REVIEWS OF INFECTIOUS DISEASES. VOL. 1, NO.1. JANUARY-FEBRUARY 1979 © 1979 by The University of Chicago. 0162-0886/79/0101-0009$01.37

Cefoxitin and Cephamycins: Microbiological Studies Edward O. Stapley, Jerome Birnbaum, A. Kathrine Miller, Hyman Wallick, David Hendlin, and H. Boyd Woodruff

From the Merck Institute for Therapeutic Research, Rahway, New Jersey

The discovery of a new family of ,8-lactam antibiotics, the cephamycins, was reported in 1972 from the Merck Sharp and Dohme Research Laboratories (Rahway, N.].) by Stapley et al. [1] and Miller et al. [2]. The independent discovery of cephamycin C had been reported by N agarajan et al. [3]. As a product of the Streptomyces, this new family of antibiotics was of interest because it exhibited important biological differences from the closely related cephalosporin antibiotics, which are produced by the filamentous fungi of the genus Cephalosporium. As shown in figure 1, both the cephamycins and the cephalosporins share the basic cephem nucleus. The natural products have the same side chain (a-aminoadipic acid) in the 7 position. However, the cephamycins have a methoxyl group in place of the hydrogen at the 7 position of the cephalosporins and, as a consequence, are resistant to degradation by ,8-lactamase. Furthermore, anyone of several substituents may be seen at the 3 position of the cephamycins, whereas the acetoxy group is found at this position on the natural cephalosporins. The presence of these changes in the side chain at the 3 position results in stability of cephamycin to mammalian enzymes that are capable of deacetylating cephalosporin C.

In accordance with the precedent for naming of antibiotics, the new family of ,B-lactam antibiotics was called cephamycin. This name recognizes the chemical nature of the material (i.e., derivation from a cephem nucleus) as well as the biological source of the material (Streptomyces, a genus of filamentous bacteria). The name cephamycin connotes the presence of the 7-a-methoxy group instead of the 7-a-hydrogen that is characteristic of the cephalosporins. Many important characteristics of the cephamycin antibiotics are related to this essential chemical difference. The many articles that refer to this group of compounds in the biological literature provide clear evidence that the new terminology has been accepted (for examples, see [49]). Studies reported by Stapley et al. [I], Miller et al. [10, 11], and Daoust et al. [12] showed that the cephamycins represented an interesting family of antibiotics with potentially valuable characteristics as judged from both in vitro and in vivo experiments. Cephamycin A was found to be a broad-spectrum antibiotic active both in vitro and in vivo against gram-positive as well as gram-negative pathogens. Cephamycins Band C, in contrast, were narrow-spectrum agents active against gram-positive and gram-negative organisms, respectively. The potency and chemical stability of cephamycins A and B left much to be desired, whereas both the potency and the chemical stability of cephamycin C were excellent. All

Please address requests for reprints to Dr. Edward O. Stapley, Merck Institute for Therapeutic Research, Box 2000, Rahway, New Jersey 07065.


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The cephamycins are a family of ,8-lactam antibiotics that are produced by actinomycetes and are structurally similar to the cephalosporins. They are characterized by the presence of a 7-a-methoxyl group, which confers unusually high resistance to ,8-lactamases. Cefoxitin, the first semisynthetic cephamycin, is resistant to almost all ,8-lactamases. Cefoxitin retains the 3-carbamoyl group of cephamycin C and thus has excellent metabolic stability. Cefoxitin is bactericidal and almost devoid of any inoculum effect. Active against many cephalothin-resistant gram-negative bacteria, cefoxitin demonstrates a very broad spectrum that includes indole-positive Proteus and many strains of Serratia. In contrast to that of the cephalosporins, cefoxitin's spectrum of activity against anaerobic pathogens includes Bacteroides fragilis. The therapeutic effectiveness of cefoxitin in experimental infections in mice confirms the excellent characteristics of this semisynthetic cephamycin and indicates that it should be a very valuable agent for treatment of bacterial infections.


Stapley et al.



three compounds were found to be highly resistant to ,B-Iactamase, and Daoust [12] suggested that this attribute might well be the reason for the excellent activity of cephamycin C against many cephalosporin-resistant pathogens. Miller et al. [11] reported, on the basis of preliminary studies, that cephamycin C was a remarkably nontoxic antibiotic. Mice were shown to survive, without evidence of toxicity, an ip dose of 10 g/kg. Thus, the cephamycins possessed many desirable characteristics. Cephamycin C was clearly the most valuable compound in terms of potency and chemical stability but lacked the breadth of spectrum that had been observed in the less stable substance cephamycin A. Cefoxitin, A Derivative of Cephamycin C

The studies performed with the cephamycins clearly indicated that it was desirable to develop a semisynthetic form of cephamycin C that would broaden its spectrum while retaining its characteristics of potency, stability, and activity against cephalosporin-resistant gram-negative pathogens.

A major program of chemical synthesis was developed in the Merck Research Laboratories because the well-known chemistry that had been applied in the development of the semisynthetic cephalosporins did not work with the cephamycins. It was necessary to develop a series of new chemical reactions to permit the preparation of semisynthetic cephamycins. This series of reactions was developed by Karady et al. [13] and resulted in the synthesis of cefoxitin from cephamycin C. The structure of cefoxitin, shown in figure 2, is comparable to that of cephalothin. Each of these semisynthetic products was created from the natural product by substitution of the thienyl acetamido group for the naturally occurringa-aminoadipoyl side chain. The structural differences between cefoxitin and cephalothin are exactly the same as those between cephamycin C and cephalosporin C. That is, cefoxitin has the 7-a-methoxyl and the 3-carbamoyl groups in place of the 7-a-hydrogen and the 3-acetoxy grou ps of cephalothin. Introduction of the thienyl acetamido group resulted in a product that not only retained the desirable characteristics

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Figure 1. Structures of cephamycins A, B, and C as compared with cephalosporin C.

Cefoxitin and Cephamycins: Microbiology


CEFOXITIN r - - - -

I I 0S





L_tt__ S

,- --





Figure 2. Structure of cefoxitin as compared with cephalothin.


I 1 0









I(" I1

: I



of cephamycin C but also acquired a spectrum greater than that demonstrated by cephalothin. Mechanism of Activity of Cefoxitin against Cephalosporin-Resistant Bacteria

