Cefmenoxime: Clinical Evaluation
Cefmenoxime was evaluated iri an open trial consisting of 41 patients. Forty infections in 36 patients could be evaluated. Thirteen patients had pyelonephritis due to Escherichia coli (two bacteremic), Pseudomonas aeruginosa, Klebsiella pneumoniae, or Streptococcus faecalip; all improved and 12 of 13 were clinically cured; but one relapse (S. faecalis) occurred at two weeks. Six· patients with cystitis due to E. coli, Citrobacter freundii, Serratia marcescens, P. aeruginosa, or S. faecalis all improved, but relapse or reinfection, or both, occurred in five clue to P. aeruginosa, S. faecalis, C. fruendii, or E. coli. Neurogenic bladder or other complications were present in five of 13 patients with pyelonephritis and five of .six with cystitis. Ten patients with pneumonia and one with tracheobronchitis due to Hemophilus infiuenzae, s. pneui'noniae, S. agalactiae, or Neisseria meningitidis all improved and seven had resolution without relapse, but P. aeruginosa eme~ged in two patients, one of whom died. Eight soft tissue infections due to Staphylococcus aureus, Peptococcus prevotti, Streptococcus species, or ·infections of mixed origin resolved In six. Sterility of blood cultures was obtained in one patient with endocarditis due to S. anginosus, but other therapy was substituted. Clinical resolution of the toxic shock syndrome and subsequent negative endocervical cultures for S. aurttus occurred In' one. Granulocytopenia of unverified cause in four (with less than 1,500 mm3) and two (with less than 2,000 mm3) was reversibie. Headache during trfjatinent occurred in six patiehts arid a possible disulfiramlike effect in three. Elevations of serum glutamic oxalacetic transaminase and alkaline phosphatase occurred in five, Coombs' positivity in two, and diarrhea in three. Clinicai efficacy of cefmenoxime was significant. Possible side effects require further study.
ROBERT L. BAKER, M.D. ROBERT L. PERKINS, M.D. Columbus, Ohio
From the Division of Infectious Diseases, Department Of Medicine, Ohio State ~nivel"$ity, Columbus, Ohio. This work was supported in part by grant from Abbott Laboratones, North Chicago, Illinois. Requests for reprints ShoUld be addressed to Or. Robert L. Perkins, N~ 1148 UniverSity Hospitals, Columbus, Ohio 43210.
a
Cefmenoxime is an amihothiazolyl cephalosporin with a 7beta-methoxyimino group and a 3-methyltetrazolthio group, which confers stability to beta-lactamases and broad antimicrobial acilvlty [1-3). High in vitro activity has been reported against the Enterobacteriaceae,. beta-lactamaseproducing Hemophilus influenzae and Neisseria gonorrhoeae, rionenterococcal streptococci, . and varitible activity against Pseudomonas aerugihosa [4-8]. Effective dose (ED50) studies in a mouse intraperito· neal infection model were favorable for a variety of challenge bacteria [4,7,8]. The present study reports the efficacy and adverse effects of cefmEmoxime in 41 hospitalized patients. MATERIAL.S AND METHODS
Patients 12 years of age or older with infections of the respiratory or urogeni" tal tract, skin or soft . tissue, skeleton, or cardiovascular system were entered in the study. Patients witt) pyelonephritis had pyuria, bacteriuria greater than 10" cfu/ml, temperature elevations greater than 38.5°C, chills,
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and costovertebral angle tenderness. Cystitis was diagnosed in symptomatic or asymptomatic patients who had pyuria and bacteriuria greater than 105 cfu/ml in a clean catch urine or greater than 5 x 104 cfu/ml in catheter-obtained urine. A diagnosis of pneumonia was considered in patients with purulent sputum samples that on gram stain showed bacteria consistent with subsequent culture results and an infiltrate on chest x-ray. Exclusion criteria included any hypersensitivity to a cephalosporin or penicillin; pregnancy or lactation, recent effective antibiotic therapy, high probability of death within 48 hours, significant renal insufficiency, or known cefmenoxime-resistant organisms. Pretreatment laboratory data included a complete blood count, white