Cephaloridine: A New Broad Spectrum Antibiotic. Effectiveness in Urogenital Infections

VoL 97, ,Jan.

THE JOURNAL OF UROLOGY

Copyright @ 1967 by The \lilliams & Wilkins Co"

Pr£nted

CEPHALORIDIJ\"J,::;: A NEvV BROAD SPECTRUl\I ANTIBIOTIC. EFFECTIVENESS IN UROGENITAL INFECTIONS RALPH H. LANDES, BYRON H. McCORMICK, ROBERT H. GRAHAM A.ND IRVING MELNICK From 1hr Dcparl111enl of C'rology, The Jfemorial Hospilal, Danville, Virginia

Cephaloridine, * a semi-synthetic antibiotic produced chemical alteration of cephalothin, t is a potent broad speetrum antibacterial drug. 1 • 2 Although resembling cephalothin in its antibacterial , it pos~esses considerable pharmacologic and clinical advantages over the parent product. Ccphaloridine is highly bactericidal against a wide Yaricty of organisms: almost all strains (including penicillin-resistant varieties) of staphylococci; beta hemolytic and Yiridans streptococci; pneumococci; most strains of Escherichia coli; Xeisseria gonorhoeae; many strains of Proteus mirabilis and P. morganii, of Salmonella and of Klcb,,iella-Aerobacter. l\Iost strains of P. vulgaris and Pseudomonas aeruginosa are resistant. 3 Resistance of bacteria to cephaloridine develops dowly and is step-wise. The penicillinresistant Staphylococcu~ aurcus develop,; no cross-resistance to cephaloridine, since the latter is not significantly affecter! by pcnicillinase. 4 Cephaloridine must be administered either intramuscularly or intravenously. It is poorly absorbed in its present. form from the bowel.3 It is rapidly absorbed 1d1en injected parenterally. Peak serum levels are achieYecl within 30 to 60 minute.~ and effective serum levels are maintained for 6 to 8 houro. It reaches an extremely Accepted for publication March 8, 1966. Supported by the Memorial Hospital Urological Research Fund and by a grant from Eli Lilly Laboratories. * Keflordin, Eli Lilly t Keflin, Eli Lilly. 1 Muggleton, P. W., O'Callaghan, C. H. and Stevens, W. K.: Laborator:v evaluation of a new antibiotic-cephaloridine (ceporin). Brit. Med. J., 0

2: 1234-1237, 1964. 2 :Murdoch, J. M., Speirs, C. F., Geddes, A. l'\L

and Wallace, E.T.: Clinical trial of cephaloridine, a new broad-spectrum antibiotic derived from cephalosporin C. Brit. l\Ied . J., 2: 1238--1240, 1964. "Wick, W. K and Boniece, WO S.: In vitro and in vivo laboratory evaluation of cephalogly· cin and cepbaloridineo Appl. Microbiol., 13: 248·-

high renal tissue level and appearn unchanged m the mine in very high concentration--ya]nable attributes in the treatment of urinary infections, Cephaloricline has low toxicity in both tlw laboratory animal and man. 3 There is apparently no cross-sensitivity with the penicillins although in 3 instances among 25 penicillin-allergic patient~ cephaloricline produced mticaria. Gastroin. te,;tinal, hepatic, bone marrow, hematologic and auditory toxicity has not been reported even with prolonged parenteral administration of relatively large doses. Dose,; of more than 6 gm daily are being investigated for possible n'nal toxicity although we have not encountered such an effect. In the presence of severe renal ment no significant cumulative serum leveLo hav(" been observed such as occm in paticnts treated ,rith potentially toxic antibiotics as kanamycin, streptomycin and chloramphenicol. As previously mentioned, cephaloricline has u number of pharmaceutical and clinical advantage,, over cephalothin: 1) It is more potent a.gainP1; gram-positive organisms, actually equaling thut of penicillin G against beta hemolytic stt·entoco1.:c1. and penicillin-sensitive staphylococci. 2) H not protein-bound while cephalothin is 20 to 30 per cent bound to serum protein in vivo." Prntein binding may play a role in the development of allergic reactions to antibiotics. 3) Cephaloridirn· serum levels remain at bactericidal coneentration for a longer period of time than cephalothm, permitting fewer daily injections. In our experi.. ence, injections at 12-hour (and occasionally at. 8-hour) intervals were adequate. Single injections of outpatients with fairly large do3es were likewise effective in most instances but. probably not ideal. Cephalothin requires injection at 3 to 6-hour intervals. 4) Cephaloridine is mu.ch more soluble than cephalothin alloVl·ing the required dose to be injected in a smaller volume or diluent. A gram of cephaloridine io easily dissolved in 2 ml. water but we usually administer 2 gm. iH

2531 1965. 4

Murdock, J. M.: Cephaloridine. Practitioner,

195: 109-113, 1965.

