administration of carbenicillin and ticarcillin—pharmaceutical aspects

Europ. d. Cancer Vol. 9, pp. 425-433. Pergamon Press 1973. Printed in Great Britain

Administration of Carbenicillin and Ticarcillin Pharmaceutical Aspects

BRIAN LYNN x~Iedical Department, Beecham Research Laboratories, Brentford, llliddlesex, England.

Abstraet--Ticarcillin is a new injectable semi-synthetic penicillin for ilfections caused by Pseudomonas aeruginosa and indole-positive Proteus spp. Its properties are compared with those of carbenicillin.

In Pseudomonas infection a regimen of 5 g carbenicillin in 100 ml of water, infused over 30 min at 4-hour intervals, would seem to meet the necessary criteria for both height and duration of serum levels. On the bases of the in vitro antibacterial activities and pharmacological data, equivalent effectiveness would be obtained using a lower dosage ofticarcillin.

THE TREATMENT of infection in patients with leukaemia, and those undergoing radiotherapy or treatment with cytotoxic agents, poses many problems. The increasing incidence in such patients in recent years of infections caused by Gram-negative bacilli, including Escherichia coli, Klebsiella, Enterobacter, Proteus and Pseudomonas, has made the situation even more difficult. Pseudomonas, in particular, is an organism against which few antibiotics are active.

Because of the overwhelming importance assumed by fl-lactamase (penicillinase)-produc- ing Staphylococcus aureus as a cause of hospital- acquired infection in the late 1950's and 1960's, the preparation of derivatives active against this organism was one of the priorities of penicillin research. This work led to the introduction of penicillins stable to staphylococcal fl-lactamase, firstly methicillin [1] and more recently the isoxazolyl compounds, cloxacitlin [2] and flucloxacillin [3]. However, with the emergence of Pseudomonas aeruginosa as an increasingly important cause of severe infections, particularly in aged, debilitated, immunodeficient, burned and post-surgical patients, and in those with chronic underlying diseases, increasing research effort in this area became a matter of urgency.

C a r b e n i c i l l i n , e-carboxybenzylpenicillin (BRL 2064), was the first available penicillin with therapeutic activity against Pseudomonas aeruginosa and indole-positive Proteus [4-6]. It is a non-toxic agent which can be given in high intravenous dosage [5, 7, 8]. Carbenicillin has been accepted as a first-line drug in the treatment of Pseudomonas infections, and laboratory and clinical experience with it has been pre-

425

sented at four international symposia [9-12]. An aspect of particular interest is the synergy which is found between carbenicillin and gentamicin against many strains of Pseudomonas aeruginosa [4, 13-17]. This synergy is very marked with some strains, less marked with others, but concurrent use of these two bactericidal antibiotics can provide extremely effective therapy for serious Pseudomonas infections [17-20].

Continued work in this field has resulted in the synthesis of a further compound with pro- mising antipseudomonal activity, namely, e- carboxy-3-thienylmethylpenicillin (BRL 2288), which has recently been given the approved name ticarcillin. This penicillin is at present undergoing clinical trial and is not yet generally available, but its antibacterial properties have been reported from several centres [21-25]. Briefly, ticarcillin is at least twofold more active than carbenicillin against Pseudomonas aeruginosa and also somewhat more active against Entero- bacter species. It is as active as, or slightly more active than, ampicillin and carbenicillin against Esch. coli, and all three agents have similar activity against strains of Proteus mirabilis which do not produce fl-lactamase. Like carbenicillin, ticarcillin is active against a high proportion of strains of indole-positive Proteus species (morganii, rettgeri, vulgaris). Most strains of Klebsiella aerogenes and Serratia marcescens are relatively resistant to both carbenicillin and ticarcillin. An interesting point is that meningo- cocci, gonococci and Haemophilus influenzae are at least as sensitive to ticarcillin as to ampicillin [23, 26].

426 Brian Lynn

Studies on the human [27] and animal [28] pharmacology of ticarcillin have also been published. In Pseudomonas infections in mice, the mean CDso values with ticarcillin were generally about half those with carbenicillin [28]. As in the case of carbenicillin, synergy against Pseudomonas is often seen when ticarcillin is used in conjunction with either gentamicin or polymyxin B, both zn vitro [23], and in experimental infections in animals [28].