The chemical synthesis studies of Karady et al. [13] and Firestone et al. [14] made available the various analogues of cefoxitin and cephamycin C that Stapley et al. [15] studied to determine the contribution of the 7-,8·thienylacetyl, 7-0lmethoxyl, and 3-carbamoyl groups in determining the characteristics of cefoxitin. The data shown in table 1 clearly indicate that the 7-,8-thienyl group confers on cefoxitin good activity against gram-positive bacteria. The MICs for several gram-positive pathogens are in the range of 1-6 JLgjml as compared with MICs of > 100 p.g/ml for the parent compound cephamycin C. It is also apparent from these data that cefoxitin is active against the gram-negative bacteria. Indeed, cefoxitin is shown to have a fourfold or greater increase in activity over that of cephamycin C against many of the cultures tested here. As pointed out previously, these two com pounds differ only by the change in the 7-,8substituent. A comparison of cefoxitin with its demethoxy (7-0l-hydrogen) analogue is reported in table 2. These data reveal that elimination of the 7-amethoxyl group increases somewhat the activity

against gram-positive bacteria but results in the loss of activity against gram-negative bacteria, particularly against ,8-lactamase-producing organisms such as the strains of Proteus morganii Table 1. Relationship of the 7-{3-thienyl group of cefoxitin to the antibacterial spectrum of the drug shown by comparison with the antibacterial spectrum of cephamycin C, which has a 7-{3-adipoyl group. MICs (J,Lg/ml) Bacteria tested Gram-positive species Staphylococcus aureus 3051 Streptococcus pyogenes 3009 Streptococcus agalactiae 1934 Corynebacterium diphtheriae 3176 Streptococcus pneumoniae 3377 Gram-negative species Escherichia coli 2017 E. coli 3349 Klebsiella pneumoniae 3083 Paracolobactrum arizonae 3271 * Proteus mirabilis 3255 P. mirabilis 3343 Proteus morganii 3202 P. morganii 3376 Proteus vulgaris 1810 Salmonella schottmuelleri 3010


Cephamycin C

6.25 0.78 0.78 6.25 3.12

>100 >100 >100 >100 >100

6.25 6.25 3.12

1.56 6.25

1.56 6.25

6.25 1.56 3.12

25 25 12.5 12.5 3.12 3.12 25 25

1.56 25

NOTE. Agar dilution tests were performed with a multipleinoculum replicating device that deposited 10"-10 5 cells of test organisms on the surface of Mueller-Hinton agar plates containing antibiotics as described by Miller et al. [16]. *Salmonella arizonae.

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Stapley et al.

Table 2. Relationship of the 7-o-methoxyl group of cefoxitin to the antibacterial spectrum of the drug shown by comparison with the antibacterial spectrum of demethoxycefoxitin, which has a 7-a-hydrogen group.

Table 3. Kinetics of acnvity of fJ-Iactamase from Enterobacter cloacae against cephamycins and cephalosporins. Antibiotic

MICs (J.Lg/ml) Bacteria tested

6.25 0.78 0.78 6.25

0.78 0.19 0.19 0.78

6.25 6.25 3.12 1.56 6.25 1.56 6.25 6.25 1.56 3.12

12.5 >100 50 1.56 6.25 1.56 >100 >100 12.5 1.56

NOTE. Agar dilution tests were performed with a multipleinoculum replicating device that deposited 10 4-10 5 cells of test organisms on the surface of Mueller-Hinton-agar plates containing antibiotics as described by Miller et al. [16]. * Salmonella arizonae.

that were tested.Cefoxitin is completely resistant to two,8-lactamases (those from Escherichia coli strain l\1B-2885 and Enterobacter cloacae strain MB-2646) under conditions in which demethoxyl cefoxitin is completely destroyed. The enzyme kinetics for the ,8-lactamase of E. cloacae on cephamycins and cephalosporins are summarized in table 3. As shown by Onishi et al. [17], all of the cephamycins are clearly less sensitive to this potent fi-Iactamase than are the cephalosporins. It is of interest that conversion of cephamycin C into cefoxitin results in almost 200-fold greater resistance to the ,8-lactamase of E. cloacae. Although cephalothin is less sensitive to this potent ,8-lactamase than the natural product, cephalosporin C, or the semisynthetic cephalosporin, cephaloridine, it is still 500-fold more sensitive than cefoxitin. It is clear from the foregoing data that the presence of the 7-a-methoxyl group .in cefoxitin is responsible for the drug's excellent resistance to degradation by ,8-lactamase. Cama et al. [18] prepared a series of compounds with substitutions at the 7a position to study further the effect of changes at this position. These work-

Cefoxitin Cephamycin A Cephamycin C Cephalothin Cephaloridine Cephalosporin C

0.019 1.2 3.3 9.1 100 200

Km(X 10-2 )t

0.6 6.2 2.4 0.6 9.2 14.3

NOTE. The methods used were those described by Onishi et al. [17]. *Maximal velocity, expressed as umol/min per mg of protein. tMichaelis constant, expressed as ~mol.

ers found that various substitutions at the 7a position resulted in excellent resistance to ,8lactamase activity. However, any group larger than the methoxyl resulted in a severe reduction in antibiotic potency. Thus it appears that the 7-a-methoxyl group is a very special substituent and that the 7-a-methoxyl group of the cephamycins is an important distinguishing characteristic of this class of compounds. Anything larger than hydrogen at the 7a position results in loss of sensitivity to ,8-lactamase, but only the 7-a-methoxyl group retains satisfactory antibiotic activity while adding the desirable characteristic of resistance to .8-lactamase. From these studies it is apparent that the stability to ,8-lactamase is conferred by steric hindrance at the active site of the enzyme. The relationship of the 3-carbamoyl group to the activity of cefoxitin is shown by the data in table 4. It has been known for several years that some mammalian enzymes are capable of deacetylating cephalothin with consequent loss of antibiotic potency [20, 21]. The data in table 4 show that cefoxitin and its 3-acetoxy analogue have similar potency in vitro. In contrast, cefoxitin is much more potent in vivo than its 3acetoxy analogue. The low potency of the 3acetoxy analogue of cefoxitin in vivo is the result of deacetylation by mammalian enzymes. The data in table 5 clearly show the relationship of the carbamoyl group to the metabolic stability of cefoxitin. When cefoxitin or its 3-acetoxy analogue is administered to test animals, the amount of antibiotic recovered from the urine is much greater for cefoxitin than for the 3-acetoxy ana-

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Gram-positive species Staphylococcus aureus 3051 Streptococcus pyogenes 3009 Strep tococcus agalactiae 1934 Corynebacterium diphtheriae 3176 Gram-negative species Escherichia coli 2017 E. coli 3349 Klebsiella pneumoniae 3083 Paracolobactrum arizonae 3271 * Proteus mirabilis 3255 P. mirabilis 3343 Proteus morganii 3202 P. morganii 3376 Proteus vulgaris 1810 Salmonella schottmuelleri 3010

DemethoxyCefoxitin cefoxitin

Vmax(X 10-3 )*


Cejoxitin and Cepharnycins: Microbiology

Table 4. Relationship of the 3-carbamoyl group of cefoxitin to the antibacterial activity of the drug shown by comparison with the antibacterial activity of the 3-acetoxy analogue of cefoxitin. MICs (J..Lg/rnl)


Bacteria tested

logue. The reason for this difference is that the 3-carbamoyl group is stable to the mammalian enzymes that remove the 3-acetoxy group, a reaction resulting in loss of antibiotic potency. The 3-carbamoyl group results in an antibiotic that is metabolically stable in comparison with the 3-acetoxy derivatives. The nature of this chemical degradation has been analyzed for both cefoxitin and cephalothin by Buhs et al. [22]. Clinical experiments by Brumfitt et al. [5] and Sonneville et al. [23] have shown that the amount of antibiotic recovered from urine of humans is greater for cefoxitin than for cephalothin. Thus, the 3-carbamoy1 group of cefoxitin results in a metabolically stable antibiotic with greater in vivo potency as compared with a 3-acetoxy compound such as cephalothin. The significance of j3-lactamase in the resistance of pathogens to treatment by j3-lactam antibiotics has been the subject of considerable controversy over the years. This controversy has been discussed by Onishi et al. [17], and it is apparent from both observational and experimental studies that resistance to ,8-lactam antibiotics Table 5. Relationship of the carbamoyl group of cefoxitin to the metabolic stability of the drug shown by comparison with the metabolic stability of the 3-acetoxy analogue of cefoxitin.