5

Abraham, E. P.: The cephalosporin story .

New ~cientist, 24: 430-431, 196-J..

147

148

LANDES AND ASSOCIATES

TABLE 1. Bacterial strains isolated: Disk sensitivity to cephaloi·idine Organism

Staph. aureus Strep. hemolyticus E.coli Proteus mirabilis Proteus morganii Proteus vulgaris Proteus rettgeri Klebsiella-Aerobacter Paracolon intermed. Pseudomonas aeruginosa Alkaligenes faec. E. freundi Paracolobacterimn coloformis

s

R

90 5 117 12 0 17 0

1 0 10

6 1 6 3

Tetracycline was substituted thereafter for the cephaloridine. For the next several days the patient was oliguric and the serum urea nitrogen TABLE 2. Comparison of sensitivity of some bactei·ial strains to cephaloridine by tube dilution and disk technique Organism

Pseudomonas aeruginosa

13

19

4

2

8

4

Proteus rettgeri

1 0 2

1 1 0

E. coli

Total: 269 strains = Sensitive; 54 strains Resistant. 3 ml. or 3 gm. in 4 or 5 ml. as a turbid suspension which easily traverses a 20 gauge needle. 5) Most impressive is the marked difference in the pain experienced by patients receiving injections of these drugs. Cephaloridine produces but little more pain than that caused by injection of the same volume of normal saline. On the other hand, injection of cephalothin is very painful.

Tube Dilution mcg/ml

R R R R R

50 >50 >50 50 50 6.25 6.25 25 25 12.5 6.25 3.13 6.25 12.5 3.13 50 25 6.25 6.25 25 6.25 50 >50 25 25 6.25 25.0 >50 >50 >50 >50 >50 50 6.25 12.5 6.25 50 50 0.1 0.2 1.6 0.1 0.2 0.1 0.1 0.1

s s s s s s s s s s

R

s s s s s

RESULTS

Cephaloridine is supplied as powder which is soluble in water. We administer it intramuscularly using 1.5 to 2 cc water for injection for each gram. It is relatively painless on injection. Patients receiving as much as 4 gm. intramuscularly in single doses daily for 3 weeks have not corn.plained of pain, nor have any areas of induration or inflarn.rn.ation developed at the injection sites. The only side effect definitely attributable to cephaloridine was urticaria which occurred in 5 patients-two quite severe with marked edema of the face and hands. The eruption subsided quickly with the withdrawal of the drug and the administration of an antihistamine. Three of these patients were highly allergic to penicillin. One of these patients, admitted to the hospital with rigors, temperature of 105F and hypotension after urethral dilatation for stricture was given 6 gm. cephaloridine intravenously. Blood culture, obtained on admission, revealed no growth but E. coli was grown from the urine culture. The rash appeared within a few hours but the fever subsided and the blood pressure rose to normal.

Disk

Paracolon intermed. E. freundi B. alkaligenes K. aerobacter

R R R

s s s

R R R R R R

Proteus vulgaris

s s s

R R

S. aureus

s s s s s s s s

CEPI-HLORIDINE: NEW BROAD SPECTRUM A;',iTlB!OTIC

ro~e to 130 mg. per 100 cc blood. Over the following week the azotemia subsided. Several weeks later the serum urea nitrogen level and phenolsulfonphthalein excretion were at normal levels. vV e believe that the azotern.ia was due to the hypotensive episode and not to the drug. There were no other instances of side reactions. There were no cases of diarrhea or other gastrointestinal disorders attributable to the drug. One humlrecl patients had complete blood counts before and after treatment 1Yith no significant alteration in the hemogram. Fifty had blood urea nitrogen determinations before and after treatment without evidence of change attributable to the drug. Twenty-five had hepatograms carried out before and after treatment with no significant evidence of liver damage. The drug 1Yas administered to 8 pregnant women with fulminant pyelonephriti::;, five of whom have since delivered normal children. One received 2 gm. intravenously 12 homs before delivery and an additional 2 gm. intravenously over a 4-hour period ending l hour before delivery. The others received 2 to 4 gn1. intranrnscularly daily for l week. X o ill effects were noted in either the patients or infants. All of these were in their second and third trimester of pregnancy. :BACTERIOLOGY

