further amino acid residue are preferred.

Of the groups exemplified above, the following are most preferred: acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoxyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, of which the acetyl and benzoyl, particularly benzoyl, groups are most preferred.

As explained previously, the lower alkanoyl groups, notably the acetyl group, are only most preferred in relation to their use with those amino acids which have relatively bulky and lipophilic groups.

In the compounds of formula (II), X represents an alkylene group having from 1 to 10, preferably from 1 to 8 and more preferably from 1 to 5, carbon atoms. Such groups may have the "free" valencies attached to different carbon atoms or to the same carbon atom. In the latter case, the groups are sometimes referred to as "alkylidene" groups. Examples include the methylene, ethylidene, ethylene, propylidene, 1-methylethylidene, 1-methylethylene, trimethylene, butylidene, 2-methylpropylidene, 1-methylpropylidene, 1,2-dimethylethylene, 1-ethylethylene, 1-methyltrimethylene, 2-methyltrimethylene, tetramethylene, pentylidene, 3-methylbutylidene, 2-methylbutylidene, 2,2-dimethylpropylidene, 1-ethylpropylidene, 1,2-dimethylpropylidene, 1-propylethylene, 1-(1-methylethyl)ethylene, 1-ethyl-2-methylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,3-dimethyltrimethylene, 1-methyltetramethylene, 2-methyltetramethylene, pentamethylene, hexylidene, 4-methylpentylidene, 3-methylpentylidene, 2-methylpentylidene, 1-methylpentylidene, 2-ethylbutylidene, 1-ethylbutylidene, 1,3-dimethylbutylidene, 1,2-dimethylbutylidene, 3,3-dimethylbutylidene, 2,3-dimethylbutylidene, 1-butylethylene, 1-methyl-2-propylethylene, 1,2-diethylethylene, 1-methyl-1-propylethylene, 2-propyltrimethylene, 1-ethyl-3-methyltrimethylene, 1-ethyltetramethylene, 2-ethyltetramethylene, 1,3-dimethyltetramethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, hexamethylene, heptylidene, 5-methylhexylidene, 4-methylhexylidene, 3-methylhexylidene, 1-methylhexylidene, 3-ethylpentylidene, 1-ethylpentylidene, 4,4-dimethylpentylidene, 2,4-dimethylpentylidene, 1,2-dimethylpentylidene, 1-propylbutylidene, 2-ethyl-1-methylbutylidene, 1-ethyl-2-methylbutylidene, 1,2,2-trimethylbutylidene, 1,2,3-trimethylbutylidene, 1-pentylethylene, 1-butyl-2-methylethylene, 1-ethyl-2-propylethylene, 1-butyl-1-methylethylene, 1-ethyl-1-propylethylene, 1-butyltrimethylene, 2-butyltrimethylene, 1,3-diethyltrimethylene, 1-methyl-3-propyltrimethylene, 1-propyltetramethylene, 2-propyltetramethylene, 1-ethyl-4-methyltetramethylene, 3-ethyl-1-methyltetramethylene, 1-ethylpentamethylene, 3-ethylpentamethylene, 1,3-dimethylpentamethylene, 1-methylhexamethylene, 3-methylhexamethylene, heptamethylene, octylidene, 6-methylheptylidene, 4-methylheptylidene, 2-methylheptylidene, 1-methylheptylidene, 4-ethylhexylidene, 3-ethylhexylidene, 2-ethylhexylidene, 1-ethylhexylidene, 3,5-dimethylhexylidene, 4,5-dimethylhexylidene, 2,4-dimethylhexylidene, 1,5-dimethylhexylidene, 1,4-dimethylhexylidene, 2-propylpentylidene, 1-propylpentylidene, 2-ethyl-4-methylpentylidene, 3-ethyl-2-methylpentylidene, 3-ethyl-1-methylpentylidene, 1-ethyl-3-methylpentylidene, 3-methyl-1-propylbutylidene, 2-methyl-1-propylbutylidene, 1-ethyl-2,3-dimethylbutylidene, 1,2-diethylbutylidene, 1-hexylethylene, 1-methyl-2-pentylethylene, 1-butyl-2-ethylethylene, 1,2-dipropylethylene, 1-pentyltrimethylene, 2-pentyltrimethylene, 1-butyl-3-methyltrimethylene, 1-butyl-2-methyltrimethylene, 1-ethyl-3-propyltrimethylene, 1,2-dimethyl-3-propyltrimethylene, 1-butyltetramethylene, 1-methyl-4-propyltetramethylene, 1-propylpentamethylene, 3-propylpentamethylene, 2-ethyl-4-methylpentamethylene, 1-ethylhexamethylene, 3-ethylhexamethylene, 1,3-dimethylhexamethylene, 1-methylheptamethylene, 4-methylheptamethylene and octamethylene groups.

The alkylene group represented by X, including those alkylene groups exemplified above, may be unsubstituted or may have at least 1, preferably from 1 to 4 and more preferably 1 or 2, substituents selected from the following groups: from 6 to 10, ring carbon atoms and which is unsubstituted or has from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, for example the phenoxy, p-tolyloxy, 4-hydroxyphenoxy, 4-aminophenoxy and 4-methoxyphenoxy groups; or has from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, for example the benzyloxy, 4-methylbenzyloxy, 4-hydroxybenzyloxy, 4-aminobenzyloxy and 4-methoxybenzyloxy groups; groups; from 6 to 10, ring carbon atoms and which is unsubstituted or has from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, for example the phenylthio, p-tolylthio, 4-hydroxyphenylthio, 4-aminophenylthio and 4-methoxyphenylthio groups; or has from 1 to 5, more preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, for example the benzylthio, 4-methylbenzylthio, 4-hydroxybenzylthio, 4-aminobenzylthio and 4-methoxybenzylthio groups; moiety, for example the carboxymethylthio and carboxyethylthio groups; example the methylamino, ethylamino and dimethylamino groups; from 6 to 14 ring carbon atoms and is unsubstituted or has from 1 to 5, preferbly from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups, and C.sub.1 -C.sub.4 alkoxy groups, such as the phenylamino, p-tolylamino, 4-hydroxyphenylamino, 4-aminophenylamino and 4-methoxyphenylamino groups; wherein the aryl moiety is unsubstituted or has from 1 to 5, preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkyl groups, such as the benzylamino, 4-methylbenzylamino, 4-hydroxybenzylamino, 4-aminobenzylamino and 4-methoxybenzylamino groups; relation to R.sup.2, R.sup.3 and R.sup.4 ; or having from 1 to 5, preferably from 1 to 3, substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; ethanesulfinyl groups; ethanesulfonyl groups; and pyrazinyl, pyrimidinyl, pyridazinyl, indolazinyl, indolyl and indazolyl groups.

Preferred groups which may be represented by X include C.sub.1 -C.sub.5 alkylene groups which are unsubstituted or have one or two substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy groups; aryloxy groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; C.sub.7 -C.sub.9 aralkyloxy groups, wherein the aryl moiety is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; arylthio groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to  3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; C.sub.7 -C.sub.9 aralkylthio groups wherein the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxyalkylthio groups in which the alkyl part has from 1 to 4 carbon atoms; amino groups; amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two aryl substituents in which the aryl ring has from 6 to 14 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; amino groups having one or two C.sub.7 -C.sub.9 aralkyl substituents in which the aryl part is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; amino groups having one or two carboxylic acyl substituents as defined in relation to R.sup.2, R.sup.3 and R.sup.4 ; aryl groups having from 6 to 14 ring carbon atoms and being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms.

More preferred groups which may be represented by X are C.sub.1 -C.sub.5 alkylene groups which are unsubstituted or have 1 or 2 substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy groups; mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; amino groups; amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two carboxylic acyl substituents as defined for R.sup.2, R.sup.3 and R.sup.4 ; aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.

Preferred amino acids which may be represented by formula (II) include glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup..delta.,N.sup..delta. -dimethylornithine, N.sup..epsilon. -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine (=2-amino-4-ethoxybutyric acid), 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid and 4-amino-3-hydroxybutyric acid.

More preferred amino acids are glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, N.sup..delta.,N.sup..delta. -dimethylornithine, methionine, ethionine, O-methylserine, O-methylthreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-ethylphenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, ornithine, lysine, phenylalanine and phenylglycine.