Test animal

Dosage, route

Mouse Monkey

20 mg/kg, sc 10 mgjkg, irn

NOTE. [19].

Percentage of dose recovered from urine 3-Acetoxy analogue Cefoxitin of cefoxitin 72 93

11 36

Tests were performed by methods of Miller et al.

3-Acetoxy analogue of cefoxitin

>100 50 >100 >100

12.5 3.15 7.55 26.5 EDso

(50% effective dose) values were determined

is the result of an interaction of several factors. Something called "intrinsic resistance," which probably indicates interference with penetration of the wall and/or membrane of the target organism to reach the site of enzyme activity, is an important factor. The importance of ,8lactamase, however, cannot be denied as contributing potential for resistance in many cases and probably being the main factor in certain instances. Darland and Birnbaum [24] have shown the relationship between formation of ,8-lactamase and resistance to j3-lactam antibiotics for the important anaerobic pathogen Bacteroides fragilis. Fortunately, there is an unusual pair of microorganisms described by Goldner et al. [25] that consists of a j3-lactamase-producing strain of E. cloacae and a spontaneous mutant of that culture which lacks the ability to make the enzyme. Both strains are pathogenic for mice, and thus the obvious experiment of comparing the responses to therapy of animals infected with bacteria with and without the enzyme can be performed in vivo. Results of such an experiment comparing the responses to cefoxitin and cephaloridine are presented in table 6. These Table 6. Relationship of fJ-Iactamase production to susceptibility of Enterobacter cloacae in vivo to cefoxitin and cephaloridine. ED

Strain of E. cloacae

2646 2647


[mgjkg X 2)*

fi-Lactamase activity

Susceptibility to cefoxitin


Cephal 0ridine


Resistant Susceptible

170 15

1,700 4.5

*The EDso (50% effective dose) values were determined by the mouse protection test of Miller et al. [19].

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NOTE. MICs were determined as described in tables 1 and 2. The in mice by procedures described by Miller et al. [19].

so [mg/kg X 2)


6.25 1.56 12.5 25.0

6.25 3.12 6.25 6.25

Staphylococcus aureus 2949 Streptococcus pyogenes 3009 Proteus rnorganii 3376 Escherichia coli 2017


3-Acetoxy analogue of cefoxitin


Stapley et al.


Antibacterial Spectrum of Cefoxitin

The antibacterial spectrum of cefoxitin was presented in detail by Wallick and Hendlin [26] in their report on studies of susceptibility to antibiotics and factors affecting susceptibility to cefoxitin. Some of these data are presented in table 7. Cefoxitin is considerably more active than cephalothin against E. coli, Proteus mirabilis, and Klebsiella, which represent organisms normally considered sensitive to the cephalosporins. Table 7. Susceptibility of gram-negative clinical isolates to cefoxitin and cephalothin. Percentage of isolates with MICs of ';;;12.5 J.Lg/ml Organism (no. tested) Escherichia coli (60) Proteus mirabilis (64) Indole-positive Proteus plus Providencia (59) Klebsiella (70) Enterobacter (36) Serratia (23) Paracolobactrum species (17)


98 98 95 83 42 22 41


68 83 5 59 31

0 24

NOTE. The data and methods have been reported by Wallick and Hendlin [26].

There was a very marked increase in susceptibility for the indole-positive Proteus species and Prouidencia, which represent gram-negative organisms that normally are resistant to cephalothin [27, 28]. Furthermore, cefoxitin showed some activity against Serratia, an organism notoriously difficult to control with antibiotics, even at the relatively modest MIC level of 12.5 p.g/ ml. On the basis of these early studies, it can be concluded that cefoxitin is superior to cephalothin against gram-negative pathogens. Cefoxitin is not only more effective against strains susceptible to cephalothin, but also is effective against cultures that are normally resistant to cephalothin. It was also shown that the gram-positive pathogens Staphylococcus aureus, Streptococcus pneumoniae, and streptococci (excluding the enterococcus and methicillin-resistant Staphylococcus) were sensitive to cefoxitin at MICs of 0.6-6 /Lg/ml, levels well within the susceptibility range for the gram-negative bacteria. Thus, although less potent against gram-positive bacteria, cefoxitin should be sufficiently active against all of the organisms normally sensitive to cephalothin; this activity results in an overall spectrum considerably improved over that of the cephalosponns. Cefoxitin's excellent resistance to ,8-lactamase may be a factor in its good activity against staphylococci since, as shown by Farrar and Gramling [29], cefoxitin showed less indication of inoculum effect than any of the cephalosporins tested (including cephalothin, cefamandole, cefazolin, cephaloridine, and SKF-59962) against a series of ,B-lactamase-producing strains of S. aureus. Fong et al. [30] showed cefoxitin to be the least susceptible of a series of cephem antibiotics to inactivation by the .,B-Iactamase of S. aureus. These studies included cefazolin, cephaloridine, cephalexin, cefradine, cefapirin, cefamandole, and cephalothin. Thus the excellent resistance of cefoxitin to ,B-Iactamase was confirmed in these. studies and may have an important role in determining cefoxitin's predictable activity against penicillin-resistant staphylococci. The excellent bactericidal activity of cefoxitin was clearly demonstrated by Jones et aI. [31], who showed that the ratios of MIC to MBC of cefoxitin were exactly the same for all of 14 strains of

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data of Miller et aI. [19] clearly demonstrate the effect of the presence of ,B-Iactamase on the resistance of E. cloacae to ,B-1 act am antibiotics. The ,B-Iactamase of this organism is one of those rare enzymes that actually has some activity against cefoxitin. Its activity against other cephem antibiotics, e.g., cephaloridine, is several hundredfold greater [17]. The dose required to achieve a 50% effective dose (ED50) of cefoxitin was II-fold greater for the ,B-Iactamase-positive strain as compared with the negative strain. This observation also correlates with results of in vitro susceptibility tests, which showed the lactamasenegative strain to be sensitive to cefoxitin, whereas the lactamase-positive strain was resistant. The same type of effect was seen with cephaloridine, except that a 378-fold increase in dose was required to achieve an ED50' These data constitute a clear confirmation of the concept that the presence of ,B-lactamase is an important factor in resistance to ,B-lactam antibiotics


