Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. B), 117-125
Clinical experience with cefoxitin sodium
Johann Wolfgang Goethe University, Internal Medicine Centre Frankfurt am Main, West Germany
Cefoxitin sodium was evaluated in 48 patients having respiratory tract (20 patients), urinary tract (8 patients), and soft-tissue (4 patients) infections and septicaemia (16 patients). Clinical cure was achieved in 38 patients: 18 of 20 respiratory tract; 4 of 8 urinary tract; 13 of 16 septicaemia, and 3 of 4 soft-tissue infections. Twenty infections were resistant to cephalothin; 14 of these were cured by cefoxitin, which is also active against strains resistant to cefamandole, cefuroxime, gentamicin and amikacin. Cefoxitin was found effective against Gram-negative bacteria, including Bacteroides fragilis, indole-positive Proteus and Serratia. Cefoxitin was well tolerated. Few side effects, none serious, were encountered.
Introduction Cefoxitin sodium is a new semi-synthetic cephalosporin with a high degree of resistance to inactivation by bacterial cephalosporinases (Onishi, Daoust, Zimmerman, Hendlin & Stapley, 1974; Kosmidis, Hamilton-Miller, Gilchrist, Kerry & Brumfitt, 1973), the class of /9-lactamases which is a major cause of bacterial resistance to cephalosporins (Jack, Sythes & Richmond, 1970). Our own in vitro and first clinical experience (Shah, Helm, Zwischenbrugger & Stille, 1975) as well as reports from other authors (Daikos, Giamarellou, Kanelakopoulou & Piperakis, 1975; Heseltine, Busch, Meyer & Finegold, 1977) showed that cefoxitin is clinically effective. Further clinical investigations, which were carried out at the Department of Internal Medicine at the University of Frankfurt am Main, are reported here.
Materials and methods The 48 patients studied were hospitalized at the Centre for Internal Medicine, University of Frankfurt am Main. Clinical findings and either prior culture or Gram-stained material suggested bacterial infection. Material Cefoxitin was supplied by Merck Sharp & Dohme International, Rahway, N.J., U.S.A., in vials containing 1 g of sodium cefoxitin. 117
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
P. M. Shah, E. B. Helm and W. StiUe
118
P. M. Shah, E. B. Helm and W. Stille
Immediately before injection, each vial was dissolved in sterile distilled water, diluted in an appropriate amount of 0-9% saline, and infused over 30 min.
Patients and diagnosis Forty-eight adults (38 men and 10 women), aged 18 to 78 years, were treated with cefoxitin between October 1973 and August 1977. The shortest period of administration was 5 days and the longest was 62 days (Table I). Eight patients were given cefoxitin in combination with other antimicrobial drugs (Table II). Table I. Outcome of infections in 48 patients treated with cefoxitin Bacteriology
Clinical
Diagnosis
No. of patients
cure
Respiratory tract infection Urinary tract infection Septicaemia Soft-tissue infection
20 8 16 4
18 4 13 3
2 4 3 1
7 7 13 1
1 1 3
Total
48
38
10
28
5
failure eradicated persisting superinfection 2 2 1 5
Note: No pathogenic organisms could be cultured in 6 patients showing clinical signs of bacterial infection. Twenty patients had respiratory tract infection, 8 had urinary tract infection, 16 had septicaemia, and 4 had soft-tissue infection. No pathogenic organisms could be cultured in 6 patients with pneumonia, although clinical signs of bacterial infections were present. The clinical and bacteriologic outcomes are summarized in Table I. Laboratory tests Tests for transaminases, alkaline phosphatase, bilirubin, blood urea, creatinine, electrolytes, complete blood cell count (with differential), and urinalysis were performed at frequent intervals to monitor possible toxicity. Adequate material for bacteriologic evaluation (blood, urine, sputum, tracheal aspirate, and swabs) was collected prior to and, whenever possible, during and after therapy. Efficacy of therapy was evaluated as to (a) clinical outcome, and (b) bacteriologic outcome. Clinical cure was defined as recovery from the infection treated with cefoxitin. Follow-up cultures were not possible in most patients with pneumonia, who had been initially subjected to tracheal aspiration. Susceptibility testing Antibiograms were obtained using 30 /xg discs of cephalothin, cefazolin, and cefoxitin. For Gram-negative aerobes, the minimum inhibitory concentration (MIC) was determined by the tube dilution method in antibiotic medium 3 (Difco) for cephalothin,
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
Regimen The regimen was generally 6 g (2 g t.i.d.); 7 patients were given 3 g (1 g t.i.d.) and 2 patients having renal insufficiency were given 4 g (2 g b.i.d.) daily. In 32 patients not provided with a central venous catheter, a new site of injection was sought at each administration.