blood cell differential, platelet count, prothrombin time, direct Coombs' test, blood urea nitrogen, creatinine, glucose, albumin, total protein, bilirubin, alkaline phosphatase, serum glutamic oxalacetic transaminase (SGOT), urinalysis, urine pregnancy test, and appropriate gram stains arid bacterial cultures. Appropriate cultures were repeated on day 1 or 2 of treatment, on day 5, weekly, and immediately after treatment before any subsequent therapy. In addition, urinary cultures were repeated five to nine days and four to six weeks after treatment as permitted by patient compliance. Follow-up clean catch urine cultures were considered significant if samples grew greater than 104 cfu/ml; any growth in catheter-obtained samples was considered significant. Minimal inhibitory concentrations (MICs) to cefmenoxime were performed on all available bacterial isolates. Hematologic and biochemical laboratory parameters were repeated on day 5 of treatment, weekly during treatment, and after treatment. After informed consent, patients were given cefmenoxirne 0.5 to 2 g every four to 12 hours, depending on the severity and site of the infectious process and renal function. Patients were treated at least five days unless toxicity or a protocol violation was observed. Efficacy of cefmenoxime was determined on the basis of clinical and bacteriologic responses; a designation of clinical cure at termination of therapy required resolution of signs and symptoms of infection, and bacteriologic cure indicated eradication of the causative bacteria. Bacteriologic persistence, recurrence, or reemergence and superinfection were determined by follow-up cultures as permitted by patient compliance and the limitations imposed by subsequent oral therapy ordered by attending physicians. RESULTS
Forty-one patients (25 male and 16 female, aged 18 to 81 years) were entered; five were excluded from efficacy evaluation because of protocol violations. There were 40 infections in the remaining 36 patients. Table I lists patients with urinary tract infection. There were 13 patients with pyelonephritis including four who had neurogenic bladders, one with nephrolithiasis, one with multiple myeloma and chronic renal failure, and one with Hodgkin's disease. Twelve were clinically cured. One uncomplicated case showed initial improvement, but therapy was discontinued because of a suspected but undocumented hypersensitivity reaction. The infecting pathogens were eradicated during treat54
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ment in 12 of 13 cases and in 10 of 13 in the 24-hour to 48-hour post-therapy samples (not done in two). In the one case of bacteriologic failure during treatment, serial specimens through a suprapubic catheter revealed a decreasing number of P. aeruginosa, but a 24-hour posttherapy culture grew 1,500 cfu/ml of P. aeruginosa, with an antibiogram identical to the original strain (cefmenoxime MIC 16 p.g/ml); a specimen one week after treatment revealed greater than 105 cfu/ml of P. aeruginosa although the patient was asymptomatic. Another patient with multiple myeloma and chronic renal failure and a mixed E. coli and S. faecalis infection (E. coli bacteremia) relapsed two weeks after therapy with S. faecalis pyelonephritis and exacerbation of renal failure. Two patients with E. coli infections, including one with nephrolithiasis and one with Hodgkin's disease (bacteremia), had negative follow-up cultures at one and four weeks. One patient had insignificant growth (three contaminating bacteria) in a one week follow-up culture but failed to return for further studies. One week or one month follow-up cultures were not assessable in eight because of post-therapy antibiotics (six) or noncompliance (two). The six cases of cystitis were complicated by urethral stricture and· fistula (one), residual urine which required intermittent catheterization (three); resected bladder carcinoma and intermittent catheterization (one), and diabetes mellitus (one). Three of the six had asymptomatic bacterturia; clinical cure was obtained in the three asymptomatic patients, and the