Cejoxitin and Cephamycins: Microbiology

of 100 strains tested by Yourassowsky et al. [37]. Norrby et al. [36] found all of 38 strains of H. in[luenzae to be inhibited by ~4 p,g/ml, and most strains were sensitive to 2 p,gjml. Similar data were reported byJones et al. [31]. A study of the susceptibility of ampicillin-sensitive and -resistant strains of H. influenzae to penicillins, cephalosporins, and ce£oxitin was reported by Kammer et al. [38]. Since these strains produce a penicillinase, the penicillins were ineffective against the ampicillin-resistant strains. Cefoxitin was found to have an MlC of~4 }Lg/ml for 90% of the strains tested. This result was superior to that observed for the cephalosporins, with the exception of cefarnandole, which is somewhat more active than cefoxitin against H. injluenzae. Numerous studies reported in the literature have confirmed the observations cited above on the antibacterial spectrum of cefoxitin. Activity against aerobic gram-positive and gram-negative pathogens has been studied by Adams et at'[4], Brumfitt et al. [5], Moellering et al. [8], Shah et al. [39], Stewart and Bodey [40], and Verbist [41]. Cefoxitin has not been shown to have much activity against Pseudomonas aeruginosa or the enterococci, and its activity against Enterobacter is weak and sporadic. These limitations are generally known to apply to the clinically used cephalosporin antibiotics. Results of Disk Susceptibility Tests

The disk susceptibility test procedure of Bauer et al. [42] has been employed for evaluation of a large sampling of clinical isolates for sensitivity to cefoxitin. On the basis of a regression analysis of data comparing size of zone of inhibition with MIC, Wallick and Hendlin [26] demonstrated that a 6-mm disk containing 30 fLg of cefoxitin could be used for susceptibility studies in a test analogous to that normally employed with cephalothin. A zone size of 18 mm was chosen as the limit to indicate susceptibility, 15-17 mm as a category of intermediate susceptibility, and ~I4 mm as indicative of resistance. Using the methods described by Bauer et al. [42], Wallick and Hendlin found that a majority (66%) of 174 clinical isolates selected at various hospitals because of their resistance to cephalosporins were

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S. aureus tested. The MBCs tended to be somewhat higher for many of these strains as compared with MICs of six cephalosporins that were evaluated in the same experiments. In summary, the studies cited have shown that cefoxitin is bactericidal and resistant to the ,B-Iactamase of S. aureus and that S. aureus is sensitive to levels of cefoxitin that are well within clinically achievable levels [23]. Thus it is not surprising that cefoxitin has shown good efficacy in therapeutic applications vs. gram-positive bacteria, an observation reported by McCloskey [32]. Cefoxitin has been shown to have remarkably resistant activity under various conditions of in vitro tests. Wallick and Hendlin [26] showed that there was very little inoculum effect and that factors such as pH and medium had very little influence on the MICs of cefoxitin for gramnegative bacteria. Jones et al. [31] showed that the excellent MBC:MIC values observed with S. aureus are also to be found with organisms such as E. coli) Klebsiella pneumoniae, and Proteus. I t is characteristic of ce£oxitin that the cidal activity is equivalent, or very close to, the concentration that is inhibitory. Washington [33] showed, for example, that an increase in inoculum size from 104 to 108 bacteria/rnl resulted in no increase in the MIC of ce£oxitin. In contrast, both cephalosporins tested (cefamandole and cefatrizine) showed large increases in the l\fIC with increasing inoculum size. Several workers have shown cefoxitin to be active against Neisseria gonorrhoeae at levels of ~l Jl-gjml [31, 34]. As might be expected, the activity of cefoxitin is the same for penicillin-sensitive and penicillin-insensitive strains. Eickhoff and Ehert [35] reported similar findings for susceptibilities of N. gonorrhoeae, except that they observed some strains that required as much as 4 }Lg/ml for inhibition. These same workers showed that the susceptibility of Neisseria meningitidis to cefoxitin was very similar to that of N. gonorrhoeae. The actual sensitivity of N. meningitidis may be greater, since both Jones et al. [31] and Norrby et al. [36] found MICs of ~0.5 p,gjml for this organism. Ce£oxitin has been reported to be active against Haemophilus iniluenzae. Although not as active as some of the cephalosporins, cefoxitin was shown to have an MIC of ~1.56 p,gjml for 80


Table 8.

Results of a survey of susceptibility to cefoxitin and cephalothin of gram-positive and gram-negative bacteria isolated from hospitalized patients in the United States. Percentage susceptible to

Bacteria Gram-positive Staphylococcus aureus Staphylococcus epidermidis Streptococcus Group A {3-Hemolytic a-Hemolytic Streptococcus pneumoniae Total Enterococcus Gram-negative (aerobes) Escherichia coli Klebsiella Proteus mirabilis Proteus (indole-positive) Providencia Serratia Ci tro bac ter Herellea Mima Salmonella Shz"gella Alcaligenes Enterobacter Total Pseudomonas Gram-negative (anaerobes) Bacteroides fragilis Bacteroides melaninogenicus Bacteroides species Total

No. of isolates

Cefoxit in


2,707 1,939

99 91

99 97

39 130 124 9

97 94 88 100

100 99 96 100

4,948 1,767

95 6

98 16

7,233 3,330 2,151 368 64 328 278 490 62 54 17 30 1,599

95 91 96 69 97 41 51 14 42 96 100 50 18

67 82 92 36 1 43 1 26 91 94 37 11

16,004 1,469

81 4

63 1

224 21 117

71 100 83

12 57 26





vey were susceptible to cefoxitin but not to cephalothin. Many more isolates of E. coli, Klebsiella, indole-positive Proteus, and Serratia were sensitive to cefoxitin than to cephalothin. These large differences clearly indicate that a new disk for susceptibility tests will be required for evaluation of nosocomial isolates for sensitivity to cefoxitin. The results of the survey of susceptibility of gram-negative anaerobic nosocomial isolates that were included in the study described above are shown in the lower portion of table 8. Although this procedure has not been formally recognized for use with anaerobic organisms, it is clear that these data reflect the same type of

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sensiuve to cefoxitin. Similar results are reported by. Jackson et al. [43], who studied a series of clinical isolates of Klebsiella resistant to both cephalothin and gentamicin. Jackson et al. found that cefoxitin was active against these strains although they were quite resistant to both cephalothin and cefamandole, as well as to gentamicin. It was demonstrated that these strains produced a f3-lactamase capable of degrading cephalosporin antibiotics but not cefoxitin. Once again, there was a good correlation between ceIoxitin's resistance to f3-lactamase and its activity against cephalosporin-resistant pathogens. Lewis et al. [44] tested a large number of cephalothinresistant Enterobacteriaceae and found that cefoxitin was the most active f3-lactam antibiotic against these strains. In contrast, they found that cefamandole and cefatrizine did not show good activity against these same strains. Thus these specific studies on cephalothin-resistant clinical isolates confirm our early observations that cefoxitin shows good activity against such pathogens. A survey of a large number of clinical isolates for susceptibility to cefoxitin, in comparison with cephalothin, was conducted with use of the method of Bauer et al. [42] and unselected, fresh clinical isolates from five major hospitals in the United States. Approximately 5,000 isolates were tested at each of these centers. The results obtained in the survey of susceptibility of 6,715 gram-positive nosocomial isolates are summarized in the top section of table 8. The data on susceptibility of these isolates are very similar for cefoxitin and cephalothin. Both compounds showed very poor activity against enterococcus and very good activity against all of the other gram-positive isolates tested. In the testing of gram-negative nosocomial isolates, however, cefoxitin showed activity against a large number of strains that were found to be resistant to cephalothin. Results for 17,473 gramnegative isolates are summarized in the middle section of table 8. If the pseudomonas isolates, not normally sensitive to either cefoxitin .or cephalosporins, are eliminated from the calculations, it is seen that 81 % of these isolates were sensitive to cefoxitin as compared with only 63% for cephalothin. These data indicate that nearly 3,000 gram-negative isolates in this sur-

Stapley et at.