Proteus vulgaris
S. pneumoniae
Echerichia coli anaerobic streptococci E. coli
P. morganii
Serratia marcescens P. aeruginosa
1. K. pneumoniae 2. K. pneumoniae 3. E. coli
pneumonia
pneumonia
septicaemia
septicaemia
septicaemia
peritonitis
cholecystitis cholecystectomy
2
19
30
31
43
44
48
Klebsiella pneumoniae Pseudomonas aeruginosa
Pathogen
pneumonia
Infection
1
Case no.
cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day azlocillin 10 g/day tobramycin 80 mg/day cefoxitin 6 g/day gentamicin 120 mg/day
cefoxitin 6 g/day carbenicillin 30 g/day amikacin 750 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day
Antimicrobial drugs
14 14 9 9 14 15 15 9 9
12 7 7 42 42 7 7 15 15
Days of treatment
Table II. Data on 8 patients receiving cefoxitin in combination with other antimicrobial drugs
djournals.org/ at The University of British Colombia Library on July 9, 2015
Serratia eliminated; P. aeruginosa relapsed Clinical cure, though strain 2 and present in bile after therapy
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
S
a.
"S
ft
5*
3
n H
i
abdominal surgery
alcoholism
attempted suicide arrythmia cholelithiasis lymphogranulomatosis asthma (bronchial) secondary syphilis alcoholism
fractured ankle none
drug intake intoxication, shock anuria
75 26 30
55
34
41 61
47
55 40
20 72
19
2t
5
6
7 9
10
12 16
18
19t
20 peptostreptococci (E)
B. fragilis (E) B. melaninogenicus (E)
pneumococci (T, B, S) K. pneumoniae (T)
pneumococci (S, B) pneumococci (S, B)
Staph. aureus (T, S)
Proteus rettgeri (T) K. pneumoniae (T)
anaerobic streptococci (T)
B. fragilis (T) E. coli (T) microaerobic streptococci (T) B. melaninogenicus (T)
Peptostreptococci (T)
Klebsiella pneumoniae (T, B) Pseudomonas aeruginosa (T, B) Proteus vulgaris (T) Staphylococcus aureus (S) Bacteroides fragilis (T) B. melaninogenicus (T)
Pathogen
11 7 27
CEF, CEZ, CMT CEF, CEZ
9 5
died of underlying 16
penicillin
cured
(Candida)
cured superinfection
(P. aeruginosa)
cured superinfection
disease
cured cured
cured 19 13 13
cured
cured cured cured
42 9 33 20
cured
Outcome
12
Days of treatment
CEF, CEZ, CXM, CMT CEF, CEZ
CEF, CEZ
CEF, CEZ, CXM, CMT penicillin CEF, CEZ
CEF, CEZ
Pathogen resistant to
p://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
* No pathogens could be cultured from 6 patients having clinical signs of bacterial infection. t Patient with combination therapy. See Table II for details. B = positive blood culture, S = sputum, T = tracheal aspirate, E = pleural empyma, CEF = cephalothin, CEZ = ccfazolin, CMT = cefamandole, CXM = cefuroxime.
3 4
car accident multiple fractures attempted suicide malnutrition attempted suicide
18
It
Underlying disease
Age (years)
Case no.
Table III. Respiratory tract infections (14 of 20 patients)*
(/>
$
3
3 E
ft
X
CD
hh
&
2
»-^
a
till
Clinical experience in 48 patients
121
cefazolin, and cefoxitin; from October 1975 onwards determinations were also made for cefamandole and cefuroxime. Isolates were considered to be resistant if the MIC was Results
Table IV. Urinary tract infections (8 patients) Case Age no. (years) 21
62
22 23 24 25
69 50 35 78
26
59
27 28
24 75
Days of treatment
Outcome
Underlying disease
Pathogen
prostatectomy acute anuria gastric carcinoma cardiac surgery kidney transplantation immunocytoma
Klebsiellapneumoniae (U)
14
cured
Proteus mirabilis (U) K. pneumoniae (U) Serratia marcescens (U) P. rettgeri (U)
8 11 14 13
relapse cured cured died superinfection Pseudomonas aeruginosa failure cured superinfection P. aeruginosa
P. mirabilis (U, B) neurogenic bladder indwelling catheter lymphogranulomatosis Escherichia coli (U) S. marcescens (U)* rectal carcinoma
12 10 13
U = urine, B = blood culture. * Strain also resistant to gcntamicin and amikacin.
In 7 patients it was possible to obtain follow-up cultures, and in all 7 the initial organisms were eradicated (most were on cefoxitin only). Eight of the infections were resistant to cephalothin and cefazolin, 3 to cefamandole, and 2 to cefuroxime. All were susceptible to cefoxitin. Urinary tract infection (Table IV) Of 8 patients with urinary infections, 6 had isolates resistant to cephalothin and cefazolin. The Serratia marcescens strain isolated in Patient no. 28 was resistant to gentamicin and amikacin as well. Five of these organisms were also resistant to cefamandole and 4 were resistant to cefuroxime. Four patients were considered cured, 2 had superinfection with P. aeruginosa, and in 1 case (Patient no. 22) the original strain was isolated after the therapy with cefoxitin was stopped. Patient no. 26—who had a neurogenic bladder and an indwelling urinary catheter—was still running high temperatures although his urine and blood cultures, during and after cefoxitin treatment, were sterile. Septicaemia (Table V) Sixteen patients with clinical signs of septicaemia were treated with cefoxitin. Blood
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
Respiratory tract infection {Table III) Table III gives details on bacterial isolates found in 14 patients with respiratory infection (in 6 others no pathogenic organisms could be cultured). Eleven of these 14 patients were cured. Patients nos. 16 and 19 had a superinfection with a cefoxitin-resistant organism, i.e., Pseudomonas aeruginosa and Candida albicans, respectively. Patient No. 10 died of the underlying disease (lymphogranulomatosis), though the infection itself was under control.