pathogens were eradi" cated during and immediately post-therapy in all six. Of the three asymptomatic cases, only the diabetic patient who had E. coli cystitis and a functionally normal urinary tract remained culture-negative four weeks after therapy. Another with prostatic hypertrophy relapsed (S. faecalis) and was reinfected (P. aeruginosa and S. faecalis) at one week after therapy. All three symptomatic patients had relapse or reinfection. The patient with prior bladder carcinoma had symptomatic relapse at one week due to P. aeruginosa with unchanged susceptibility to cefmenoxime (MIC 16 p.g/ml). Symptomatic reinfection with a new E. coli as well as S. faecalis occurred in another patient at four weeks after cure of E. coli cystitis complicated by post-voiding residual urine. The third symptomatic patient, who also had post-voiding residual urine, obtained cure of S. marcescens cystitis, but developed asymptomatic reinfection with P. aeruginosa (cefmenoxime MIC 32 p.g/ml) at the one week follow-up. Ten patients with pneumonia and one with tracheobronchitis were treated (Table II); two were quadraplegic, one had colon carcinoma and pulmonary metastasis, one had laryngeal carcinoma with prior irradiation treatment, one had multiple myeloma and prior laryngectomy for carcinoma, one had muscular dystrophy and severe scoliosis, and three had altered sensoria. All 11 patients improved and seven were cured clinically without relapse; all of the seven had bacteriologic cures, including one who demonVolume
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TABLE I Patient
Urinary Tract Infections Treated with Intravenous Cefmenoxime Pathogen(s)
MIC (p.g/ml)
Underlying Diseases
Dose lnlerval Duration Clinical Bacteriologic Cure• Cure• (g) (hours) (days)
Comments
Pyelonephritis s:0.13
None
6
5
12
Escherichia coli E. coli
s:0.13
None
6
3
17
E. coli
s:0.03
Sickle cell trait
6
5
+
+
18
E. coli
0.13
6
11
+
+
21
E. coli
s:0.03
Paraplegia/neurogenic bladder None
12
7
+
+
22
E. coli
0.13
Nephrolithiasis
6
11
+
+.
24
E. coli
0.13
None
6
8
+
+
32
E. colit
s:0.03
Hodgkin's disease
6
9
+
+
38
E. coli
s:0.25
None
6
5
+
+
13
E. coli/ Streptococcus faecalist Klebsiella pneumoniae Pseudomonas aeruginosa
s:0.13 NO
Multiple myeloma and chronic renal insufficiency Paraplegia/neurogenic bladder Paraplegia/neurogenic bladder
12
15
+
+
6
9
+
+
6-8
7
+
6
16
+
+
Diabetes mellitus
12
13
A*
+
8
16 41
19
P. aeruginosa/ K. pneumoniae
0.25 16
16 0.13
Quadraplegia/ neurogenic bladder
+
+ +
Antibiotic given after therapy Therapy changed because of suspected adverse reaction Antibiotic given after therapy Antibiotic given after therapy Insignificant growth 1 week after therapy, no 4-week follow-up. No growth to 4 weeks after therapy Antibiotic given after therapy No growth to 4 weeks after therapy No 1- or 4-week post-therapy cultures done Clinical relapse with S. faecalis 2 weeks after therapy Antibiotic given after therapy Decreasing number of bacteria during therapy; >100,000 cfu/ml P. aeruginosa 1 week after therapy, patient asymptomatic No 1- or 4-week posttherapy cultures done
Cystitis 3
E. coli
s:0.13
5
E. coli
0.13
Post-void residual/ intermittent catheterization
12
7
+
+
27
Citrobacter freundii
16
Urethral stricture and fistula
12
6
A*
+
34
Serratia marcescens
s:0.25
12
9
+
+
36
P. aeruginosa
16
6
10
+
+
S. faecalis
128
Post-void residual/ intermittent catheterization Bladder carcinoma resection Prostatic hypertrophy
6
16
A*
+
6
Negative cultures to 4 weeks after therapy Symptomatic reinfection with E. coli and S. faecalis 4 weeks after therapy Asymptomatic C. freundii, P. aeruginosa and S. faecalis 1 week after therapy Asymptomatic P. aeruginosa 1 week after therapy Symptomatic recurrence 1 week after therapy Asymptomatic P. aeruginosa and S. faecalis 1 week after therapy
MIC = minimum inhibitory concentration; NO = not done. *Clinical cure refers to resolution of signs and symptoms of infection at termination of therapy; bacteriologic cure refers to eradication of the infecting organism or organisms in 24-hour post-therapy cultures. tE. coli bacteremia. *A= asymptomatic.