Cejoxitin and Cephamycins: Microbiology


whereas only 7% of 299 strains tested were susceptible to that amount of cephalothin. It is obvious from both sets of data that cefoxitin has very good activity against B. [ragilis, a pathogen quite resistant to the cephalosporins. Anderson and Sykes [48], Del Bene and Farrar [49], and Olsson et al. [50] have reported that B. tragi lis produces a ,8-lactamase with activity typical of a cephalosporinase. A study of the importance of this enzyme in the susceptibility and resistance of B. [ragilis to ,8-lactam antibiotics has been reported by Darland and Birnbaum [22]. Their studies indicate that at least two different types of enzymes may be produced that differ with regard to cellular distribution as well as substrate specificity. Cefoxitin is not degraded by either enzyme but was found to be an efficient competitive inhibitor. In a study in which sensitive and resistant isolates of B. [ragilis were compared in regard to their ability to produce ,8lactamase, a significant correlation was found between the presence of ,8-lactamase activity and resistance to the cephalosporins cefamandole,



80 70


Figure 3. Cumulative percentage of isolates of Bacteroides [ragilis suscep' tible in vitro to cefoxitin and cephalothin (data from [24, 45-47]).






'3 E











Minimum Inhibitory Concentration C",o/ml)


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difference in susceptibility; of 362 cultures tested 76% were sensitive to cefoxitin as compared with only] 9% that were sensitive to cephalothin. The important pathogen B. [ragilis was significantly more sensitive to cefoxitin than to cephalothin. All of the isolates reported in table 8 to be sensitive had zones of inhibition with diameters of ~18 mm when tested by the method of Bauer et aI., a fact indicating that these isolates would be susceptible (MIC, ~14 fLgjml) to cefoxitin [25]. Since levels of drug jn serum considerably in excess of this concentration can be achieved in clinical studies [21], these data represent a conservative estimate of the percentage of this large collection of clinical isolates that should be treatable with cefoxitin. Since data from disk susceptibility tests are not generally accepted for anaerobic organisms, a summary of data on MICs reported by Darland and Birnbaum [24], Ernst et aI. [45], Sutter and Finegold [46], and Tally et al. [47] is presented in figure 3. These data show that 81 % of 340 strains of B. iragilis were susceptible to cefoxitin (MIC, 16 fLgjml),


Therapeutic Effectiveness of Cefoxitin in Experimental Infections

Miller et al. [19] reported an extensive evaluation of the therapeutic effectiveness of cefoxitin in experimental infections in laboratory animals. The results of treatment of four infections due to gram-positive bacteria and 17 infections due to gram-negative bacteria with cefoxi-

tin, cephamycin C, and cephalothin are reported in table 9. These tests were performed with mice infected by ip injection and treated with two sc doses of the antibiotic. The results with the four infections due to gram-positive bacteria show that, in comparison with cephamycin C, cefoxitin has the same relative activity in vivo that was observed in vitro. Thus, enormous doses of cephamycin C are required to obtain an ED 50 (if one can be obtained at all) against the infections with gram-positive organisms. In contrast to the results with the natural product, cefoxitin shows good potency against all four infections caused by gram-positive bacteria. Although not as potent as cephalothin in these studies, cefoxitin had ED 50 values that are well within the range of reasonable doses required for infections due to gram-negative bacteria. By both in vitro and in vivo criteria, cefoxitin is a true broad-spectrum agent. It has essentially the same range of potency against gram-positive and gram-negative bacteria. All 17 of the experimental infections with gram-negative pathogens responded to treatment by cefoxitin. The doses required for E. cloacae strain 2646, P. mirabilis strain Maurer, and Serratia strain 3374 were admittedly high. However, results were superior to those observed with the natural product cephamycin C, and infections with these organisms could not be controlled at all by cephalothin. It is of interest that the difficult pathogen P. morganii, of which three strains were tested, responded very well in the in vivo trials. These studies showed that cefoxitin is distinctly superior to cephalothin. The results of in vivo studies correlated very well with those of in vitro studies of cefoxitin and demonstrate that it has a very broad spectrum of activity that can be translated into practical results in the control of experimental infections. It will be recalled that the two strains of E. cloacae, strains 2646 and 2647, differ only in the fact that strain 2646 can make ,8-lactamase, an ability that was lost from the spontaneous mutant, strain 2647 [25]. Accordingly, even enormous doses of cephamycin C and cephalothin were unable to control infections with E. cloacae strain 2646, whereas both of these antibiotics were reasonably active against the f3-lactamase-negative mutant. The better resistance of cefoxitin to ,8-lactamases is shown clear-

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cefazolin, and cephaloridine. No significant association between the presence of ,8-lactamase activity and susceptibility or resistance to cefoxitin was observed. These results suggest that f3lactamase plays an important role in the resistance of B. fragilis to cephalosporins and provide one explanation for the superiority of cefoxitin against this important group of pathogens. In these studies it was shown that enzymes derived from B. fragilis degraded cephaloridine, cephalothin, cefazolin, cefamandole, and even cefuroxime, which has been reported to be resistant to ,8-lactamase from both aerobic and facultative organisms [51]. Unlike the cephalosporins, cefoxitin was not degraded by these enzymes. Again, these results emphasize the importance of ,8-lactamase in determining susceptibility and resistance of pathogens to f3-lactam antibiotics. A survey of the susceptibility of other anaerobic organisms has been reported by Tally et al. [47], who found that ~16 ftg of cefoxitinjml was active against most (82%) of 155 gram-negative isolates. These studies included 11 strains of Fusobacterium species, 19 strains of Peptococcus (100% were sensitive to ~4 ftgjml), 24 strains of Peptostreptococcus, nine strains of Veillonella (100% were susceptible to ~2 ftgjml), 15 strains of Clostridium perfringens (1001,000 427 265.5 158.5

Entero bacter aerogenes 3148 Enterobacter cloacae 2646 E. cloacae 2647 Escherichia coli 2017 E. coli Moran Klebsiella pneumoniae AD 3068 K. pneumoniae B Pasteurella multocida 1590 Proteus mirabilis 3201 P. mirabilis Maurer Proteus morganii 3202 P. morganii 3376 P. morganii Collier Proteus vulgaris 1810 Salmonella scho ttmuelleri 3010 Salmonella typhimurium 2637 Serratia 3374

4.55 171 15.1 20.7 41.35 39.7 22.2 5.15 23.55 100 25 7.55 25 3.8 12.5 12.65 100

10.35 >2,000 11.8 12.5 >302 20.7 23.55 6.25 67 133.5 25 12.5 60.5 6.25 7.25 6.25 >200

2.5 1.55 1.2 4.7 10.35 >2,000 53 100 > 1,000 121 29 1.55 53 >400 >400 > 1,000 >400 7.55 60.5 39.45 >200

*Tests were performed with mice given two sc doses of the indicated antibiotic at zero-time and 6 hr after infection [19].