kidney transplantation rectum carcinoma haemodialysis cardiac surgery none hyperthyroid diabetes mellitus chronic lymphadenosis car accident drug addiction prostatectomy immunosarcoma diverticulitis peritonitis
25 66 51 21 30 52
51 42 24 68 58 68 43
31* 32 33 34 35 36
37 38 39 41 42 43* 44*
Strep, pyogenes Proteus mirabilis\ Staph. aureus Citrobacter B. fragilis P. morganii Serratia marcescens Pseudomonas aeruginosa
Escherichia coli E. coli anaerobic streptococci E. coli Bacteroides fragilis Staphylococcus aureus Staph. aureus Streptococcus pyogenes Strep, pyogenes
Pathogen
Resistant to
CEF, CEZ CEF, CEZ, CMT CEF, CEZ, CMT, CXM
CEF, CEZ penicillin
CEF, CEZ penicillin penicillin
• Patients with combination therapy. See Table VI for details. t Strain also resistant to gentamictn; susceptibility to cefamandole and ccfuroxime not done. CEF.•» cephalothin, CEZ = cefazolin, CMT = cefamandole, CXM = cefuroxime.
none abdominal tumour
74 46
29 30*
Underlying disease
Age (years)
Case no.
23 5 11 13 8 9 15
14 14 10 35 13 10
14 15
Days of treatment
cured died failure cured cured cured Serratia eliminated
cured cured cured cured cured cured
cured cured
Outcome
Table V. Septicaemia (15 of 16 patients—no pathogen cultured from 1 patient showing clinical signs of infection and clinical improvement)
journals.org/ at The University of British Colombia Library on July 9, 2015
5"
•a
1 •
15
S
n
.Ppi"
k
y
Clinical experience in 48 patients
123
Table VL Soft-tissue infections (4 patients) Case Age no. (yrs)
Underlying disease
Pathogen
Days of treatment
Outcome
45
28
cholelithiasis cholangitis cholecystectomy
E. colt (I, D)
14
46
10
tonsillitis
10
47
64
62
failure
48*
30
leukaemia, hyperuricemia post-operative wound infection cholecystitis cholecystectomy
Strep, pyogenes (S) Staph. aureus P. mirabilis
cure (E. coli present in bile after therapy) cured
1. K. pneumoniae (I, D) 2. K. pneumoniae (I, D) 3. E. colt (I, D)
9
cure (strain 1 eliminated; 2 and 3 present in bile after therapy)
* Patient with combination therapy. See Table II for details. I = intraoperative, D = T-drain bile, S = swab. Soft-tissue infection {Table VI) Of the 4 patients with soft-tissue infection, 3 were considered to be clinically cured, though in Patients nos. 45 and 48 bacteriologic cure was not achieved. Both of these patients had been running high fever prior to drug therapy and surgery. In both cases, the strains were isolated from intra-operative bile. T-drain bile was sterile under therapy. However, the original pathogen was present in cultures taken after therapy, even though no signs of infection were present. In Patient no. 47 the number of bacteria per ml of wound secretions was markedly reduced. Combination therapy (Table If) Table II describes the 8 patients who were treated with cefoxitin in combination with other antimicrobial drugs. In Patient nos. 1 and 44 the mixed infection with P. aeruginosa required treatment with an antipseudomonal drug. The combination therapy was well tolerated by all 8 patients. Adverse effects {Table VII) Three patients had allergic rash under therapy with cefoxitin. No specific measures were required and the rash disappeared promptly after cefoxitin was discontinued. Transient
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
cultures taken prior to therapy in Patient no. 40 failed to yield a pathogen (therefore no. 40 is not shown in Table V). This patient had undergone cardiac surgery, and displayed all the clinical signs of a bacterial infection. She showed prompt recovery during treatment with cefoxitin. Patient no. 39—a drug addict—had recurrent staphylococcal bacteraemia while receiving 6 g/day of cefoxitin. A right-heart endocarditis was suspected. Five of the 15 strains isolated were considered to be resistant to cephalothin and cefazolin, 2 to cefamandole and 1 to cefuroxime. The Proteus mirabilis strain isolated in Patient no. 38 was also resistant to gentamicin (MIC: 16/ig/ml). This patient died without regaining consciousness.
124
P. M. Shah, E. B. Helm and W. StIUe Table VII. Side effects (11 of 48 patients)
Case no.