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SYMPOSIUM CEFMENOXIME-BAKER and PERKINS
TABLE II
Patient
Respiratory Infections Treated with Intravenous Cefmenoxime Pathogen(s)
MIC (#Lg/ml)
Dose Interval Duration Clinical Bacteriologic (g) (hours) (days) Cure* Cure*
Underlying Diseases
Comments
Pneumonia
30
Hemophilus influenzae
:s0.03
Colon carcinoma, pulmonary metastasis
35
H. influenzae
:s0.03
39
H. influenzae
:s0.03
Multiple myeloma, laryngectomy for carcinoma Quadraplegia
40
H. influenzae/ Streptococcus pneumoniae S. pneumoniae Streptococcus agalactiae
:s0.03 :s0.03
Duchenne's muscular dystrophy/scoliosis
:s0.13 :s0.13
14
15
28
Mouth florat
33
Mouth florat
6
3l
H. influenzae*/ Klebsiella pneumoniae/ Veillonella parvula/ Fusobacterium gonidiaformans/ Mouth florat Proteus mirabilis*t Mouth flora t
:s0.13 1
+
6
7
6
11
+
+
8
11
+
+
6
8
+
+
Quadriplegia Diabetes mellitus
6 12
9 11
+
+
Normal pressure hydrocephalus/ dementia Laryngeal carcinoma
12
9
+
+
8
6
+
Prior cerebrovascular accident with seizure disorder
6
16
+
Cerebrovascular accidenVseizure disorder
6
11
2
+
2 NO
:s0.03
Initial response; death with P. aeruginosa pneumonia
Eradication of H. influenzae during therapy; no sputum after therapy
Probably primary tuberculosis and probably coincidental bacterial pneumonia No sputa available after therapy Relapse of pneumonia 1 week after therapy The post-therapy purulent sputum contained P. aeruginosa, but the patient was clinically asymptomatic Patient improved with therapy, but P. mirabilis persisted; the patient probably had reaspiration
Tracheobronchitis 4
Neisseria meningiditis/ E. coli/ Mouth florat
0.13
Chronic obstructive lung disease
0.5
6
7
+
+
0.25
MIG= minimum inhibitory concentration; NO= not done. *Clinical cure refers to resolution of signs and symptoms of infection at termination of therapy; bacteriologic cure refers to eradication of infecting organism or organisms in after-therapy cultures or resolution of sputum production. tMouth flora refers to Streptococcus, Neisseria, Hemophilus species, or diphtheroids not classically pathogens. *Transtracheal aspiration performed.
strated eradication during treatment but could produce no sputum post-treatment, one who was unable to produce sputum after initiation of cefmenoxime, and 1 with an altered sensorium and recent cerebral vascular accident who became superinfected asymptomatically with P. aeruginosa (cefmenoxime MIC 16-32 ILg/ml) during therapy. The patient with metastatic colon carcinoma and Hemo-
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philus influenzae pneumonia initially improved on cefmenoxime, but subsequently worsened. He expired despite change of antibiotic therapy. Post-mortem examination revealed severe bronchopneumonia; large numbers of P. aeruginosa were grown from post-mortem lung specimens. Of note was the presence of small numbers of P. aeruginosa (cefmenoxime MIC 16 ILg/ml) in the pretherapy sputum cultures.