The most preferred amino acids are .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine and phenylglycine.

When the amino acid derivative is an oligopeptide compound, such as a dipeptide or tripeptide, this type of compound is preferably formed by suitable combination of such amino acids as glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, phenylglycine, phenylalanine, methionine and histidine. Examples include leucylglycine, glycyl-.beta.-alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine and glycylglycylhistidine.

Specific examples of the amino acid compounds which may be employed in the present invention are given in the following list. It should, of course, be appreciated that these compounds can exist in the D-, L- and DL-forms and any of these forms can be employed. The compounds are hereinafter referred to by the numbers appended to them in this list. In the case of the mono-acylated derivatives of ornithine or substituted ornithine compounds, the acyl group can be present on either the N.sup..alpha. - or the N.sup..delta. -position, whilst, in the case of mono-acylated derivatives of lysine or substituted lysine compounds, the acyl group can be present on either the N.sup..alpha. - or N.sup..epsilon. -position. Of course, the respective individual mono-acylated derivatives or a mixture of the N.sup..alpha. and N.sup..delta. or N.sup..alpha. and N.sup..epsilon. derivatives may be used. When the compounds of the invention are hereinafter referred to by the numbers appended to them in the following list, the N.sup..alpha. isomer is identified by the appropriate number followed by the character ".alpha." , the N.sup..delta. isomer is identified by the number followed by ".delta." and the N.sup..epsilon. isomer is identified by the number followed by ".epsilon.". Where the number alone is given, a mixture is meant. Where the compound is identified by the number followed by ".alpha./.delta." or ".alpha./.epsilon.", this defines specifically the three options: the isolated N.sup..alpha. isomer; the isolated N.sup..delta. isomer or N.sup..epsilon. isomer; or a mixture of these two isomers. Other derivatives of amino acids having 2 or more amino groups (e.g. 2,3-diaminopropionic acid, 2,4-diaminobutyric acid and arginine) are identified similarly.

1. Glycine derivatives

2. .beta.-Alanine derivatives

3. 4-Aminobutyric acid derivatives.

4. 5-Aminovaleric acid derivatives

5. 6-Aminohexanoic acid derivatives.

6. 8-Aminooctanoic acid derivatives.

7. Alanine derivatives.

8. 2-Aminobutyric acid derivatives.

9. Norvaline derivatives.

10. Valine derivatives.

11. Leucine derivatives.

12. Isoleucine derivatives.

13. Norleucine derivatives.

14. Ornithine derivatives. -isobutyrylornithine -ethoxycarbonylornithine -butoxycarbonylornithine -methoxycarbonylornithine -cyclopropanecarbonylornithine

15. Lysine derivatives. -isobutyryllysine -cyclohexanecarbonyllysine -cyclohexanecarbonyllysine

16. Phenylalanine derivatives.

17. Phenylglycine derivatives.

18. Tyrosine derivatives.

19. O-Methyltyrosine derivatives.

20. Aspartic acid derivatives.

21. Glutamic acid derivatives.

22. 4-Carboxyglutamic acid derivatives.

23. 3-Methylaspartic acid derivatives.

24. 2-Aminoadipic acid derivatives.

25. 2-Aminopimelic acid derivatives.

26. 2-Aminosuberic acid derivatives.

27. 3-Hydroxyaspartic acid derivatives.

28. 3-Hydroxyglutamic acid derivatives.

29. 2,3-Diaminopropionic acid derivatives. acid -(.alpha.-phenyl-.alpha.-ethylacetyl)-2,3-diaminopropionic acid

30. 2,4-Diaminobutyric acid derivatives. acid -(.alpha.-phenyl-.alpha.-ethylacetyl)-2,4-diaminobutyric acid

31. 5-Hydroxylysine derivatives. -(.alpha.-phenyl-.alpha.-cyclopentylacetyl)-5-hydroxylysine

32. Arginine derivatives.

33. N.sup..delta.,N.sup..delta. -Dimethylornithine derivatives. -dimethylornithine -dimethylornithine -dimethylornithine -dimethylornithine -dimethylornithine -(.alpha.-phenyl-.alpha.-methylacetyl)-N.sup..delta.,N.sup..delta. -dimethylornithine -dimethylornithine -dimethylornithine -dimethylornithine

34. N.sup..epsilon. -Methyllysine derivatives.

35. Cysteine derivatives.

36. Methionine derivatives.

37. Ethionine derivatives.

38. S-Carboxymethylcysteine derivatives.

39. S-Benzylcysteine derivatives.

40. Methionine S-oxide derivatives.

41. Ethionine S-oxide derivatives.

42. Methionine S,S-dioxide derivatives.

43. Cysteic acid derivatives.

44. Serine derivatives.

45. O-methylserine derivatives.

46. Threonine derivatives.

47. O-Methylthreonine derivatives.

48. Homoserine derivatives.

49. Ethoxinine derivatives.

50. 3-Methoxyvaline derivatives.

51. 3-Phenylserine derivatives.

52. 3-Methyl-3-phenylalanine derivatives.

53. Histidine derivatives.

54. Tryptophan derivatives.

55. 2-Methylalanine derivatives.

56. 2-Methylserine derivatives.

57. 2-Hydroxyisoleucine derivatives.

58. 2-Methylmethionine derivatives.

59. 2-Ethyl-2-phenylglycine derivatives.

60. 3-Aminobutyric acid derivatives.

61. 3-Amino-4-methylvaleric acid derivatives.

62. 3-Amino-3-phenylpropionic acid derivatives.

63. 3-Amino-2-hydroxypropionic acid derivatives.

64. 4-Amino-3-hydroxybutyric acid

Of the amino acid derivatives listed above, the following are particularly preferred: Compounds No. 2-5, 2-6, 2-7, 2-18, 2-22, 4-6, 5-11, 5-18, 5-33, 6-3, 7-3, 7-5, 7-14, 8-4, 9-3, 10-4, 10-29, 10-45, 11-3, 11-24, 13-5, 14-27, 14-28, 14-29, 14-37, 14-38, 14-68, 15-27, 15-28, 15-29, 15-40, 15-41, 15-68, 15-71, 16-2, 16-3, 16-9, 16-15, 16-16, 16-24, 16-31, 16-36, 16 -44, 17-2, 17-13, 17-14, 17-19, 17-26, 19-3, 36-4, 36-11, 36-21, 37-2, 37-14, 46-3, 53-5, 53-6, 53-7, 60-3 and 62- 1. Of these, Compounds No. 2-22 and 10-45, especially No. 2-22, are most preferred.

The amino acid derivatives employed in the present invention are acids and, as such, are capable of forming salts; any pharmaceutically acceptable salt of these amino acids may be employed. Examples of such salts include: alkali metal salts such as the sodium or potassium salts; alkaline earth metal salts, such as the calcium salt; other metal salts, such as the magnesium, aluminum, iron, zinc, copper, nickel and cobalt salts; the ammonium salt; and salts with amino sugars, such as glucosamine and galactosamine.

The compositions of the invention may be prepared by any suitable method which involves mixing the antibiotic with the amino acid derivative and the invention is not intended to be limited by any particular method of preparation. Since the amino acid derivatives employed in this invention have, in general, very limited solubility in water, it is preferred that they should first be dispersed in water and then converted to a suitable salt by adding an aqueous solution of an appropriate base, for example: a metal compound, such as sodium hydroxide or potassium hydroxide, ammonia; or an amino sugar, such as glucosamine or galactosamine. Sufficient of the base is preferably added to adjust the pH of the mixture to a value within the range from 5.5 to 9, more preferably from 6 to 9.

The penem or carbapenem antibiotic is then added to the resulting solution. The mixed solution thus obtained may be employed as such or it may first be lyophilized to give a powdery mixture, which may be subsequently formulated into an appropriate dosage form suitable for the chosen route of administration, either by the manufacturer or prior to use.

The above mixing and preparation steps may take place at any temperature at which the components are fluid (especially the media) and are not decomposed, e.g. from 0.degree. to 100.degree. C., more conveniently from 0.degree. to 50.degree. C. and most conveniently at about ambient temperature.