ly by the fact that, although very large doses were required, it was possible to demonstrate an ED50 of cefoxitin against strain 2646. Miller et al. [19] studied the effect of administration of cefoxitin by various routes and determined that it was relatively inactive when given orally. Miller et al. [19] also compared the therapeutic efficacy of cefoxitin for penicillin-resistant and penicillin-sensitive S. aureus. Their results showed that although the sc dosage required for an ED 5 0 against S. aureus was greater for cefoxitin than for cephalothin, no significant increase in the dosage of cefoxitin was required for treatment of infections due to penicillin-resistant staphylococci. In contrast, a very large increase of from 17- to 37-fold in the dose of cephalothin was required for treatment of infections due to penicillin-resistant strains of S. aureus, as compared with the dosage for the penicillin-sensitive isolate. Cephaloridine, which is even more sensitive to f3-lactamase than cephalothin, showed a proportionately greater increase in the amount of antibiotic required for an EDfiO against the penicillin-resistant strains as compared with the sensitive strains. As in previous instances cited, the

importance of the resistance of cefoxitin to degradation by f3-lactamase is shown in these resuIts. Cefoxitin shows the same level of potency regardless of the presence of penicillinase in such isolates. Determination of the concentrations of cefoxitin in serum and tissues by Miller et al. [19] showed that the serum and tissue levels of cefoxitin were significantly higher than those of cephalothin. For example, at 30 min after a 20-mg/kg sc dose, the concentration of cefoxitin in serum was 9.3 iLg/ml. The concentration in serum of cephalothin was only 3.2 iLg/ml under the same conditions. This difference must, in part, reflect the deacetylation of cephalothin, which was discussed earlier and is known to be greater in mouse serum than in human serum. It is obviously an additional positive factor for cefoxitin that there are higher blood and tissue levels of the antibiotic, which is essentially more active against many of the difficult gram-negative bacterial pathogens. The results of the experiments on dosage are summarized in figure 4. If the ED 50 value (in mg/ kg) of 50 is chosen as the cutoff point for a

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Staphylococcus aureus 2949 Streptococcus py ogenes 1685 S. pyogenes 3009 Streptococcus pneumoniae 3377


Stapley et al.


100 C






2' 80

__----C;phamycin C




~ oS




:: :J


2' ~




~ c .cephalothin

50 c


Figure 4. Cumulative percentage of 17 gram-negative pathogens susceptible in vivo to cefoxitin, cephamycin C, and cephalothin, as measured by 50% effective doses (EDso).

e ~













EDso (mo/ko) x 2.S.C. Doses

reasonable dose in an infected mouse, cefoxitin was seen to control 84% of the 17 gram-negative bacterial infections at a dosage level at which cephalothin controlled only 34%. It was also shown that cefoxitin produced higher concentrations in serum when given in combination with a dose of probenecid. Although the concentration of cephalothin in serum also is increased by probenecid, the absolute concentration reached is still less than half of that observed with cefoxitin. The higher levels in blood that were produced with probenecid reduced the ED 50; hence probenecid enhanced therapeutic efficacy. These results indicate that cefoxitin is excreted by the renal tubules as well as by glomerular filtration. Miller et al. [16] recently have reported studies showing that the in vitro activity of cefoxitin can predict accurately its in vivo activity. The results with the cephalosporin compound, cefamandole, indicated that in vitro results were not as accurate a predictor of in vivo response. This

discrepancy was noted in particular for strains that produce ,B-lactamase and illustrates again the importance of the excellent resistance of cefoxitin to ,B-lactamase with respect to activity against cephalosporin-resistant organisms. Mode of Action of Cefoxitin

Like other ,B-lactam antibiotics, cefoxitin is active against the cell wall structure of the target bacterium. The exact nature of the interactions that determine the final results is not yet completely understood. A number of factors, however, are quite clear. Zimmerman and Stapley [52] showed that cefoxitin induced filaments at subinhibitory levels; this activity is characteristic of most of the cephalosporins and penicillins. The ability to produce these filaments at concentrations below the MIC appears to be associated with the six- or seven-position substituents in penicillins or cephalosporins examined. Those compounds that had an aromatic substituent usu-

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• c•


Cefoxitin and Cephamycins: Microbiology

foxitin to the proteins of the bacterial membrane is relatively irreversible. It is possible that the irreversible nature of the cefoxitin binding may be related to its excellent bactericidal activity and to the fact that cefoxitin shows little, if any, inoculum effect and has a bactericidal action at, or slightly above, its inhibitory level. A practical demonstration of this observation was produced by the studies of Goodwin and Hill [6], who showed that high concentrations of E. coli and Klebsiella were killed by cefoxitin under conditions that permitted eventual recovery and growth in the presence of cefuroxime or cephalothin. The potent bactericidal activity of cefoxitin may well contribute to its superior activity as compared with that of cephalosporins in combating experimental infections due to gram-negative bacteria. Conclusions

Studies reported from our laboratories and laboratories in many different institutions around the world have shown that cefoxitin is a superior antibiotic both in vitro and in vivo. It is clear from all of these studies that cefoxitin is a major improvement over the cephalosporins presently used in clinical medicine. Cefoxitin has the 7methoxyl group, characteristic of cephamycins, which confers excellent resistance to almost all ,8-lactamases. It is metabolically stable as a result of the presence of the carbamoyl group, rather than the acetoxy group found in cephalothin, at the 3 position. Cefoxitin has a broader spectrum than any of the cephalosporins. Its spectrum includes activity against cephalothin-resistant gramnegative bacteria, especially E. coli and Klebsiella, as well as other strains such as P. morganii, Proteus vulgaris, Proteus rettgeri, Serratia, and the anaerobes, especially B. jragilis. Many of these organisms are quite resistant to the cephalosporin antibiotics. In addition to valuable characteristics mentioned above, it has been shown that cefoxitin shows almost no inoculum effect; this phenomenon reflects cefoxitin's resistance to ,8-lactamases. Furthermore, the bactericidal level of cefoxitin is very nearly coincident with its inhibitory concentration. These points result in the fact that in vitro determinations of activity have excellent predictive value for in vivo response. The truth

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ally produced filaments, whereas those with nonaromatic substituents frequently did not induce formation of filaments. Since therapeutically effective agents were found among the compounds that induce filaments as well as among those that do not, it is unlikely that the filament formation has any special clinical significance. As reported by Onishi et al. [53], under special conditions of protective osmotic pressure spheroplasts are produced by susceptible gram-negative bacteria when they are grown in the presence of a concentration of cefoxitin equal to or higher than the :MIC. Spheroplasts produced by cefoxitin are osmotically sensitive and can be lysed by dilution of the protective medium. Thus, the basic effect of exposure of a susceptible bacterium to cefoxitin is the destruction of the cell in an irreversible bactericidal action similar to that produced by other cell-wall active antibiotics such as penicillins and cephalosporins. In these same studies, the binding of cefoxitin to gram-negative and gram-positive bacteria was reported. It was found that 4-9 pmol of cefoxitinjmg of dry cell weight were bound by bacteria. It was demonstrated that the binding of cefoxitin to bacterial cells was irreversible. In the case of gram-negative bacteria, cephalosporin and penicillin competed very poorly with cefoxitin for the binding sites on the bacteria. In contrast, both penicillin and cephalosporin compete very well with cefoxitin for the binding sites of the grampositive bacteria. The significance of these data is open to question in view of the information developed more recently by Spratt [54, 55], who studied the binding of cefoxitin by E. coli. Spratt showed that penicillin binds to six proteins in the cell membrane of E. coli. Binding to proteins I and 3 of his series appears to be associated with cell death and lysis. Cefoxitin was shown to bind to five of the six sites, including proteins I and 3. Protein 2, which does not bind cefoxitin, is the site at which mecillinam is bound. Binding at this site appears to be associated with the development of rounded, osmotically stable cells from bacilli and represents a mode of action distinct from that of most of the ,B-Iactam antibiotics. It is not clear whether this site is involved in the bactericidal action of ,B-Iactam antibiotics. These studies confirmed the fact that binding of ce-