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The patient with radiation-treated laryngeal carcinoma and mixed aspiration pneumonia was clinically cured after six days of cefmenoxime therapy but relapsed one week after treatment. Another patient with a previous cerebral vascular accident, altered sensorium, and mixed aspiration pneumonia demonstrated persistence of Proteus mirabilis and normal mouth flora in transtracheal aspirates despite clinical improvement during therapy. The fourth case considered a clinical failure had S. agalactiae pneumonia; the patient improved during 11 days of cefmenoxime treatment but was switched to antituberculous therapy due to an increasing pleural effusion and a positive tuberculin skin test. There were eight patients with soft tissue infections (Table Ill). Six of the eight were cured. One patient with diabetes had a felon due to Staphylococcus aureus which failed to resolve on therapy. Adequate surgical drainage was not achieved until after cefmenoxime had been stopped. .one patient with a mixed infection due to Fusobacterium nucleatum, Peptococcus asaccharolyticus, Corynebacterium pyogene$, and S. auerus at a previous ankle muscle flap site, relapsed 8 months
TABLE Ill Patient
after cefmenoxime had been discontinued; osteomyelitis was evident at relapse. He had initially received 21 days of cefmenoxime (1 g every six hours intravenously) and refused further therapy or evaluation. Endocarditis due to Streptococcus anginosus-constellatus, presumably involving the tricuspid valve, was present in one patient who had a permanent intravenous pacemaker. The bacteremia cleared during cefmenoxime therapy but penicillin was subsequently substituted for cefmenoxime when the diagnosis of endocarditis was substantiated. The final patient had toxic shock syndrome and improved on cefmenoxime; S. auerus was eradicated from endocervical cultures. Six patients complained of .headache during cefmenoxime therapy; three of the six gave histories of chronic headaches which worsened. One patient received an oral · potassium chloride solution containing ethanol and two others had had ethanol ingestion within 24 hours before hospitalization. Ethyl alcohol and acetaldehyde blood levels were not done. No patient required discontinuance of cefmenoxime because of headaches. During therapy three patients developed multiple liquid stools. Two had stool samples positive for Clostridium dif-
Soft Tissue Infections Treated with Intravenous Cefmenoxime Pathogen(s)
2 Staphylococcus aureus 3 S. aureus
MIC
(~£g/ml)
2
7 S. aureus 11 S. aureus/ S. pyogenes/ Enterobacter cloacae 23 S. aureus/ Corynebacterium pyogenes/ Peptococcus asaccharolyticus/ Fusobacterium nucleatum
2 0.5 :50.13 :50.13
9 Beta-hemolytic Streptococcus (not A, B, D) 29 ·Peptococcus prevotti 4 Unknown
:50.13
2 0.06
Site of Infection Left antecubital fossa abscess Felon, left fourth finger
Underlying Disease
DoselntervaiDuratlonCiinicaiBacterlologic Cure• (g) (hours) (days) Cure*
+
+
Hodgkin's disease
6
8
Diabetes mellitus
12
13
6 6
9
6
21
Right leg cellulitis Skin graft/ hypesthesia
6
6
+
+
Left foot cellulitis
6
7
+
+
6
7
+
ut
Right leg abscess None Multiple Subcutanecius abscesses drug abuse on right forearm and left leg Left ankle Prior trauma/ cellulitis/abscess muscle flap
2 0.5
7
+
+ +
+ +
NO
:50.03
0.5
None
Right leg cellulitis Varicose veins
0.5
Comments No follow-up cultures because of clinical cure Felon improved, bacteria eradicated, but therapy changed to nafcillin; complete resolution occurred after surgical drainage No follow-up cultures because of clinical cure Cl.inical improvement, eradication of pathogens during treatment but relapse ·8 months after therapy with osteomyelitis and isolation of original pathogens No follow-up cuHures because of clinical cure No follow-up cultures because of clinical cure
MIC = minimum inhibitory concentration; NO = not done. *Clinical cure referS to resolution of lesions and signs and symptoms of infection at termination of therapy. Bacteriologic cure refers to eradication of infecting OrQanism or organisms in post-therapy cultures. tunknown.