Infection
Underlying condition
Measures taken
1 2
respiratory respiratory
6 8
respiratory respiratory
9
respiratory
cholelithiasis
14
respiratory
rectal carcinoma
20 28
respiratory urinary
drug addiction rectum carcinoma
29
none septicaemia elevated transaminases rise in alkaline phosphatase and prior to therapy with cefoxitin o transaminases returned to normal under therapy transient rise in septicaemia hyperthyroid none alkaline phosphatase diabetes mellitus drug fever septicaemia diverticulitis therapy ended
allergic rash allergic rash
therapy ended therapy ended
none transient eosinophilia transient rise of none; alkaline phosphatase central venous thrombophlebitis catheter removed rise of alkaline none phosphatase after therapy transient rise of none alkaline phosphatase and transaminases therapy ended allergic rash therapy reduced to rise in blood urea 3 g/day; superinfecand creatinine tion with P. aeruginosa
36 43
eosinophilia was seen in 1 patient. Drug-related rise in alkaline phosphatase and/or transaminases were noticed in 3 patients (nos. 8, 14 and 36). Patient 29, who had elevated transaminases prior to therapy, showed a mild rise in alkaline phosphatase. We saw only 1 patient develop thrombophlebitis and 1 have a rise in blood urea and creatinine. Patient 43 developed signs of drug fever on the ninth day. His temperature returned to normal after cefoxitin was discontinued. Discussion Due to its stability against /J-lactamases (Onishi et al., 1974; Kosmidis et al., 1973), cefoxitin sodium is active against cephalothin-resistant Gram-negative bacteria, including Bacteroides fragilis (Sutter & Finegold, 1975), indole-positive Proteus and S. marcescens (Verbist, 1976). Cefoxitin is more active than cefamandole and cefuroxime against cephalothin-resistant strains (Verbist, 1976). Susceptibility testing against strains isolated from our patients supports the finding that cefoxitin is active against cephalothin-resistant bacteria, including B. fragilis. Twenty of the 48 patients had infections resistant to cephalothin. Fourteen of these 20 patients were cured with cefoxitin. Cefoxitin was well tolerated in our clinical trial. Thrombophlebitis was seen only in 1 case. This is in contradiction to reports by other authors (Heseltine et al., 1977) who
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
car accident malnutrition allergic diathesis alcoholism pulmonary embolism thrombosis of left leg
Adverse reactions
Clinical experience in 48 patients
125
References Daikos, G. K., Gaiamarellou, H., Kanelakopoulou, K., Piperakis, G. Qinical evaluation of cefoxitin. 9th International Congress of Chemotherapy, London (1975). Heseltine, P. N. R., Busch, D. F., Meyer, R. D. & Finegold, S. M. Cefoxitin: clinical evaluation in thirty-eight patients. Antimicrobial Agents and Chemotherapy 11: 427-34 (1977). Jack, G. W., Sykes, R. B. & Richmond, M. H. The ^-lactamases of gram-negative bacteria. Postgraduate Medical Journal 46: (Oct. suppl.): 41-3 (1970). Kosmidis, J., Hamilton-Miller, J. M. T., Gilchrist, J. N. G., Kerry, D. W., Brumfitt, W. Cefoxitin, a new semi-synthetic cephamycin: an in-vitro and in-vivo comparison with cephalothin. British MedicalJournal iv: 653-5 (1973). OniEhi, H. R., Daoust, D. R., Zimmerman, S. B., Hendlin, D., Stapley, E. O. Cefoxitin, a semi-synthetic cephamycin antibiotic. III. Resistance to /J-lactamase inactivation. Antimicrobial Agents and Chemotherapy 5: 38-48 (1974). Shah, P. M., Helm, E. B., Zwischenbrugger, H. & Stille, W. Cefoxitin: clinical and laboratory studies. 15th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington D.C.(1915). Sutter, V. L., Finegold, S. M. Susceptibility of anaerobic bacteria to carbenicillin, cefoxitin and related drugs. Journal of Infectious Diseases 131: 417-22 (1975). Verbist, L. Comparison of the antibacterial activity of nine cephalosporins against enterobacteriaceae and nonfermentative Gram-negative bacilli. Antimicrobial Agents and Chemotherapy 10: 657-63 (1976).
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
reported phlebitis in one-third of the 38 patients treated. This difference might be due to the mode of administration. Whereas Heseltine et al. changed infusion sites at least every 72 h or at the first sign of inflammation, we changed the infusion site at each injection in all patients except those provided with a venous catheter (16 patients). Our overall experience with cefoxitin in treating a variety of infections in seriously ill patients is encouraging. No serious side effects were encountered. Cefoxitin sodium was effective in infections resistant to cephalothin, cefamandole, cefuroxime, gentamicin and amikacin. Our experience so far is promising and merits further, broader-scale studies on the clinical efficacy of cefoxitin.