References 1. Stapley, E. 0., Jackson, M., Hernandez, S., Zimmerman, S. B., Currie, S. A., Mochales, S., Mata, J. M., Woodruff, H. B., Hendlin, D. Cephamycins, a new family of {j-Iactam antibiotics. I. Production by actinomycetes including Streptomyces lactamditrans sp. n. Antimicrob. Agents Chemother. 2:122-131,1972. 2. Miller, T. W., Goegelman, R. T., Weston, R. G., Putter, I., Wolf, F. J. Cephamycins, a new family of {Jlactam antibiotics. II. Isolation and chemical characterization. Antimicrob. Agents Chemother. 2:132135,1972. 3. Nagarajan, R., Boeck, L. D., Gorman, M., Hamill, R. L., Higgins, C. E., Hoehn, M. M., Stark, W. M., Whitney, J. G. {J-Lactam antibiotics from Streptomyces. J. Am. Chern. Soc. 93:2308-2310,1971. 4. Adams, H. G., Stilwell, G. A., Turck, M. In vitro evaluation of cefoxitin and cefamandole. Antimicrob. Agents Chemother. 9:1019-1024, 1976. 5. Brumfitt, W., Kosmidis, J., Hamilton-Miller, J. M. T., Gilchrist, J. N. Cefoxitin and cephalothin: antimicrobial activity, human pharmacokinetics and toxicology. Antimicrob. Agents Chemother. 6:290-299, 1974. 6. Goodwin, C. S., Hill, J. P. Lysis of enterobacteria by cefoxitin, cefuroxime, and cephalothin. Antimicrob. Agents Chemother. 11:26-30, 1977. 7. Hamilton-Miller, J. M. T., Kerry, D. W., Brumfitt, W. An in vitro comparison of cefoxitin, a semisynthetic cephamycin, with cephalothin. J. Antibiot. (Tokyo) 27:42-48,1974. 8. Moellering, R. C., Dray, M., Kunz, L. J. Susceptibility of clinical isolates of bacteria to cefoxitin and cephalothin. Antimicrob. Agents Chemother. 6:320-324, 1974. 9. Neu, H. C. Cefoxitin, a semisynthetic cephamycin antibiotic: antibacterial spectrum and resistance to hydrolysis by gram-negative beta-lactamases, Antimicrob. Agents Chemother. 6:170-176,1974. 10. Miller, A. K., Celozzi, E., Pelak, B. A., Stapley, E. 0., Hendlin, D. Cephamycins, a new family of {J-Iactam









antibiotics. III. In vitro studies. Antimicrob. Agents Chemother. 2:281-286,1972. Miller, A. K., Celozzi, E., Kong, Y., Pelak, B. A., Kropp, H., Stapley, E. 0., Hendlin, D. Cephamycins, a new family of {J-lactam antibiotics. IV. In vivo studies. Antimicrob. Agents Chemother. 2:287-290, 1972. Daoust, D. R., Onishi, H. R., Wallick, H., Hendlin, D., Stapley, E. O. Cephamycins, a new family of {J-lactam antibiotics: antibacterial activity and resistance to {J-lactamase degradation. Antimicrob. Agents Chemother. 3:254-261, 1973. Karady, S., Pines, S. H., Weinstock, L. M., Roberts, F. E., Brenner, G. S., Hoinowski, A. M., Cheng, T. Y., Sletzinger, M. Semisynthetic cephalosporins via a novel acyl exchange reaction. J. Am. Chern. Soc. 94: 1410-1411,1972. Firestone, R. A., Schelechow, N., Johnston, D. B. R., Christensen, B. G. Substituted penicillins and cephalosporins. II. C-6 (7)-alkyl derivatives. Tetrahedron Letters 375-378, 1972. Stapley, E. 0., Daoust, D. R., Hendlin, D., Miller, A. K., Zimmerman, S. B., Birnbaum, J., Cama, L. D., Christensen, B. G. Ce£oxitin: mechanism of activity against cephalosporin-resistant bacteria. In Proceedings of the Symposium on Microbial Resistance, Tokyo, Japan, October 1977 (in press). Miller, A. K., Celozzi, E., Pelak, B. A., Birnbaum, J., Stapley, E. O. Comparison of in vitro and in vivo activities of cefoxitin, cefamandole, cephalothin and cefazolin.In W. Siegenthaler and R. Luthy [ed} Current chemotherapy. Proceedings of the 10th International Congress of Chemotherapy, Zurich, Switzerland, Vol. 2. American Society of Microbiology, Washington, D. C., 1978, p. 741-742. Onishi, H. R., Daoust, D. R., Zimmerman, S. B., Hendlin, D., Stapley, E. O. Cefoxitin, a semisynthetic cephamycin antibiotic: resistance to beta-lactamase inactivation. Antimicrob. Agents Chemother. 5:38-48, 1974. Cama, L. D., Leanza, W. J., Beattie, T. R., Christensen, B. G. Substituted penicillin and cephalosporin derivatives. I. Stereospecific introduction of the C-6 (7) methoxy group. J. Am. Chern. Soc. 94: 1408-1410, 1972. Miller, A. K., Celozzi, E., Kong, Y., Pelak, B. A., Hendlin, D., Stapley, E. O. Cefoxitin, a semisynthetic cephamycin antibiotic: in vivo evaluation. Antimicrob. Agents Chemother. 5:33-37, 1974. Wick, W. E. In vitro and in vivo laboratory comparison of cephalothin and desacetylcephalothin. Antimicrob. Agents Chemother. 1964:870-875, 1965. Kirby, W. M. M., de Maine, J. B., Serrill, W. S. Pharmacokinetics of the cephalosporins in healthy volunteers and uremic patients. Postgrad. Med. J. 47 (Suppl.):41-46,1971. Buhs, R. P., Maxim, T. E., Allen, N., Jacob, T. A., Wolf, F. J. Analysis of cefoxitin, cephalothin and their deacylated metabolites in human urine by high performance liquid chromatography. J. Chromatog. 99: 609-618, 1974.

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of this statement has been borne out by experience with experimental infections in animals. As mentioned earlier, the favorable results observed in clinical trials are not unexpected in view of the overall characteristics of cefoxitin. Since cefoxitin is unique among the f3-lactam antibiotics in having good activity against the important anaerobic pathogen B. [ragilis, it should be an unusually valuable therapeutic agent for treatment of infections involving a risk of the presence of that organism. In addition, cefoxitin should be much more reliable than cephalosporins (e.g., cephalothin) in the treatment of infections due to gram-negative bacteria.