Although it is convenient to administer the antibiotic and the amino acid derivative simultaneously in a single composition, it is, of course, clear that the two compounds may be administered separately, provided that they are administered sufficiently closely in time to each other that the amino acid derivative has a suitable concentration in the blood for all or most of the time that the antibiotic is present. Normally, it is anticipated that this will be achieved if the two compounds are administered within about one hour of each other, the amino acid preferably being administered before the antibiotic.

The composition of the invention is particularly suitable for use by intravenous administration.

There is no particular restriction on the relative proportions of the amino acid derivative and the penem or carbapenem antibiotic; in general, we have found that weight proportions of amino acid derivative to antibiotic of from 0.1:1 to 4:1 give good results, but equally proportions outside this range may successfully be employed. Approximately equal weights are generally most convenient.

The invention includes a method of treating a mammal suffering from a bacterial infection by administering to said mammal an antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics capable of causing renal damage; and an effective amount of a pharmaceutically acceptable N-acylated derivative of an amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof wherein said effective amount is at least sufficient to reduce, alleviate or eliminate said renal damage. A preferred composition comprises (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2- carbapenem-3-carboxylic acid; and N-benzoyl-.beta.-alanine. The weight ratio of said carbapenem to said alanine is from about 1:0.1 to 1:4 and preferably about 1:1.

The invention is further illustrated by the following Examples and Activity Tests. In the following, the penem or carbapenem antibiotics are referred to by the numbers appended to them in the foregoing list and are identified as "(Carba)-Penem Cpd No" whilst the amino acid derivatives are also identified by the numbers appended to them in the foregoing list and are referred to as "Amino Acid Cpd No.

5 g of N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine (Amino Acid Compound No. 15-27) were weighed out and dispersed in 80 ml of water. A 1N aqueous solution of sodium hydroxide was slowly added to this dispersion, and dissolved the N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine when the pH of the solution reached a value of 7-8. Then, 5 g of (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2- carbapenem-3-carboxylic acid (Carbapenem Compound No. 6) were dissolved in this solution, to give a total volume of 100 ml.

5 g of N-benzoyl-.beta.-alanine (Amino Acid Compound No. 2-22) were weighed out and dispersed in 40 ml of water. A 1N aqueous solution of sodium hydroxide was slowly added to this dispersion, and dissolved the N-benzoyl-.beta.-alanine when the pH of the solution reached a value of 7-8. Then, 5 g of (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2- carbapenem-3-carboxylic acid (Carbapenem Compound No. 6) were dissolved in this solution, to give a total volume of 50 ml.

Similar procedures to those described in Examples 1 and 2 were carried out, using the other penem or carbapenem antibiotic substances and the other acylated amino acid derivatives shown in the following Table, in the amounts shown in that Table.

In this Table, where the amino acid derivatives are not specified as being D- or L-, then they are the DL-form.

The preparation obtained by the procedure described in Example 1 was injected into the ear vein of a rabbit (about 3 kg body weight) in an amount of 3 ml/kg [that is 150 mg/kg of the carba penem Compound No. 6+150 mg/kg of N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine (amino acid Compound No. 15-27)]. A preparation which had been obtained by the same procedure as that described in Example 1 but not including the N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine was injected into another rabbit, as a control, in a similar manner to the above.

After one week, the kidneys of both rabbits were excised and examined. A change was observed in the renal tissue of the rabbits to which had been administered the preparation without the N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine, but no such change at all was observed in the renal tissue of rabbits to which had been administered the preparation containing the N.sup..alpha.,N.sup..epsilon. -dibenzoyllysine.

Similar experiments were carried out on other preparations which were prepared from other penem or carbapenem antibiotic substances and other amino acid derivatives. The Table also shows the results of these experiments.

The observed change in the renal tissue of the control rabbits was a degenerative necrosis of the proximal renal tubules in the region of the renal cortex. In the following Table, where the proportion of the total area of this region which exhibited such necrosis was from 0 to 25%, this is shown as +++. Where the area is less than 50% this is shown as ++ and where it is less than 75% this is shown as +. Where different animals within each test group exhibited different responses, this is shown as e.g. +++--++ or ++--+.