Clinical experience with cefoxitin sodium
Johann Wolfgang Goethe University, Internal Medicine Centre Frankfurt am Main, West Germany
Cefoxitin sodium was evaluated in 48 patients having respiratory tract (20 patients), urinary tract (8 patients), and soft-tissue (4 patients) infections and septicaemia (16 patients). Clinical cure was achieved in 38 patients: 18 of 20 respiratory tract; 4 of 8 urinary tract; 13 of 16 septicaemia, and 3 of 4 soft-tissue infections. Twenty infections were resistant to cephalothin; 14 of these were cured by cefoxitin, which is also active against strains resistant to cefamandole, cefuroxime, gentamicin and amikacin. Cefoxitin was found effective against Gram-negative bacteria, including Bacteroides fragilis, indole-positive Proteus and Serratia. Cefoxitin was well tolerated. Few side effects, none serious, were encountered.
Introduction Cefoxitin sodium is a new semi-synthetic cephalosporin with a high degree of resistance to inactivation by bacterial cephalosporinases (Onishi, Daoust, Zimmerman, Hendlin & Stapley, 1974; Kosmidis, Hamilton-Miller, Gilchrist, Kerry & Brumfitt, 1973), the class of /9-lactamases which is a major cause of bacterial resistance to cephalosporins (Jack, Sythes & Richmond, 1970). Our own in vitro and first clinical experience (Shah, Helm, Zwischenbrugger & Stille, 1975) as well as reports from other authors (Daikos, Giamarellou, Kanelakopoulou & Piperakis, 1975; Heseltine, Busch, Meyer & Finegold, 1977) showed that cefoxitin is clinically effective. Further clinical investigations, which were carried out at the Department of Internal Medicine at the University of Frankfurt am Main, are reported here.
Materials and methods The 48 patients studied were hospitalized at the Centre for Internal Medicine, University of Frankfurt am Main. Clinical findings and either prior culture or Gram-stained material suggested bacterial infection. Material Cefoxitin was supplied by Merck Sharp & Dohme International, Rahway, N.J., U.S.A., in vials containing 1 g of sodium cefoxitin. 117
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
P. M. Shah, E. B. Helm and W. StiUe
118
P. M. Shah, E. B. Helm and W. Stille
Immediately before injection, each vial was dissolved in sterile distilled water, diluted in an appropriate amount of 0-9% saline, and infused over 30 min.
Patients and diagnosis Forty-eight adults (38 men and 10 women), aged 18 to 78 years, were treated with cefoxitin between October 1973 and August 1977. The shortest period of administration was 5 days and the longest was 62 days (Table I). Eight patients were given cefoxitin in combination with other antimicrobial drugs (Table II). Table I. Outcome of infections in 48 patients treated with cefoxitin Bacteriology
Clinical
Diagnosis
No. of patients
cure
Respiratory tract infection Urinary tract infection Septicaemia Soft-tissue infection
20 8 16 4
18 4 13 3
2 4 3 1
7 7 13 1
1 1 3
Total
48
38
10
28
5
failure eradicated persisting superinfection 2 2 1 5
Note: No pathogenic organisms could be cultured in 6 patients showing clinical signs of bacterial infection. Twenty patients had respiratory tract infection, 8 had urinary tract infection, 16 had septicaemia, and 4 had soft-tissue infection. No pathogenic organisms could be cultured in 6 patients with pneumonia, although clinical signs of bacterial infections were present. The clinical and bacteriologic outcomes are summarized in Table I. Laboratory tests Tests for transaminases, alkaline phosphatase, bilirubin, blood urea, creatinine, electrolytes, complete blood cell count (with differential), and urinalysis were performed at frequent intervals to monitor possible toxicity. Adequate material for bacteriologic evaluation (blood, urine, sputum, tracheal aspirate, and swabs) was collected prior to and, whenever possible, during and after therapy. Efficacy of therapy was evaluated as to (a) clinical outcome, and (b) bacteriologic outcome. Clinical cure was defined as recovery from the infection treated with cefoxitin. Follow-up cultures were not possible in most patients with pneumonia, who had been initially subjected to tracheal aspiration. Susceptibility testing Antibiograms were obtained using 30 /xg discs of cephalothin, cefazolin, and cefoxitin. For Gram-negative aerobes, the minimum inhibitory concentration (MIC) was determined by the tube dilution method in antibiotic medium 3 (Difco) for cephalothin,
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
Regimen The regimen was generally 6 g (2 g t.i.d.); 7 patients were given 3 g (1 g t.i.d.) and 2 patients having renal insufficiency were given 4 g (2 g b.i.d.) daily. In 32 patients not provided with a central venous catheter, a new site of injection was sought at each administration.