Stapley et al.

Cefoxitin and Cephamycins: Microbiology

40. Stewart, D., Bodey, G. P. Comparative in vitro activity of cephalosporins. J. Antibiot. (Tokyo) 29:181-186, 1976. 41. Verbist, L. Comparison of the antibacterial activity of nine cephalosporins against Enterobacteriaceae and nonfermentative gram-negative bacilli. Antimicrob. Agents Chemother. 10:657-663, 1976. 42. Bauer, A. W., Kirby, W. M. M., Sherris, J. C., Turck, M. Antibiotic susceptibility testing by a standardized single disc method. Am. J. Clin. Pathol. 45 :493496,1966. 43. Jackson, R. T., Thomas, F. E., Alford, R. H. Cefoxitin activity against multiply antibiotic-resistant Klebsiella pneumoniae. Antimicrob. Agents Chemother. 11:84-87,1977. 44. Lewis, R. P., Meyer, R. D., Kraus, L. L. Antibacterial activity of selected beta-lactam and aminoglycoside antibiotics against cephalothin-resistant Enterobacteriaceae. Antimicrob. Agents Chemother. 9:780786,1976. 45. Ernst, E. C., Berger, S., Barza, M., Jacobus, N. V., Tally, F. P. Activity of cefamandole and other cephalosporins against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 9:852-855, 1976. 46. Sutter, V. L., Finegold, S. M. Susceptibility of anaerobic bacteria to carbenicillin, cefoxitin and related drugs. J. Infect. Dis. 131:417-422, 1975. 47. Tally, F. P., Jacobus, N. V., Bartlett, J. G., Gorbach, S. L. Susceptibility of anaerobes to cefoxitin and other cephalosporins. Antimicrob. Agents Chemother. 7:128-132,1975. 48. Anderson, J. D., Sykes, R. B. Characterization of a ,8lactamase obtained from a strain of Bacteroides jragilis resistant to ,8-lactam antibiotics. J. Med. MicrobioI. 6:201-206, 1973. 49. Del Bene, V. E., Farrar, W. E., Jr. Cephalosporinase activity in Bacteroides fragilis. Antimicrob. Agents Chemother. 3:369-372, 1973. 50. Olsson, B., Nord, C. E., Wadstrom, T. Formation of beta-Iactamase in Bacteroides iragilis: cell bound and extracellular activity. Antimicrob. Agents Chemother.9:727-735,1976. 51. O'Callaghan, C. H., Sykes, R. B., Griffiths, A., Thornton, J. E. Cefuroxime, a new cephalosporin antibiotic: activity in vitro. Antimicrob. Agents Chemother.9:511-519,1976. 52. Zimmerman, S. B., Stapley, E. O. Relative morphological effects induced by cefoxitin and other ,8-lactam antibiotics in vitro. Antimicrob. Agents Chemother. 9:318-326, 1976. 53. Onishi, H. R., Zimmerman, S. B., Stapley, E. O. Observations on the mode of action of cefoxitin. Ann. N.Y. Acad. Sci. 235:406--425,1974. 54. Spratt, B. G. Distinct penicillin binding proteins involved in the division, elongation and shape of Escherichia coli K12. Proc. Natl. Acad. Sci. U.S.A. 72: 2999-3003, 1975. 55. Spratt, B. G. Properties of the penicillin-binding proteins of Escherichia coli K12. Eur. J. Biochem. 72: 341-352,1977.

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23. Sonneville, P. F., Kartodirdjo, R. R., Skeggs, H., Till, A. E., Martin, C. M. Comparative clinical pharmacology of intravenous cefoxitin and cephalothin. Eur. J. Clin. Pharmacol. 9:397-403,1976. 24. Darland, G., Birnbaum, J. Cefoxitin resistance to betalactamase: a major factor for susceptibility of Bacteroides to the antibiotic. Antimicrob. Agents Chemother. 11:725-734, 1977. 25. Goldner, M., Glass, D. G., Fleming, P. C. Spontaneous mutant with loss of ,8-lactamase in Aerobacter cloacae. J. Bacteriol. 97:961,1969. 26. Wallick, H., Hendlin, D. Cefoxitin, a semisynthetic cephamycin antibiotic: susceptibility studies. Antimicrob. Agents Chemother. 5:25-32,1974. 27. Griffith, R. S., Block, H. R. Cephalothin, a new antibiotic. J.A.M.A. 189:823-828,1964. 28. Wick, W. E., Preston, D. A. Biological properties of three 3-heterocyclicthiomethyl cephalosporin antibiotics. Antimicrob. Agents Chemother. 1:221-234, 1972. 29. Farrar, W. E., Jr., Gramling, P. K. Antistaphylococca1 activity and ,8-lactamase resistance of newer cephalosporins. J. Infect. Dis. 133:691-695, 1976. 30. Fong, I. W., Engelking, E. R., Kirby, W. M. M. Relative inactivation by Staphylococcus aureus of eight cephalosporin antibiotics. Antimicrob. Agents Chemother. 9:939-944, 1976. 31. Jones, R. N., Thornsberry, C., Barry, A. L., Fuchs, P. C., Gavan, T. L., Gerlach, E. H. BL-S786, a new parenteral cephalosporin. II. In vitro antimicrobial activity in comparison with six related cephalosporins. J. Antibiot. (Tokyo) 30:583-592, 1977. 32. McCloskey, R. V. Results of a clinical trial of cefoxitin, a new cephamycin antibiotic. Antimicrob. Agents Chemother. 12:636-641, 1977. 33. Washington, J. A. II The in vitro spectrum of cephalosporins. Mayo Clin. Proc. 51:237-250, 1976. 34. Phillips, I., King, A., Warren, C., Watts, B., Stoate, M. W. The activity of penicillin and eight cephalosporins on Neisseria gonorrhoeae. J. Antimicrob. Chemother.2:31-39,1976. 35. Eickhoff, T. C., Ehret, J. M. In vitro comparison of cefoxitin, cefamandole, cephalexin and cephalothin. Antimicrob. Agents Chemother. 9:994-999, 1976. 36. Norrby, R., Brorsson, J. E., Seeberg, S. Comparative study of the in vitro antibacterial activity of cefoxitin, cefuroxime and cephaloridine. Antimicrob. Agents Chemother. 9:506-510, 1976. 37. Yourassowsk y, E., Schou tens, E., Vanderlinen, M. P. Antibacterial activity of eight cephalosporins against Haemophilus influenzae and Streptococcus pneumoniae. J. Antimicrob. Chemother. 2:55-59,1976. 38. Kammer, R. B., Preston, D. A., Turner, J. R., Hawley, L. C. Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to sixteen antibiotics. Antimicrob. Agents Chemother. 8:9194, 1975. 19. Shah, P. M., Zwischenbrugger, H., Stille, W. In vitro activity of cefoxitin, a new cephalosporin. Munch. Med. Wochenschr. 118:1469-I472, 1976.


Cefoxitin and cephamycins: microbiological studies.

REVIEWS OF INFECTIOUS DISEASES. VOL. 1, NO.1. JANUARY-FEBRUARY 1979 © 1979 by The University of Chicago. 0162-0886/79/0101-0009$01.37 Cefoxitin and C...
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