It should be noted that, whenever penem or carbapenem antibiotic substances which were not combined with amino acid derivatives were administered, a change in the renal tissue was observed. Hence, all of the experiments carried out (even where the effect is only "+") demonstrated a significant protective effect of the amino acid derivative. ______________________________________ Amino (Carba)-Penem Amount   Acid      Amount Cpd. No.  mg/kg    Cpd. No.  mg/kg  Effect ______________________________________ 6         150      1-5       150    + 6         150      1-8       150    ++ 6         150       1-10     150    + 6         150       1-11     150    ++ 6         150       1-12     150    + 6         150      2-3       150    ++ 6         150      2-4       150    ++ 6         150      2-5       150    +++ 6         250      2-6       250    +++ 6         150      2-7       150    +++ 6         150       2-10     150    ++ 6         150       2-11     150    ++ 6         150       2-13     150    ++ 6         150       2-14     150    ++ 6         150       2-15     150    ++ 6         250       2-18     250    +++ 6         150       2-22     150    +++ 6         200       2-22     200    +++ 6         300       2-22     300    +++ 6         300       2-22     150    ++ 6         400      3-3       400    +++ 6         150      3-6       150    + 6         150      3-8       150    + 6         150       3-15     150    + 6         150      4-1       150    + 6         150      4-4       150    + 6         150      4-5       150    ++ 5         150      4-6       150    +++ 6         150      5-3       150    ++ 6         150       5-11     150    ++ 6         150       5-14     150    + 6         250       5-18     250    ++ 6         150       5-33     150    +++ 6         150      6-2       150    ++ 6         50       6-3       150    +++ 6         150       6-11     150    ++ 6         150      7-2       150    + 6         150      7-3       150    +++ 6         150      7-5       150    +++ 6         150       7-12     150    ++ 6         150       7-18     150    ++ 6         150      8-2       150    + 6         150      8-4       150    +++ 6         150      8-8       150    ++ 6         150       8-10     150    + 6         150      9-3       150    +++ 6         150      9-5       150    + 6         150      10-4      150    +++ 6         250      10-19     250    ++ 6         150      10-24     150    + 6         150      10-30     150    + 6         150      10-32     150    + 6         150      10-33     150    + 6         150      10-34     150    ++ 6         150      10-35     150    ++ 6         150      10-45     150    +++ 6         400      10-45     400    +++ 6         400      10-45     200    ++ 6         150      11-3      150    +++ 6         150      11-6      150    + 6         150      11-7      150    + 6         150      11-8      150    + 6         150      11-24     150    +++ 6         150      12-1      150    ++ 6         150      12-4      150    ++ 6         150      13-1      150    ++ 6         150      13-2      150    ++ 6         150      13-5      150    +++ 6         150      13-12     150    + 6         150      14-18     150    +++-++ 6         150      14-21     150    +++-++ 6         150      14-26     150    +++-++ 6         150      14-27     150    +++ 6         150      14-28     150    +++ 6         150      14-29     150    +++ 6         150      14-44     150    +++-++ 6         150      14-65     150    ++ 6         150      14-71     150    + 6         150      15-18     150    +++-++ 6         150      15-21     150    +++-++ 6         150      15-26     150    +++-++ 6         150      15-27     300    +++ 6         150      15-27     150    +++ 6         150      15-27      75    +++ 6         150      15-27       37.5 +++-++ 6         150        .sub.--L-15-27 150    +++-++ 6         150       .sub.--D-15-27 150    +++ 6         150      15-28     150    +++-++ 6         150      15-29     150    +++ 6         150       .sub.--D-15-29 150    +++ 6         150      15-30     150    +++-++ 6         150      15-35     150    +++-++ 6         150      15-36     150    +++-++ 6         150      15-42     150    +++-++ 6         150      15-47     150    +++-++ 6         150      .sup.  15-55.alpha. 150    +++-++ 6         150      15-67     150    ++ 6         150      15-68     150    +++ 6         150      15-69     150    ++ 6         150      15-70     150    + 6         150      15-72     150    ++ 6         150      15-73     150    + 6         150      16-1      150    ++ 6         150       .sub.--D-16-1 150    ++ 6         150       .sub.--L-16-1 150    ++ 6         150      16-2      300    +++ 6         150      16-2      150    ++-+++ 6         150      16-2       75    ++ 6         150      16-2        37.5 +-++ 6         150       .sub.--D-16-2 150    ++-+++ 6         150       .sub.--L-16-2 150    ++-+++ 6         150      16-3      150    +++ 6         150      16-9      150    +++ 6         150      16-15     150    +++ 6         150      16-16     150    +++ 6         150      16-18     150    + 6         150      16-20     150    ++ 6         150      16-22     150    + 6         150      16-23     150    + 6         150      16-24     150    +++ 6         150      16-25     150    ++ 6         150      16-27     150    + 6         150      16-36     150    +++ 6         150      16-37     150    + 6         150      16-38     150    ++ 6         150      16-39     150    + 6         150      16-41     150    + 6         150      16-44     150    +++ 6         150      17-1      150    ++ 6         150       .sub.--D-17-1 150    ++ 6         150       .sub.--L-17-1 150    ++ 6         150      17-2      300    +++ 6         150      17-2      150    +++ 6         150      17-2       75    ++-+++ 6         150      17-2        37.5 ++ 6         150       .sub.--L-17-2 150    +++ 6         150      17-4      150    + 6         150      17-5      150    + 6         150      17-7      150    ++ 6         150      17-12     150    ++ 6         150      17-13     150    +++ 6         150      17-14     150    +++ 6         150      17-16     150    ++ 6         150      17-18     150    ++ 6         150      17-19     150    +++ 6         150      17-24     150    + 6         150      17-26     150    +++ 6         150      17-30     150    ++ 6         150      18-1      150    + 6         150      19-3      150    +++ 6         150      20-1      150    ++ 6         150      20-3      150    + 6         150      20-8      150    + 6         150      21-2      150    + 6         150      22-2      150    + 6         150      22-3      150    + 6         150      24-4      150    + 6         150      25-6      150    + 6         150      26-3      150    ++ 6         150      27-2      150    ++ 6         150      28-2      150    + 6         150      29-1      150    + 6         150      30-3      150    + 6         150      33-9      150    + 6         150      34-5      150    + 6         400      36-4      400    +++ 6         150      36-5      150    ++ 6         150      36-7      150    + 6         150      36-11     150    +++ 6         150      36-14     150    ++ 6         150      36-15     150    + 6         150      36-16     150    + 6         150      36-20     150    ++ 6         150      37-2      150    +++ 6         150      37-3      150    ++ 6         150      37-6      150    + 6         150      37-8      150    + 6         150      37-12     150    ++ 6         150      37-13     150    ++ 6         150      37-14     150    +++ 6         150      38-3      150    + 6         150      39-3      150    ++ 6         150      40-3      150    ++ 6         150      42-2      150    ++ 6         150      44-2      150    + 6         150      44-4      150    ++ 6         150      44-7      150    + 6         150      45-2      150    ++ 6         150      46-1      150    + 6         150      46-3      150    +++ 6         150      46-5      150    + 6         150      46-7      150    ++ 6         150      46-8      150    ++ 6         150      47-3      150    ++ 6         150      48-5      150    + 6         150      49-1      150    ++ 6         150      50-3      150    ++ 6         150      51-2      150    + 6         150      51-5      150    ++ 6         150      51-9      150    + 6         150      52-2      150    + 6         150      52-7      150    + 6         400      53-5      400    +++ 6         150      53-6      150    +++ 6         150      53-7      150    +++ 6         150      53-10     150    ++ 6         150      53-12     150    ++ 6         150      54-1      150    ++ 6         150      55-6      150    ++ 6         150      56-1      150    ++ 6         150      57-1      150    ++ 6         150      58-3      150    ++ 6         150      59-3      150    ++ 6         150      60-3      150    +++ 6         150      60-4      150    ++ 6         150      60-6      150    + 6         150      60-7      150    + 6         150      61-1      150    + 6         150      61-3      150    ++ 6         150      61-6      150    + 6         150      61-9      150    + 6         150      62-1      150    +++ 6         150      62-4      150    ++ 6         150      62-7      150    ++ 6         150      63-2      150    + 6         150      63-6      150    + 6         150      64-2      150    ++ 1         150       2-22     150    ++ 1         150      3-3       150    ++ 1         250       5-11     250    +++ 1         150       5-18     150    +++ 1         150      10-45     150    ++ 1         150      16-36     150    +++ 1         150      36-4      150    +++ 1         150      37-10     150    ++ 1         150      53-5      150    ++ 2         150      4-6       150    +++ 2         150       5-11     150    +++ 2         150       7-14     150    +++ 2         250      9-3       250    +++ 2         150      10-23     150    ++ 2         150      36-15     150    ++ 2         250      53-5      250    ++ 2         150      53-23     150    ++ 3         150       5-11     150    +++ 3         250      10-29     250    +++ 3         250      13-5      250    ++ 3         150      13-13     150    ++ 3         150      36-20     150    ++ 3         250      37-2      250    ++ 3         150      53-12     150    ++ 7         150       2-22     150    +++ 7         250       5-11     250    ++ 7         150      10-45     150    +++ 7         150      .sup.  14-14.alpha. 150    ++ 7         150      14-27     150    +++-++ 7         150      14-28     150    +++-++ 7         150      15-4.epsilon. 150    ++-+ 7         150      .sup.  15-12.alpha. 150    ++ 7         150      15-27     150    +++-++ 7         150      15-29     150    +++-++ 7         150      15-44     150    ++-+ 7         150      16-1      150    ++ 7         150      16-2      150    ++ 7         150      16-31     150    ++ + 7         150      17-1      150    ++ 7         150      17-2      150    ++-+++ 7         150      53-6      150    +++ 8         150       2-22     150    ++ 8         150       6-11     150    +-++ 8         150      14-29     150    +++-++ 8         150      15-27     150    +++ 8         150      16-1      150    ++ 8         150      16-2      150    ++-+++ 8         150      17-1      150    ++ 8         150      17-2      150    +++ 8         250      53-5      250    ++-+++ 9         150      36-6      150    + 9         250      53-5      250    ++ 10        150      13-5      150    ++ 10        150      21-6      150    + 11        150       2-22     150    ++ 11        150      15-28     150    +++ 11        150      16-2      150    ++-+++ 11        150      17-2      150    +++ 15        150      10-45     150    +++ 15        150      15-26     150    +++-++ 15        150      17-2      150    ++ 19        150        .sub.--L-10-45 150    ++ 19        150      15-27     150    +++ 19        150      17-2      150    ++ 22        250      36-4      250    ++ 22        150      37-15     150    +-++ 23        150       2-22     150    +++ 23        150      15-27     150    +++ 23        150      15-29     150    +++ 23        150      16-2      150    ++ 23        150      17-2      150    +++ 24        150       2-22     150    +++ 24        150      10-45     150    +++ 24        150       .sub.--D-10-45 150    +++ 24        150        .sub.--L-10-45 150    +++ 24        150      14-27     150    +++ 24        150      14-28     150    +++-++ 24        150      14-29     150    +++-++ 24        150      15-18     150    ++ 24        150      15-26     150    ++ 24        150      15-27     150    +++- ++ 24        150      15-28     150    +++-++ 24        150      15-29     150    +++ 24        150      15-47     150    ++ 24        150      16-1      150    ++ 24        150      16-2      150    ++-+++ 24        150      17-1      150    ++ 24        150      17-2      150    +++ 24        150      21-5      150    + 25        150      9-3       150    ++ 28        150       3-18     150    + 28        150      36-21     150    +++ 32        150       2-22     150    ++ 32        150      14-27     150    +++ 32        150      15-27     150    +++ 32        150      16-2      150    ++ 32        150      17-2      150    ++ 38        150       2-22     150    +++ 38        300      14-27     150    ++ 38        300      15-27     150    ++ 38        300      16-2      150    ++ 38        300      17-2      150    ++ 39        150      10-45     150    ++ 39        300      14-27     150    ++ 39        300      15-27     150    ++ 39        300      16-2      150    ++ 39        300      17-2      150    ++ 40        150       2-22     150    +++ 40        300      14-27     150    +++ 40        300      15-27     150    +++ 40        300      16-2      150    ++ 40        300      17-2      150    ++ 66        250      3-3       250    ++ 67        150       5-19     150    ++ 67        150      12-4      150    +-++ 71        250       2-18     250    +++ 71        250       5-21     250    ++ 73        150      11-27     150    + 73        150      37-10     150    ++ 75        150      16-36     150    ++ 75        150      36-9      150    ++ ______________________________________

## Claims

1. An antibiotic composition comprising: carbapenem antibiotics having renal toxicity; and wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof in an amount at least sufficient to reduce or eliminate said renal toxicity.