Proteus vulgaris
S. pneumoniae
Echerichia coli anaerobic streptococci E. coli
P. morganii
Serratia marcescens P. aeruginosa
1. K. pneumoniae 2. K. pneumoniae 3. E. coli
pneumonia
pneumonia
septicaemia
septicaemia
septicaemia
peritonitis
cholecystitis cholecystectomy
2
19
30
31
43
44
48
Klebsiella pneumoniae Pseudomonas aeruginosa
Pathogen
pneumonia
Infection
1
Case no.
cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day azlocillin 10 g/day tobramycin 80 mg/day cefoxitin 6 g/day gentamicin 120 mg/day
cefoxitin 6 g/day carbenicillin 30 g/day amikacin 750 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day cefoxitin 6 g/day gentamicin 80 mg/day
Antimicrobial drugs
14 14 9 9 14 15 15 9 9
12 7 7 42 42 7 7 15 15
Days of treatment
Table II. Data on 8 patients receiving cefoxitin in combination with other antimicrobial drugs
djournals.org/ at The University of British Colombia Library on July 9, 2015
Serratia eliminated; P. aeruginosa relapsed Clinical cure, though strain 2 and present in bile after therapy
Cured
Cured
Cured
Cured
Cured
Cured
Outcome
S
a.
"S
ft
5*
3
n H
i
abdominal surgery
alcoholism
attempted suicide arrythmia cholelithiasis lymphogranulomatosis asthma (bronchial) secondary syphilis alcoholism
fractured ankle none
drug intake intoxication, shock anuria
75 26 30
55
34
41 61
47
55 40
20 72
19
2t
5
6
7 9
10
12 16
18
19t
20 peptostreptococci (E)
B. fragilis (E) B. melaninogenicus (E)
pneumococci (T, B, S) K. pneumoniae (T)
pneumococci (S, B) pneumococci (S, B)
Staph. aureus (T, S)
Proteus rettgeri (T) K. pneumoniae (T)
anaerobic streptococci (T)
B. fragilis (T) E. coli (T) microaerobic streptococci (T) B. melaninogenicus (T)
Peptostreptococci (T)
Klebsiella pneumoniae (T, B) Pseudomonas aeruginosa (T, B) Proteus vulgaris (T) Staphylococcus aureus (S) Bacteroides fragilis (T) B. melaninogenicus (T)
Pathogen
11 7 27
CEF, CEZ, CMT CEF, CEZ
9 5
died of underlying 16
penicillin
cured
(Candida)
cured superinfection
(P. aeruginosa)
cured superinfection
disease
cured cured
cured 19 13 13
cured
cured cured cured
42 9 33 20
cured
Outcome
12
Days of treatment
CEF, CEZ, CXM, CMT CEF, CEZ
CEF, CEZ
CEF, CEZ, CXM, CMT penicillin CEF, CEZ
CEF, CEZ
Pathogen resistant to
p://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
* No pathogens could be cultured from 6 patients having clinical signs of bacterial infection. t Patient with combination therapy. See Table II for details. B = positive blood culture, S = sputum, T = tracheal aspirate, E = pleural empyma, CEF = cephalothin, CEZ = ccfazolin, CMT = cefamandole, CXM = cefuroxime.
3 4
car accident multiple fractures attempted suicide malnutrition attempted suicide
18
It
Underlying disease
Age (years)
Case no.
Table III. Respiratory tract infections (14 of 20 patients)*
(/>
$
3
3 E
ft
X
CD
hh
&
2
»-^
a
till
Clinical experience in 48 patients
121
cefazolin, and cefoxitin; from October 1975 onwards determinations were also made for cefamandole and cefuroxime. Isolates were considered to be resistant if the MIC was Results
Table IV. Urinary tract infections (8 patients) Case Age no. (years) 21
62
22 23 24 25
69 50 35 78
26
59
27 28
24 75
Days of treatment
Outcome
Underlying disease
Pathogen
prostatectomy acute anuria gastric carcinoma cardiac surgery kidney transplantation immunocytoma
Klebsiellapneumoniae (U)
14
cured
Proteus mirabilis (U) K. pneumoniae (U) Serratia marcescens (U) P. rettgeri (U)
8 11 14 13
relapse cured cured died superinfection Pseudomonas aeruginosa failure cured superinfection P. aeruginosa
P. mirabilis (U, B) neurogenic bladder indwelling catheter lymphogranulomatosis Escherichia coli (U) S. marcescens (U)* rectal carcinoma
12 10 13
U = urine, B = blood culture. * Strain also resistant to gcntamicin and amikacin.
In 7 patients it was possible to obtain follow-up cultures, and in all 7 the initial organisms were eradicated (most were on cefoxitin only). Eight of the infections were resistant to cephalothin and cefazolin, 3 to cefamandole, and 2 to cefuroxime. All were susceptible to cefoxitin. Urinary tract infection (Table IV) Of 8 patients with urinary infections, 6 had isolates resistant to cephalothin and cefazolin. The Serratia marcescens strain isolated in Patient no. 28 was resistant to gentamicin and amikacin as well. Five of these organisms were also resistant to cefamandole and 4 were resistant to cefuroxime. Four patients were considered cured, 2 had superinfection with P. aeruginosa, and in 1 case (Patient no. 22) the original strain was isolated after the therapy with cefoxitin was stopped. Patient no. 26—who had a neurogenic bladder and an indwelling urinary catheter—was still running high temperatures although his urine and blood cultures, during and after cefoxitin treatment, were sterile. Septicaemia (Table V) Sixteen patients with clinical signs of septicaemia were treated with cefoxitin. Blood
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
Respiratory tract infection {Table III) Table III gives details on bacterial isolates found in 14 patients with respiratory infection (in 6 others no pathogenic organisms could be cultured). Eleven of these 14 patients were cured. Patients nos. 16 and 19 had a superinfection with a cefoxitin-resistant organism, i.e., Pseudomonas aeruginosa and Candida albicans, respectively. Patient No. 10 died of the underlying disease (lymphogranulomatosis), though the infection itself was under control.