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SYMPOSIUM CEFMENOXIME-BAKER and PERKINS
ficile toxin. One of the two died and at autopsy the colon was normal. The second patient had a normal sigmoidoscopy to 18 em. No patient required discontinuance of therapy because of diarrhea. One patient complained of diffuse pruritus toward the end of therapy and another developed photophobia and periorbital edema. Cefmenoxime was discontinued in both cases, but the relation of these symptoms to the drug is unknown. Six patients were noted to become leukopenic during therapy. Two patients with pyelonephritis developed granulocyte counts to less than 2,000/mm3 noted on day 5 and day 9 of therapy; one was black with Stage I Hodgkin's disease (normal bone marrow one week before becoming leukopenic) and was bacteremic, and the other was receiving prochlorperazine. Four patients with normal pretherapy granulocyte counts developed granulocytopenia to less than 1,500/mm3 three to six days after initiation of cefmenoxime; two of the four were black and had prior leukopenic episodes of unknown cause. A third patient with multiple myeloma and pyelonephritis with bacteremia also became transiently more thrombocytopenic (134,000/mm 3 ~ 90,000/mm3 ~ 147,000/mm3 ) during therapy. The fourth patient received nafcillin one month after cefmenoxime therapy and again became normal either during therapy (three) or after therapy (three). Leukopenia did not prompt cessation of therapy in any case. Two patients developed positive direct Coombs' tests during therapy. Hemolytic anemia was suspected but unproved in one case, and therapy was discontinued. Mild elevations in serum glutamic oxalacetic transaminase (SGOT) and alkaline phosphatase occurred in five patients each. These abnormalities were asymptomatic and therapy was not discontinued. One of the patients with elevation of alkaline phosphatase was subsequently found to have osteomyelitis. COMMENTS
Cefmenoxime was an effective antimicrobial agent in this study. All infections improved clinically and 72 percent resolved without clinical relapse. Clinical failure or relapse occurred in patients with complicating underlying diseases or in those who failed to receive optimal adjunctive therapy. Bacteriologic failure, relapse, reinfection, or superinfection occurred in 33 percent of the cases, most commonly due to S. faecalis and P. aeruginosa. In the patients with urinary tract infections, the only severe clinical and bacteriologic relapse occurred due to S. faecalis at two weeks in a patient with multiple myeloma and chronic renal failure. Other patients with bacteriologic failure, relapse, or reinfection had complicating functional urinary tract abnormalities. Difficulty in eradicating bacteriuria and preventing relapse in complicated uri-
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nary tract infections and problems with eradication of P. aeruginosa in those treated with cefmenoxime has been described [6,9, 10]. Because all but one patient with respiratory infections had a complicating underlying disease, most of which resulted in difficulty with clearing pulmonary secretions, it is not surprising that clinical relapses occurred. The most notable failure occurred in the patient with metastatic colon carcinoma; a superinfection with P. aeruginosa was associated with deterioration and subsequent demise. Side effects required cessation of therapy in only three patients. Three of the six patients with headache had consumed some form of ethanol either before or during therapy. The methyltetrazolthio group of cefmenoxime may confer disulfuram-like activity similar to that reported with moxalactam and cefoperazone [11, 12]. Disulfuram effect related to cefmenoxime has been reported [13]. Six patients developed granulocytopenia during therapy. Leukopenia thought to be related to cefmenoxime has been reported [3]. Twenty-five cases of leukopenia in 1,403 patients (1.8 percent) given cefmenoxime including eight of 666 in phase three studies and one case of reversible agranulocytosis have been observed (personal communication, Dr. Frank Steinberg). The unusually high number of patients who developed leukopenia in the present study was unexplained. However, underlying diseases, other drugs, race and septicemia may have contributed more significantly than cefmenoxime to the development of granulocytopenia in most instances. One patient also became leukopenic with subsequent nafcillin administration. In all cases, the granulocytopenia was noted early in cefmenoxime therapy. While granulocytopenia has been reported early in therapy with other cephalosporins, most cases have occurred after therapy of several days or weeks [14-17]. A report of granulocytopenia initially assumed to be cephalothin-related but which did not recur when cephalothin was given again to the same patient, suggests that cause-and-effect relations may be difficult to verify [18]. Abnormalities of liver function tests were noted in this study but were mild and reversible. Liver function abnormalities have been previously reported [9]. In conclusion, cefmenoxime was an effective antimicrobial agent in uncomplicated urinary tract infections and in pulmonary and soft tissue infections due to susceptible pathogens, including patients with underlying diseases. However, P. aeruginosa and S. faecalis were difficult to eradicate and were frequent causes of relapses, reinfection, or superinfection. Effective use of cefmenoxime against these pathogens may be doubtful even in urinary tract sites in which antibiotic concentrations may far exceed MICs. Side effects of cefmenoxime noted in this study deserve further investigation to help clarify casual relations.
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