A total of 323 consecutive positive urine cultures obtained from patients with clinical evidence of urinary tract infection were subjected to a battery of disk sensitivity tests following isolation and identification of the organisms (table 1). The specimens were obtained by catheterization in the female patients and by midstream catch in the male patients. Of the 323 bacterial strains isolated, 269 (83 per cent) were found sensitive to cephaloridine by disk technique. E. coli was the most common organism, 127 strains, of which 117 were sensitive to cephaloridine. Ninety-one strains of hemolytic Staphylococcus aureus were isolated, all but one of which were sensitive to cephaloridine while half of them were penicillin G resistant. Twelve of 18 strains of Proteus mirabilis, 17 of 23 strains of Proteus vulgaris, 13 of 32 strains of Klebsiella}_cerobacter and 8 of 12 strains of Pseudomonas aeruginosa were disk sensitive to cephaloridine. In 46 instances both tube dilution and disk sensitivities were carried out with almost perfect correlation, indicating that the disk containing 30

mcg. of cephaloridine is suitable and realistic. Tb,, dependability of the disk technique led us to abandon the more difficult and time-consuming tube-dilution semitivity test for the most part (table 2). SERU:vr, URJKE A:\TD TfSi:,UE CO"ICEKTRNl'lO>
The serum concentration rises rapidly follm1·ing a single dose to a maximum within an declines fairly rapidly over the next :3 to 4 hours and is practically negligible ,,-ithin 24 hour~. Th,, lli'inary concentration, ranging from 10 t.o more than 100 times the concentration in the sernm, remains elevated for a much longer period of time with bactericidal levels present, as a rule, at hours. In no imtance was there any evidence of cumulative effect even with vt'ry large, dose~. Thus serum levels obtained 21 to 24 hours after the last of 6 to 10 daily intramuscular injection2 of from 2 to 6 gm. of the drug never exceeded mcg. per ml. and usually were less than l mcg. per ml. (table :3). This held true even in with markedly reduced renal function. In one anuric azotemic patient given a single intramuscu. lar injection of 2 gm. cephaloridine, the serum level at 1 hour was 75 mcg. per ml., at 8 hour:c; was 30 mcg. per ml. and at 11 hours was 20 mc:g. ver ml. Another terminally ill azotemic and anm·ic patient was found to have serum levels of :34!:, mcg. per ml. at :3 hours and 103 mcg. per ml. at 16 hours after a single intramuscular injection of 4 grn. A pregnant patient with very severe acute pyelonephritis received 2 gm. intravenollsly 12 hours before delivery and another 2 gm. over 4-hour period ending 1 hour before delivery. delivery a blood sample from the mother and u sample of cord blood were obtained. These revealed a cephaloridine serum level of 12 mcg per ml. in the infant and 10 mcg. per ml. in 1hc mother. Renal tissue concentration was determined in patients. The first patient had far advanced hydronephrosis. N ephrectomy was performed .2 J:i hours after a 6 gm. intramuscular injection of cephaloridine. Urine from the dilated renal contained 4930 mcg. per ml. Renal cortex con· tained 2:34 mcg. per gm. while renal medulla contained 166 mcg. per gm. The second patient received 6 gm. of cephaloridine intrarnuseularly l hour before nephrectorny for hypernephroma. Th0

150

LANDES AND ASSOCIATES TABLE

3. Serum and urine levels (mcg. per ml.) at various times after intramuscular injection of cephaloridine 4 Gm. Cephaloridine

2 Gm. Cephaloridine Time Serum

Urine

Serum

6 Gm. Cephaloridine

Urine

Serum

72.5

15 min. 30 min. 1 hr.

47.6

2060.0

52.4 40.0

1510.0

266.0

306.0 262.0 61.0

5300.0 3400.0 2365.0

52.0 26.0 54.0 27.0 28.0 50.0 40.0 172.0 348.0

4100.0 307.0 392.0 1190.0 7600.0 3800.0 5900.0 8200.0 9000.0

262.0

3440

165.0 232.0 66.8

26,480

2 hrs.

3 hrs.

30.5 168.0

4 hrs.

14.3 10.7

8700.0

5 hrs. 12 hrs. 24 hrs.

Urine

0.77 4.06 0.275 0.46

105 1600 23.1 52.3

168.0 9.7 18.4

3120.0 15,850.0

42.2 38.5

3656.0 3460.0

2.8

499.0

0.3 0.0 0.5 3.0 0.0 0.5 0.0 0.3 0.4 0.7 0.5 1.8 2.2

23.1 260.0

tumor contained 233 mcg. per gm. while the uninvolved portion of kidney contained 41 mcg. per gm. The tissue concentration in a prostatic adenoma enucleated 2 hours following the intramuscular injection of 6 gm. cephaloridine was found to be

137.0

1.07

6350.0 2150.0 37,600

147.0

171 11.2 71.8 72.6 73.0 25.2 134.0 56.8 201.0 93.6

62 mcg. per gm. The serum level at this time was 165 mcg. per ml. CLINICAL RESULTS