kidney transplantation rectum carcinoma haemodialysis cardiac surgery none hyperthyroid diabetes mellitus chronic lymphadenosis car accident drug addiction prostatectomy immunosarcoma diverticulitis peritonitis
25 66 51 21 30 52
51 42 24 68 58 68 43
31* 32 33 34 35 36
37 38 39 41 42 43* 44*
Strep, pyogenes Proteus mirabilis\ Staph. aureus Citrobacter B. fragilis P. morganii Serratia marcescens Pseudomonas aeruginosa
Escherichia coli E. coli anaerobic streptococci E. coli Bacteroides fragilis Staphylococcus aureus Staph. aureus Streptococcus pyogenes Strep, pyogenes
Pathogen
Resistant to
CEF, CEZ CEF, CEZ, CMT CEF, CEZ, CMT, CXM
CEF, CEZ penicillin
CEF, CEZ penicillin penicillin
• Patients with combination therapy. See Table VI for details. t Strain also resistant to gentamictn; susceptibility to cefamandole and ccfuroxime not done. CEF.•» cephalothin, CEZ = cefazolin, CMT = cefamandole, CXM = cefuroxime.
none abdominal tumour
74 46
29 30*
Underlying disease
Age (years)
Case no.
23 5 11 13 8 9 15
14 14 10 35 13 10
14 15
Days of treatment
cured died failure cured cured cured Serratia eliminated
cured cured cured cured cured cured
cured cured
Outcome
Table V. Septicaemia (15 of 16 patients—no pathogen cultured from 1 patient showing clinical signs of infection and clinical improvement)
journals.org/ at The University of British Colombia Library on July 9, 2015
5"
•a
1 •
15
S
n
.Ppi"
k
y
Clinical experience in 48 patients
123
Table VL Soft-tissue infections (4 patients) Case Age no. (yrs)
Underlying disease
Pathogen
Days of treatment
Outcome
45
28
cholelithiasis cholangitis cholecystectomy
E. colt (I, D)
14
46
10
tonsillitis
10
47
64
62
failure
48*
30
leukaemia, hyperuricemia post-operative wound infection cholecystitis cholecystectomy
Strep, pyogenes (S) Staph. aureus P. mirabilis
cure (E. coli present in bile after therapy) cured
1. K. pneumoniae (I, D) 2. K. pneumoniae (I, D) 3. E. colt (I, D)
9
cure (strain 1 eliminated; 2 and 3 present in bile after therapy)
* Patient with combination therapy. See Table II for details. I = intraoperative, D = T-drain bile, S = swab. Soft-tissue infection {Table VI) Of the 4 patients with soft-tissue infection, 3 were considered to be clinically cured, though in Patients nos. 45 and 48 bacteriologic cure was not achieved. Both of these patients had been running high fever prior to drug therapy and surgery. In both cases, the strains were isolated from intra-operative bile. T-drain bile was sterile under therapy. However, the original pathogen was present in cultures taken after therapy, even though no signs of infection were present. In Patient no. 47 the number of bacteria per ml of wound secretions was markedly reduced. Combination therapy (Table If) Table II describes the 8 patients who were treated with cefoxitin in combination with other antimicrobial drugs. In Patient nos. 1 and 44 the mixed infection with P. aeruginosa required treatment with an antipseudomonal drug. The combination therapy was well tolerated by all 8 patients. Adverse effects {Table VII) Three patients had allergic rash under therapy with cefoxitin. No specific measures were required and the rash disappeared promptly after cefoxitin was discontinued. Transient
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
cultures taken prior to therapy in Patient no. 40 failed to yield a pathogen (therefore no. 40 is not shown in Table V). This patient had undergone cardiac surgery, and displayed all the clinical signs of a bacterial infection. She showed prompt recovery during treatment with cefoxitin. Patient no. 39—a drug addict—had recurrent staphylococcal bacteraemia while receiving 6 g/day of cefoxitin. A right-heart endocarditis was suspected. Five of the 15 strains isolated were considered to be resistant to cephalothin and cefazolin, 2 to cefamandole and 1 to cefuroxime. The Proteus mirabilis strain isolated in Patient no. 38 was also resistant to gentamicin (MIC: 16/ig/ml). This patient died without regaining consciousness.
124
P. M. Shah, E. B. Helm and W. StIUe Table VII. Side effects (11 of 48 patients)
Case no.