2. A composition as claimed in claim 1, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

3. A composition as claimed in claim 2, wherein said amino acid is a compound of formula (II): wherein X represents a C.sub.1 -C.sub.10 alkylene group or a C.sub.1 -C.sub.10 alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, C.sub.6 -C.sub.14 aryloxy groups, substituted C.sub.6 -C.sub.14 aryloxy groups, C.sub.7 -C.sub.9 aralkyloxy groups, substituted C.sub.7 -C.sub.9 aralkyloxy groups, mercapto groups, C.sub.1 -C.sub.4 alkylthio groups, C.sub.6 -C.sub.14 arylthio groups, substituted C.sub.6 -C.sub.14 arylthio groups, C.sub.7 -C.sub.9 aralkylthio groups, substituted C.sub.7 -C.sub.9 aralkylthio groups, C.sub.2 -C.sub.5 carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting of C.sub.6 -C.sub.14 aryl groups, C.sub.7 -C.sub.9 aralkyl groups, substituted C.sub.7 -C.sub.9 aralkyl groups and carboxylic acyl groups. carboxy groups, amidino groups, sulfo groups, C.sub.1 -C.sub.4 alkylsulfinyl groups, C.sub.1 -C.sub.4 alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups,

4. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of: C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents is selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups, sulfo groups and halogen atoms; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 and is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and phenyl groups; araliphatic acyl groups in which the aryl ring is a carbocyclic ring having from 6 to 14 carbon atoms and which is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups, sulfo groups and halogen atoms, and in which the alkyl moiety has from 1 to 4 carbon atoms; heterocyclic acyl groups which have saturated or unsaturated ring systems, the rings having 5 or 6 ring atoms, of which from 1 to 3 are hetero-atoms independently selected from the group consisting of nitrogen, sulfur and oxygen atoms and the ring being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and hydroxy groups; C.sub.2 -C.sub.7 alkoxycarbonyl groups; aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

5. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of: acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; atoms; araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom; alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

6. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of: which is unsubstituted or has a single substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, hydroxy groups and amino groups; alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms; phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms; atoms and has 0 or 1 substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy group; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

7. A composition as claimed in claim 3, wherein the N-acyl group is selected from the group consisting of: acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

8. A composition as claimed in claim 3, wherein X represents a C.sub.1 -C.sub.5 alkylene group which is unsubstituted or has one or two substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy groups; aryloxy groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; C.sub.7 -C.sub.9 aralkyloxy groups, wherein the aryl moiety is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; arylthio groups wherein the aryl ring has from 6 to 14 ring carbon atoms and which is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; C.sub.7 -C.sub.9 aralkylthio groups wherein the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxyalkylthio groups in which the alkyl part has from 1 to 4 carbon atoms; amino groups, amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two aryl substituents in which the aryl ring has from 6 to 14 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; amino groups having one or two C.sub.7 -C.sub.9 aralkyl substituents in which the aryl part is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; amino groups having one or two carboxylic acyl substituents; aryl groups having from 6 to 14 ring carbon atoms and being unsubstituted or having from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms.

9. A composition as claimed in claim 3, wherein X represents a C.sub.1 -C.sub.5 alkylene group which is unsubstituted or has 1 or 2 substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy groups; mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; amino groups; amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two carboxylic acyl substituents; aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.

10. A composition as claimed in claim 2, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup..delta.,N.sup..delta. -dimethylornithine, N.sup..epsilon. -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.

11. A composition as claimed in claim 2, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, N.sup..delta.,N.sup..delta. -dimethylornithine, methionine, ethionine, O-methylserine, O-methylthreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-ethylphenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, ornithine, lysine, phenylalanine or phenylglycine.

12. A composition as claimed in claim 2, wherein said amino acid is .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.

13. A composition as claimed in claim 2, wherein said amino acid is leucylglycine, glycyl-.beta.-alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.

14. A composition as claimed in claim 2, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, norvaline, valine, leucine, isoleucine, norleucine, N.sup..delta.,N.sup..delta. -dimethylornithine, methionine, ethionine, O-methylserine, O-methylthreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-ethylphenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acic, ornithine, lysine, phenylalanine or phenylglycine, and is N-acylated with an N-acyl group selected from the group consisting of: aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent; alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms; phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

15. A composition as claimed in claim 2, wherein said N-acylated amino acid is selected from the group consisting of:

16. A composition as claimed in claim 2, wherein said antibiotic is selected from the group consisting of compounds of formula (I): ##STR102## in which: Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii); substituents (i): selected from the group consisting of substituents (iii), C.sub.1 -C.sub.4 alkylideneamino groups, C.sub.1 -C.sub.4 aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alkoxyalkyl groups where the alkoxy and alkyl parts are each C.sub.1 -C.sub.4, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, C.sub.1 -C.sub.4 haloalkyl groups, heterocyclic acrylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C.sub.1 -C.sub.6 alkanoyl groups, C.sub.1 -C.sub.6 alkanesulfonyl groups, C.sub.1 -C.sub.6 alkanesulfinyl groups, hydroximino groups, C.sub.1 -C.sub.4 alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C.sub.1 -C.sub.4 and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups and C.sub.1 -C.sub.4 iminoalkyl groups; -C.sub.6 alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and pharmaceutically acceptable salts thereof.

17. A composition as claimed in claim 16, wherein Y represents a sulfur atom, a methylene group, or the group CH.sub.13 --CH<, CH.sub.3 O--CH< or (CH.sub.3).sub.2 C<.

18. A composition as claimed in claim 17, wherein R.sup.1 represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N.sup.1 -(2-carbamoyloxyethyl)-N.sup.1 -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.

19. A composition as claimed in claim 16, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid.

20. An antibiotic composition comprising: N-acylated derivatives of compounds of formula (II): -C.sub.10 alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, C.sub.6 -C.sub.14 aryloxy groups, substituted C.sub.6 -C.sub.14 aryloxy groups, C.sub.7 -C.sub.9 aralkyloxy groups, substituted C.sub.7 -C.sub.9 aralkyloxy groups, mercapto groups, C.sub.1 -C.sub.4 alkylthio groups, C.sub.6 -C.sub.14 arylthio groups, substituted C.sub.6 -C.sub.14 arylthio groups, C.sub.7 -C.sub.9 aralkylthio groups, substituted C.sub.7 -C.sub.9 aralkylthio groups, C.sub.2 -C.sub.5 carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting of C.sub.6 -C.sub.14 aryl groups, C.sub.7 -C.sub.9 aralkyl groups, substituted C.sub.7 -C.sub.9 aralkyl groups and carboxylic acyl groups, carboxy groups, amidino groups, sulfo groups, C.sub.1 -C.sub.4 alkylsulfinyl groups, C.sub.1 -C.sub.4 alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxyl groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; and pharmaceutically acceptable salt thereof; and formula (I): ##STR103## in which: Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii); selected from the group consisting of substituents (iii), C.sub.1 -C.sub.4 alkylideneamino groups, C.sub.1 -C.sub.4 aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkyl groups; alkoxyalkyl groups where the alkoxy and alkyl parts are each C.sub.1 -C.sub.4, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, C.sub.1 -C.sub.4 haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C.sub.1 -C.sub.6 alkanoyl groups, C.sub.1 -C.sub.6 alkanesulfonyl groups, C.sub.1 -C.sub.6 alkanesulfinyl groups, hydroximino groups, C.sub.1 -C.sub.4 alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C.sub.1 -C.sub.4 and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups and C.sub.1 -C.sub.4 iminoalkyl groups; -C.sub.6 alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; an amount at least sufficient to reduce or eliminate said renal toxicity.

21. A composition as claimed in claim 20, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

22. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of: acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy group; alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms; araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom; alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

23. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of: aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy group, hydroxy groups and amino groups; alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms; phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 or 1 substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

24. A composition as claimed in claim 21, wherein the N-acyl group is selected from the group consisting of: acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, napththoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

25. A composition as claimed in claim 21, wherein X represents a C.sub.1 -C.sub.5 alkylene group which is unsubstituted or has 1 to 2 substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy group; mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; amino groups; amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two carboxylic acyl substituents; aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.