The clinical response to treatment with cephaloridine was very impressive. The acute infections

CJ<~P!fALORIDI1'iE: l\EW BHOAD SPEC'l'RUM ANTIBIOTIC

T,,Bl.E ·L Hes1171s according to organism !3acterioiogic Rl'sull

Clinical Result Organism

Satisfactory

;33 20 D

E. coli Kle bsie lla-AAro baetAr Proteus v11lgaris Proteus mirnbilis Proteus rettgeri Parncolon intenned. S. aureus Pseudomonas aerng. Tubercle bacillus "No growth"

(i

1 4 2 0

2

0

:3

Good

Relapse

2(i

4 1

8 Ii 4

:3 12 2

2 () ()

0

13

0

0

4

()

4

l)

0

2 2

()

2 0 2

17 11

Unl~11mvn

;)

4

0 0

2

0

0

n

Codeo

Satisfactory: asymptomatic and apyuric for 1--3 weeks after treatment.. TJnsat.isfactory: less ttia.n satisfactory even though patient may be improved Good: sterile urinA. Relapse. recurren1., culture after at least 1 1iegative cultnre with or witlwut syrnptorno . .Poor. persistent bacteritLria. Unknown: no post-treatment cultun-; obtained. "No growth" climcally ill, pyuric patients with no growth reported in original minn ('ttltnre. TABLB

5. Results accorcl-ing to chagnosis*t Clinical ResuI t ----·------------

Good

Satisfactory -

Bacteriologic Result -----·--- - - - - - - - ·---·-- -------- -----·-··--.

Urethral stricture ;yith ill feet.ion Acute prostatitis Chronic pros ta ti tis Epididymitis, acute Bactercmia Acute cystitis Cbronic cystitis Bladder diverticulmn and dirrniic cysti tis Chronic cystitis with [,HJ110J' Acute pyelonephritis Acute pyelonephritis of pregnaucy Chronic pyelonephritis Chronic pyclonephritis ,,it[1 stone Polycystic kidneys and chronJ_c pyelonephritis TB pyelonepliritis

cellulifo

Poor

7 lO

5

5

l 2 0

3 20

0 2

3

0

10

1

18 7

1

0

0

0 28 8

l

0

2

21

4

0

7

1

1 l

2

0

15 4 l

lj'

7

0

2 0

21

l

Unknown (I

0 l G 0

9

12 8

Rch1pse

----- ---- ·-·----·--

-------------------~---··--

(J

,,

1

'I.

0 0 D

I)

,)

2 J

0 IJ

4

0 2' 0

(I

p

:i 0

0

;J

()

0

0

0 0

0

()

n

0

* Inclndes patients ,vith multiple diagnoses allCl mixecl infections.

't Cocle of resnlis can be fonnd in table 1-!.

responded qmckly both and bacteriologically, even m many instances associated with resistant ~uwbrnb (tables 4 and 5). As would he number of

bacteriologic failures were associated with tJir Klebsiella-Aerobacter group, Pseudomo11a'., nnd Proteus organisms.

The 2 patientt, with

infedi0t1s

152

LANDES AND ASSOCIATES

found to be due to tuberculosis did not respond either clinically or bacteriologically to cephaloridine therapy. The chronic infections in many instances responded quite dramatically, both clinically and bacteriologically, but the greatest number of failures and relapses was in this group. As usual, patients with stones, tumors and obstructive lesions usually had more resistant organisms and were more prone to bacteriologic failure and relapse. Cephaloridine therapy of staphylococcus and E. coli infections was extremely effective, correlating very well with the in vitro sensitivity tests. The favorable response of infections due to Pseudomonas, Aerobacter and Proteus exceeded what one would expect from sensitivity tests and may be related to the extremely high urinary concentration of the drug. SUMMARY AND CONCLUSION

Cephaloridine is a potent broad spectrum antibiotic of low antigenicity and toxicity. It is ef-

fective in vivo and vitro against many common gram-positive and negative organisms. Our study has demonstrated its effectiveness, clinically and bacteriologically, in the majority of urinary infections. It is an important development in the field of antibacterial therapy of urinary tract infections because of: 1) its effectiveness against penicillinresistant staphylococci; 2) its usefulness m treating penicillin-sensitive patients; 3) its slowness in inducing resistant strains; 4) its safety in the presence of impaired renal function; 5) its ability to produce extremely high bactericidal concentrations in the serum, kidney parenchyma, prostate and urine; 6) its predictable clinical efficacy against infections caused by organisms shown to be susceptible by the disk sensitivity test; 7) its frequent clinical success in urinary infections due to organisms reported disk-resistant, probably attributable to its high urinary concentration.