Infection
Underlying condition
Measures taken
1 2
respiratory respiratory
6 8
respiratory respiratory
9
respiratory
cholelithiasis
14
respiratory
rectal carcinoma
20 28
respiratory urinary
drug addiction rectum carcinoma
29
none septicaemia elevated transaminases rise in alkaline phosphatase and prior to therapy with cefoxitin o transaminases returned to normal under therapy transient rise in septicaemia hyperthyroid none alkaline phosphatase diabetes mellitus drug fever septicaemia diverticulitis therapy ended
allergic rash allergic rash
therapy ended therapy ended
none transient eosinophilia transient rise of none; alkaline phosphatase central venous thrombophlebitis catheter removed rise of alkaline none phosphatase after therapy transient rise of none alkaline phosphatase and transaminases therapy ended allergic rash therapy reduced to rise in blood urea 3 g/day; superinfecand creatinine tion with P. aeruginosa
36 43
eosinophilia was seen in 1 patient. Drug-related rise in alkaline phosphatase and/or transaminases were noticed in 3 patients (nos. 8, 14 and 36). Patient 29, who had elevated transaminases prior to therapy, showed a mild rise in alkaline phosphatase. We saw only 1 patient develop thrombophlebitis and 1 have a rise in blood urea and creatinine. Patient 43 developed signs of drug fever on the ninth day. His temperature returned to normal after cefoxitin was discontinued. Discussion Due to its stability against /J-lactamases (Onishi et al., 1974; Kosmidis et al., 1973), cefoxitin sodium is active against cephalothin-resistant Gram-negative bacteria, including Bacteroides fragilis (Sutter & Finegold, 1975), indole-positive Proteus and S. marcescens (Verbist, 1976). Cefoxitin is more active than cefamandole and cefuroxime against cephalothin-resistant strains (Verbist, 1976). Susceptibility testing against strains isolated from our patients supports the finding that cefoxitin is active against cephalothin-resistant bacteria, including B. fragilis. Twenty of the 48 patients had infections resistant to cephalothin. Fourteen of these 20 patients were cured with cefoxitin. Cefoxitin was well tolerated in our clinical trial. Thrombophlebitis was seen only in 1 case. This is in contradiction to reports by other authors (Heseltine et al., 1977) who
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
car accident malnutrition allergic diathesis alcoholism pulmonary embolism thrombosis of left leg
Adverse reactions
Clinical experience in 48 patients
125
References Daikos, G. K., Gaiamarellou, H., Kanelakopoulou, K., Piperakis, G. Qinical evaluation of cefoxitin. 9th International Congress of Chemotherapy, London (1975). Heseltine, P. N. R., Busch, D. F., Meyer, R. D. & Finegold, S. M. Cefoxitin: clinical evaluation in thirty-eight patients. Antimicrobial Agents and Chemotherapy 11: 427-34 (1977). Jack, G. W., Sykes, R. B. & Richmond, M. H. The ^-lactamases of gram-negative bacteria. Postgraduate Medical Journal 46: (Oct. suppl.): 41-3 (1970). Kosmidis, J., Hamilton-Miller, J. M. T., Gilchrist, J. N. G., Kerry, D. W., Brumfitt, W. Cefoxitin, a new semi-synthetic cephamycin: an in-vitro and in-vivo comparison with cephalothin. British MedicalJournal iv: 653-5 (1973). OniEhi, H. R., Daoust, D. R., Zimmerman, S. B., Hendlin, D., Stapley, E. O. Cefoxitin, a semi-synthetic cephamycin antibiotic. III. Resistance to /J-lactamase inactivation. Antimicrobial Agents and Chemotherapy 5: 38-48 (1974). Shah, P. M., Helm, E. B., Zwischenbrugger, H. & Stille, W. Cefoxitin: clinical and laboratory studies. 15th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington D.C.(1915). Sutter, V. L., Finegold, S. M. Susceptibility of anaerobic bacteria to carbenicillin, cefoxitin and related drugs. Journal of Infectious Diseases 131: 417-22 (1975). Verbist, L. Comparison of the antibacterial activity of nine cephalosporins against enterobacteriaceae and nonfermentative Gram-negative bacilli. Antimicrobial Agents and Chemotherapy 10: 657-63 (1976).
Downloaded from http://jac.oxfordjournals.org/ at The University of British Colombia Library on July 9, 2015
reported phlebitis in one-third of the 38 patients treated. This difference might be due to the mode of administration. Whereas Heseltine et al. changed infusion sites at least every 72 h or at the first sign of inflammation, we changed the infusion site at each injection in all patients except those provided with a venous catheter (16 patients). Our overall experience with cefoxitin in treating a variety of infections in seriously ill patients is encouraging. No serious side effects were encountered. Cefoxitin sodium was effective in infections resistant to cephalothin, cefamandole, cefuroxime, gentamicin and amikacin. Our experience so far is promising and merits further, broader-scale studies on the clinical efficacy of cefoxitin.