26. A composition as claimed in claim 21, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenyglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup..delta.,N.sup..delta. -dimethylornithine, N.sup..delta. -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.

27. A composition as claimed in claim 21, wherein said amino acid is .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.

28. A composition as claimed in clsim 21, wherein said amino acid is leucylglycine, glycyl-.beta.-alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glyclylalanylvaline, glycylphenylalanylleucine, or glycylglycylhistidine.

29. A composition as claimed in claim 21, wherein said N-acylated amino acid is selected from the group consisting of:

30. A composition as claimed in 21 wherein Y represents a sulfur atom, a methylene group, or the group CH.sub.3 --CH<, CH.sub.3 O--CH< or (CH.sub.3).sub.2 C<.

31. A composition as claimed in claim 30, wherein R.sup.1 represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo-[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N.sup.1 -(2-carbamoyloxyethyl)-N.sup.1 -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.

32. A composition as claimed in claim 21, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid.

33. A composition as claimed in claim 32, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup..delta.,N.sup..delta. -dimethylornithine, N.sup..epsilon. -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.

34. A composition as claimed in claim 32, wherein said amino acid is .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.

35. A composition as claimed in claim 32, wherein said amino acid is leucylglycine, glycyl-.beta.-alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.

36. An antibiotic composition comprising: carbapenem antibiotics having renal toxicity; and wherein said derivative is selected from the group consisting of N-benzoylvaline and N-benzoyl-.beta.-alanine in an amount at least sufficient to reduce or eliminate said renal toxicity.

37. A composition as claimed in claim 36, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

38. A composition as claimed in claim 37, wherein said antibiotic is selected from the group consisting of compounds of formula (I): ##STR104## in which: Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii); selected from the group consisting of substituents (iii), C.sub.1 -C.sub.4 alkylideneamino groups, C.sub.1 -C.sub.4 aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alkoxyalkyl groups where the alkoxy and alkyl parts are each C.sub.1 -C.sub.4, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, C.sub.1 -C.sub.4 haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C.sub.1 -C.sub.6 alkanoyl groups, C.sub.1 -C.sub.6 alkanesulfonyl groups, C.sub.1 -C.sub.6 alkanesulfinyl groups, hydroximino groups, C.sub.1 -C.sub.4 alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub. 1 -C.sub.4 alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C.sub.1 -C.sub.4 and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups and C.sub.1 -C.sub.4 iminoalkyl groups; -C.sub.6 alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups;

39. A composition as claimed in claim 38, wherein Y represents a sulfur atom, a methylene group, or the group CH.sub.3 --CH<, CH.sub.3 O--CH< or (CH.sub.3).sub.2 C<.

40. A composition as claimed in claim 39, wherein R.sup.1 represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group.

41. A composition as claimed in claim 37, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid.

42. An antibiotic composition comprising: carbapenem antibiotics having renal toxicity; and is selected from the group consisting of ornithine, lysine, phenylglycine and phenylalanine and salts thereof in an amount at least sufficient to reduce or eliminate said renal toxicity.

43. A composition as claimed in claim 42, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

44. A composition as claimed in claim 43, wherein said N-acylated amino acid is a compound of formula (IV): wherein: hydrogen atoms and carboxylic acyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen; or a pharmaceutically acceptable salt thereof.

45. A composition as claimed in claim 44, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen atoms; C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups; provided that R.sup.3 and R.sup.4 are not both hydrogen.

46. A composition as claimed in claim 44, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen atoms.

47. A composition as claimed in claim 44, wherein at least one of R.sup.3 and R.sup.4 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

48. A composition as claimed in claim 43, wherein said N-acylated amino acid is a compound of formula (V): wherein:

49. A composition as claimed in claim 48, wherein R.sup.2 is selected from the group consisting of: C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups.

50. A composition as claimed in claim 48, wherein R.sup.2 is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

51. A composition as claimed in claim 48, wherein R.sup.2 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

52. A composition as claimed in claim 43, wherein said N-acylated amino acid is selected from the group consisting of:

53. A composition as claimed in claim 43, wherein said antibiotic is selected from the group consisting of compounds of formula (I): ##STR105## wherein: Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoro-propyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group.

54. A composition as claimed in claim 53, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and roxyethyl]-2-carbapenem-3-carboxylic acid.

55. An antibiotic composition comprising: compounds of formula (IV): hydrogen atoms and carboxylic acyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen, and compounds of formula (V): formula (I): ##STR106## wherein: Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and N.sup.1,N.sup.1 -dimethyl-amidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallyl-amidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group an amount at least sufficient to reduce or eliminate said renal toxicity.

56. The composition as claimed in claim 55, wherein the weight ratio of said N-acylated amino acid to said antibiotic is about from 0.1:1 to 4:1.

57. A composition as claimed in claim 56, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen atoms; C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups; provided that R.sup.3 and R.sup.4 are not both hydrogen.

58. A composition as claimed in claim 56, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen atoms.

59. A composition as claimed in claim 56, wherein at least one of R.sup.3 and R.sup.4 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

60. A composition as claimed in claim 56, wherein R.sup.2 is selected from the group consisting of: C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups.

61. A composition as claimed in claim 56, wherein R.sup.2 is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

62. A composition as claimed in claim 56, wherein R.sup.2 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

63. A composition as claimed in claim 56, wherein said N-acylated amino acid is selected from the group consisting of: and said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid.

64. The antibiotic composition comprising: (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)hydroxyethyl]-2-c arbapenem-3-carboxylic acid; and 1:0.1 to 1:4.

65. A composition as claimed in claim 64, wherein said weight ratio is about 1:1.

66. An antibiotic composition comprising: (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)hydroxyethyl]-2-c arbapenem-3-carboxylic acid; and eliminate renal toxicity of said carbapenem.

67. A composition as claimed in claim 66, wherein the weight ratio of (a) to (b) is from about 1:0.1 to 1:4.

68. A composition as claimed in claim 67, wherein said weight ratio is about 1:1.

69. A method of treating a mammal suffering from a bacterial infection by administering to said mammal: carbapenem antibiotics capable of causing renal damage in an amount effective to treat said bacterial infection; and amino acid wherein the amino group and the carboxylic acid group are attached to a saturated aliphatic carbon chain or carbon atom, or a salt thereof at least sufficient to reduce, alleviate or prevent said renal damage; mammal sufficiently closely in time to each other that the amino acid derivative has a suitable concentration in the blood while said antibiotic is in the blood to reduce, alleviate or prevent said renal damage.

70. The method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered concurrently.

71. The method as claimed in claim 70, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

72. The method as claimed in claim 69, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

73. A method as claimed in claim 72, wherein said amino acid is a compound of formula (II): wherein X represents a C.sub.1 -C.sub.10 alkylene group or a C.sub.1 -C.sub.10 alkylene group having at least one substituent selected from the group consisting of hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, C.sub.6 -C.sub.14 aryloxy groups, substituted C.sub.6 -C.sub.14 aryloxy groups, C.sub.7 -C.sub.9 aralkyloxy groups, substituted C.sub.7 -C.sub.9 aralkyloxy groups, mercapto groups, C.sub.1 -C.sub.4 alkylthio groups, C.sub.6 -C.sub.14 arylthio groups, substituted C.sub.6 C.sub.14 arylthio groups, C.sub.7 -C.sub.9 aralkylthio groups, substituted C.sub.7 -C.sub.9 aralkylthio groups, C.sub.2 -C.sub.5 carboxyalkylthio groups, amino groups, amino groups having one or two substituents selected from the group consisting of C.sub.6 -C.sub.14 aryl groups, C.sub.7 -C.sub.9 aralkyl groups, substituted C.sub.7 -C.sub.9 aralkyl groups and carboxylic acyl groups, C.sub.6 -C.sub.14 aryl groups, substituted C.sub.6 -C.sub.14 aryl groups, carboxy groups, amidino groups, sulfo groups, C.sub.1 -C.sub.4 alkylsulfinyl groups, C.sub.1 -C.sub.4 alkylsulfonyl groups and heterocyclic groups having from 5 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, said substituted aryloxy, aralkyloxy, arylthio, aralkylthio, aryl and aralkyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups, or a pharmaceutically acceptable salt thereof.

74. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of: saturated aliphatic acyl groups having from 1 to 8 carbon atoms; aromatic acyl groups in which the aryl moiety has from 6 to 10 ring carbon atoms and is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alicyclic acyl groups in which the cycloalkane ring has from 3 to 6 carbon atoms; araliphatic acyl groups in which the aryl ring has from 6 to 10 ring carbon atoms and the alkyl group has from 1 to 4 carbon atoms, the aryl ring being unsubstituted or having from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; heterocyclic acyl groups in which the heterocyclic ring is saturated or unsaturated and has 5 or 6 ring atoms of which one is a nitrogen, sulfur or oxygen hetero-atom; alkoxycarbonyl groups having a total of from 2 to 7 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl moiety has from 7 to 9 carbon atoms and the aryl ring is unsubstituted or has from 1 to 3 substituents independently selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

75. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of: aromatic acyl groups in which the aryl ring has from 6 to 10 ring atoms and which is unsubstituted or has a single substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups, hydroxy groups and amino groups; alicyclic acyl groups in which the cycloalkane moiety has from 3 to 6 carbon atoms; phenylaliphatic acyl groups in which the phenyl group is unsubstituted or has a single C.sub.1 -C.sub.4 alkyl substituent, and in which the alkyl part has from 1 to 4 carbon atoms; alkoxycarbonyl groups having a total of from 4 to 6 carbon atoms; aralkyloxycarbonyl groups in which the aralkyl part has from 7 to 9 carbon atoms and has 0 to 1 substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and acyl groups derived from an amino acid by removal of OH from the carboxylic acid group and N-acylation of the amino group with at least one of the above-mentioned acyl groups.

76. A method as claimed in claim 73, wherein the N-acyl group is selected from the group consisting of: acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, napththoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

77. A method as claimed in claim 73, wherein X represents a C.sub.1 -C.sub.5 alkylene group which is unsubstituted or has 1 or 2 substituents independently selected from the group consisting of: hydroxy groups; C.sub.1 -C.sub.4 alkoxy groups; mercapto groups; C.sub.1 -C.sub.4 alkylthio groups; amino groups; amino groups having one or two C.sub.1 -C.sub.4 alkyl substituents; amino groups having one or two carboxylic acyl substituents; aryl groups having from 6 to 14 carbon atoms wherein the aryl ring is unsubstituted or has from 1 to 3 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, amino groups and C.sub.1 -C.sub.4 alkoxy groups; carboxy groups; and heterocyclic groups having from 5 to 9 ring atoms, of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen and oxygen hetero-atoms.

78. A method as claimed in claim 72, wherein said amino acid is glycine, .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 8-aminooctanoic acid, alanine, 2-aminobutyric acid, norvaline, valine, leucine, isoleucine, norleucine, phenylglycine, phenylalanine, tyrosine, O-methyltyrosine, aspartic acid, glutamic acid, 4-carboxyglutamic acid, 3-methylaspartic acid, 2-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid, 3-hydroxyaspartic acid, 3-hydroxyglutamic acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, 5-hydroxylysine, arginine, N.sup..delta.,N.sup..delta. -dimethylornithine, N.sup..epsilon. -methyllysine, cysteine, methionine, ethionine, S-carboxymethylcysteine, S-benzylcysteine, methionine S-oxide, ethionine S-oxide, methionine S,S-dioxide, cysteic acid, serine, O-methylserine, threonine, O-methylthreonine, homothreonine, ethoxinine, 3-methoxyvaline, 3-phenylserine, 3-methyl-3-phenylalanine, histidine, tryptophan, 2-methylalanine, 2-methylserine, 2-hydroxyisoleucine, 2-methylmethionine, 2-ethyl-2-phenylglycine, 3-aminobutyric acid, 3-amino-4-methylvaleric acid, 3-amino-3-phenylpropionic acid, 3-amino-2-hydroxypropionic acid or 4-amino-3-hydroxybutyric acid.

79. A method as claimed in claim 72, wherein said amino acid is .beta.-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, alanine, valine, leucine, norleucine, methionine, histidine, ornithine, glycine, phenylalanine or phenylglycine.

80. A method as claimed in claim 72, wherein said amino acid is leucylglycine, glycyl-.beta.-alanine, glycylalanine, valylalanine, leucylalanine, glycylvaline, alanylvaline, leucylvaline, valylleucine, phenylalanylleucine, histidylleucine, glycylphenylalanine, alanylphenylalanine, leucylphenylalanine, glycylmethionine, valylmethionine, glycylhistidine, alanylvalylglycine, glycylalanylvaline, glycylphenylalanylleucine or glycylglycylhistidine.

81. A method as claimed in claim 72, wherein said antibiotic is selected from the group consisting of compounds of formula (I): ##STR107## in which: Y represents a sulfur atom, a methylene group or a methylene group having 1 or 2 substituents selected from the group consisting of methyl and methoxy groups; and group having at least one substituent selected from the group consisting of substituents (i) or a heterocyclic group having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms where said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii); selected from the group consisting of substituents (iii), C.sub.1 -C.sub.4 alkylideneamino groups, C.sub.1 -C.sub.4 aminoalkylideneamino groups, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), heterocyclic groups having from 4 to 14 ring atoms of which from 1 to 5 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms wherein said heterocyclic group is unsubstituted or has at least one substituent selected from the group consisting of substituents (ii), imino groups, cyano groups, carbamoyl groups and carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; alkoxyalkyl groups where the alkoxy and alkyl parts are each C.sub.1 -C.sub.4, carbamoyl groups, carbamoyl groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, C.sub.1 -C.sub.4 haloalkyl groups, heterocyclic acylimidoyl groups where the heterocyclic part has from 5 to 9 ring atoms of which from 1 to 3 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur hetero-atoms, amidino groups, amidino groups having from 1 to 3 substituents selected from the group consisting of substituents (iii), imino groups, oxygen atoms, C.sub.1 -C.sub.6 alkanoyl groups, C.sub.1 -C.sub.6 alkanesulfonyl groups, C.sub.1 -C.sub.6 alkanesulfinyl groups, hydroximino groups, C.sub.1 -C.sub.4 alkoximino groups, carbamoyloxy groups, carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups, carbamoyloxyalkyl groups where the alkyl part is C.sub.1 -C.sub.4 and the carbamoyl part is unsubstituted or has at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups and C.sub.1 -C.sub.4 iminoalkyl groups; -C.sub.6 alkynyl groups, oxygen atoms and said alkyl, alkenyl and alkynyl groups having at least one substituent selected from the group consisting of halogen atoms, carbamoyloxy groups and carbamoyloxy groups having at least one substituent selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups and C.sub.1 -C.sub.4 alkoxy groups; and pharmaceutically acceptable salts thereof.

82. A method as claimed in claim 81, wherein Y represents a sulfur atom, a methylene group, or the group CH.sub.3 --CH<, CH.sub.3 O--CH< or (CH.sub.3).sub.2 C<.

83. A method as claimed in claim 82, wherein R.sup.1 represents an ethyl, 2-fluoroethyl, 2-(aminomethyleneamino)ethyl, N.sup.1,N.sup.1 -dimethylamidinomethyl, N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl, 1-carbamoylethyl, 2-(1-aminoethylideneamino)ethyl, 1-amidino-3-pyrrolidinyl, 2-methyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 2-methoxymethyl-1,3-diazabicyclo[3.3.0]oct-2-en-7-yl, 5-imino-2-pyrrolidinyl, 2-imino-5-piperidinyl, 1-acetimidoyl-5-methylcarbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-methoxycarbamoyl-3-pyrrolidinyl, 2-imino-2-(S-oxothiomorpholino)ethyl, 2-imino-2-(1,1-dioxo-1,3-thiazolidin-3-yl)ethyl, 2-imino-2-(S,S-dioxothiomorpholino)ethyl, 2-imino-2-(3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3,5-dioxo-1-piperazinyl)ethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-acetyl-3-oxo-1-piperazinyl)ethyl, 2-imino-2-(4-methanesulfonyl-3-oxo-1-piperazinyl)ethyl, N.sup.1 -(2-carbamoyloxyethyl)-N.sup.1 -methylamidinomethyl, 2-(3-hydroximino-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-methoximino-1-pyrrolidinyl)ethyl, 2-(4-hydroximinopiperidino)-2-iminoethyl, 2-imino-2-(4-methoximinopiperidino)ethyl, 2-(3-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-imino-2-(3-oxo-1-piperazinyl)ethyl, 2-(3-carbamoylpiperidino)-2-iminoethyl, 2-(3-carbamoyloxypiperidino)-2-iminoethyl, 2-(2-carbamoyloxy-1-pyrrolidinyl)-2-iminoethyl, 2-(2-carbamoyloxymethyl-1-pyrrolidinyl)-2-iminoethyl, 2-(4-carbamoyloxypiperidino)-2-iminoethyl, 2-(4-formyl-1-piperazinyl)-2-iminoethyl, 2-(4-acetyl-1-piperazinyl)-2-iminoethyl, 1-formyl-3-azetidinyl, 1-iminomethyl-3-azetidinyl, 1-methyl-4-piperidyl, 1-acetimidoyl-4-piperidyl or 1-acetyl-3-pyrrolidinyl group.

84. A method as claimed in claim 82, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-.beta.-alanine.

85. A method as claimed in claim 81, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid -methyl-2-carbapenem-3-carboxylic acid -methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid and said N-acylated amino acid is selected from the group consisting of:

86. A method as claimed in claim 81, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-.beta.-alanine.

87. A method as claimed in claim 86, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.

88. A method as claimed in claim 86, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.

89. The method as claimed in claim 86, wherein said antibiotic and said N-acylated derivatives of an amino acid are administered concurrently.

90. A method as claimed in claim 72, wherein said N-acylated derivative of an amino acid is selected from the group consisting of N-benzoylvaline and N-benzoyl-.beta.-alanine.

91. A method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.

92. The method as claimed in claim 91, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

93. A method as claimed in claim 69, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.

94. The method as claimed in claim 93, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

95. A method of treating a mammal suffering from a bacterial infection by administering to said mammal: said antibiotic selected from the group consisting of penem antibiotics and carbapenem antibiotics having renal toxicity; and amino acid selected from the group consisting of ornithine, lysine, phenylglycine and phenylalanine at least sufficient to reduce or eliminate said renal toxicity; sequentially within one hour of each other.

96. A method as claimed in claim 95, wherein the weight ratio of said N-acylated amino acid to said antibiotic is from about 0.1:1 to 4:1.

97. A method as claimed in claim 96, wherein said N-acylated amino acid is a compound of formula (IV): wherein: hydrogen atoms and carboxylic acyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen; or a pharmaceutically acceptable salt thereof.

98. A method as claimed in claim 97, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of: hydrogen atoms; C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl group where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups; C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxyl groups; provided that R.sup.3 and R.sup.4 are not both hydrogen.

99. A method as claimed in claim 97, wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen atoms and acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups, provided that R.sup.3 and R.sup.4 are not both hydrogen atoms.

100. A method as claimed in claim 97, wherein at least one of R.sup.3 and R.sup.4 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

101. A method as claimed in claim 96, wherein said N-acylated amino acid is a compound of formula (V): wherein: acceptable salt thereof.

102. A method as claimed in claim 101, wherein R.sup.2 is selected from the group consisting of: C.sub.1 -C.sub.18 alkanoyl groups; C.sub.3 -C.sub.8 alkenoyl groups; C.sub.3 -C.sub.8 alkynoyl groups; aromatic acyl groups wherein the aryl part is C.sub.6 -C.sub.14 carbocyclic aryl and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of C.sub.1 -C.sub.4 alkyl groups, hydroxy groups, C.sub.1 -C.sub.4 alkoxy groups, amino groups and sulfo groups; cycloalkanecarbonyl groups where the cycloalkane part is C.sub.3 -C.sub.8 ; C.sub.2 -C.sub.7 alkoxycarbonyl groups; and aralkyloxycarbonyl groups where the aralkyl part has from 7 to 9 carbon atoms and is unsubstituted or has from 1 to 5 substituents selected from the group consisting of amino groups, C.sub.1 -C.sub.4 alkyl groups, C.sub.1 -C.sub.4 alkoxy groups and hydroxy groups.

103. A method as claimed in claim 101, wherein R.sup.2 is selected from the group consisting of acetyl, benzoyl, cyclohexanecarbonyl, cyclopropanecarbonyl, hexanoyl, isobutyryl, crotonoyl, ethoxycarbonyl, 4-hydroxybenzoyl, anisoyl, 4-aminobenzoyl, naphthoyl, toluoyl, benzyloxycarbonyl and 4-methoxybenzyloxycarbonyl groups.

104. A method as claimed in claim 101, wherein R.sup.2 represents an acyl group selected from the group consisting of acetyl and benzoyl groups.

105. A method as claimed in claim 96, wherein said N-acylated amino acid is selected from the group consisting of:

106. A method as claimed in claim 96, wherein said antibiotic is a compound of formula (I): ##STR108## wherein: Y represents a sulfur atom, a methylene group, or a methylene group having 1 or 2 methyl substituents; and N.sup.1,N.sup.1,N.sup.2 -trimethylamidinomethyl, 3-pyrrolidinyl, 1-formimidoyl-3-pyrrolidinyl, 1-acetimidoyl-3-pyrrolidinyl, 1-propionimidoyl-3-pyrrolidinyl, 2-methyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 2-methoxymethyl-1,4,5,6-tetrahy dro-5-pyrimidinyl, 3-azetidinyl, 1-acetimidoyl-3-azetidinyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidinomethyl, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -(3-fluoropropyl)-N.sup.1 -methylamidinomethyl, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidinomethyl, 1-(3-azetidinyl)ethyl, 1-(1-acetimidoyl-3-azetidinyl)ethyl, 1,4,5,6-tetrahydro-2-pyrimidinylmethyl, 1-(4,5-dihydro-2-thiazolyl)ethyl, 5-carbamoyl-3-pyrrolidinyl, 1-acetimidoyl-5-carbamoyl-3-pyrrolidinyl, 2-chloromethyl-1,4,5,6-tetrahydro-5-pyrimidinyl, 1-butyrimidoyl-3-pyrrolidinyl, 1-nicotinimidoyl-3-pyrrolidinyl, N.sup.1,N.sup.1 -diallyl-amidinomethyl, N.sup.1 -methyl-N.sup.1 -(2-propynyl)amidino, N.sup.1 -(2-fluoroethyl)-N.sup.1 -methylamidino, N.sup.1 -(3-fluoro-propyl)-N.sup.1 -methylamidino, N.sup.1 -methyl-N.sup.1 -(2,2,2-trifluoroethyl)amidino, N.sup.1 -allyl-N.sup.1 -methylamidinomethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-cyano-1-methylethyl, 2-aminoethyl or 1-carbamoylethyl group and pharmaceutically acceptable salts thereof.

107. A method as claimed in claim 106, wherein said antibiotic is selected from the group consisting of: apenem-3-carboxylic acid arbapenem-3-carboxylic acid arbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid )-methyl-2-carbapenem-3-carboxylic acid and droxyethyl]-2-carbapenem-3-carboxylic acid.

108. A method as claimed in claim 96, wherein said antibiotic and said N-acylated derivative of an amino acid are administered together.

109. A method as claimed in claim 96, wherein said antibiotic and said N-acylated derivative of an amino acid are administered sequentially within 1 hour of each other.

110. The method of treating a mammal suffering from a bacterial infection by administering to said mammal: (5R,6S)-2-[(3S)-1-acetimidoylpyrrolidin-3-ylthio]-6-[1(R)-hydroxyethyl]-2- carbapenem-3-carboxylic acid in an amount effective to treat said bacterial infection; and renal toxicity of said carbapenem; and sufficiently closely in time to each other that concentration in the blood while said antibiotic is in the blood, is sufficient to reduce or eliminate said renal toxicity.

111. The method as claimed in claim 110, wherein the weight ratio of (a) to (b) is from about 1:0.1 to 1:4.

112. The method as claimed in claim 111, wherein said weight ratio is about 1:1.

113. The method as claimed in claim 111, wherein (a) and (b) are administered together.

114. The method as claimed in claim 110, wherein (a) and (b) are administered concurrently.

115. The method as claimed in claim 110, wherein (a) and (b) are administered sequentially within one hour of each other.

116. The method as claimed in claim 110, wherein (a) and (b) are administered together.