Various physical and pharmaceutical properties of carbenicillin have been reported previously [29-33]. The present paper is the first account of these aspects of ticarcillin. The characteristics of the two compounds will be compared, and some of the factors relevant to their intravenous usage will be discussed.

STRUCTURES

The structures of carbenicillin and ticarcillin are shown in Fig. 1. In both cases the available compound is a mixture of the D- and L-isomers.

Side-cha in of disodium i corben[c i l Iin (BRL2064) I }

C O O N a

~S.~. - - N H - - H C - - C H C(CH.,)~

I I / ~ " O C - - N - - C H . C O O N a

COONa

Side-chain of disodium • ticorcillin ( B R L 2 2 8 8 )

Fig. 1. Structures of the disodium salts of carbenicillin and ticarcillin.

It has been established that the presence of a polar grouping on the a-carbon atom of the side-chain in penicillin derivatives is associated with activity against Gram-negative bacteria. In both carbenicillin and ticarcillin the ~- substituent is a carboxyl group, which is apparently the key to their activity against Pseudomonas and their relative stability to the

fl-lactamases produced by indole-positive species of Proteus. The chemical difference between the two is that ticarcillin has a 3-thienyl group (thiophene ring) in place of the phenyl group (benzene ring) of carbenicillin.

PHYSICAL PROPERTIES

Some of the more important physical characteristics of the two compounds are summarized in Table 1. Their properties are, in fact, closely comparable. Both penicillins are used as disodium salts, which are very hygroscopic and freely soluble in water. The sodium content is worth bearing in mind in the treatment of patients in whom sodium restriction is indicated. Neither agent is sufficiently stable at gastric acid pH to be administered orally. The vials of dry powder should be stored in the refrigerator, at which temperature little or no decomposition takes place during storage for 12 months or more.

STABILITY IN AQUEOUS SOLUTION

Tables 2 and 3 give figures for the stability of disodium carbenicillin and disodium ticarcit- lin, respectively, in aqueous solution at the concentrations used for intramuscular injection. Determinations of antibiotic were carried out by plate assay using Pseudomonas aeruginosa. Though carbenicillin is somewhat more stable than ticarcillin, in neither case is there much loss of activity in three days at 5°C. We never- theless recommend that intramuscular solutions should be used within 30 min of preparation, because small amounts of polymer are formed by penicillins and cephalosporins in solution especially at high concentration. The clinical significance, if any, of polymer formation is unknown, but polymers could be involved in the occurrence of delayed skin rashes.

We have also studied the stability of buffered and unbuffered 10% solutions of disodium carbenicillin over a period of eight days

Table 1. Physical characteristics of disodium carbenicillin (BRL 2064) and disodium ticarcillin (BRL 2288)

Sodium content Isotonic Stability at pH2

(per weight solution pH and 37°C equivalent Solubili ty (volume ( 10 % w/v (half-life in

Molecular to 1 g free in water of water solution in 0.1% w/v weight acid) (20°C) per g) COl- f ree water) solution)

Disodium 422.4 5.4 m eqw 1 in 1-2 28-5 ml 6.0-8.0 approx. 30 rain Carbenici l l in

Disodium 428.4 5"2 m eqw > 1 in 1 28.0 ml 6.0-8.0 approx. 45 rain Ticarci l l in

Administration o[ Carbenicillin and Ticarcillin--Pharmaceutical Aspects 427

Table 2. Stability of disodium carbenicillin in con- centrated aqueous solution (amount of disodium salt

equivalent to 1 g free acid, dissolved in 2 ml water)

Residual Residual Days potency ~ potency 9/0

stored at 5°C at 23°C

1 98 94 3 100 81 6 99

Table 3. Stability of disodium ticarcillin in concen- trated aqueous solution (amount of disodium salt equivalent

to 500 mg free acid, dissolved in 1 ml water)

5oc 25oc Days Residual Residual

stored pH potency ~ pH potency

0 6-9 7.0 1 6.6 97 5.8 93 3 6.3 95 5.6 73 7 5.8 91

Table 4.

at 23°C, and the results obtained by micro- biological assay are summarized in Table 4. Differences were negligible at 1 day and small at 3 days. At 8 days the unbuffered solution at pH 7.3 retained the highest degree of activity, while the solution in pH 6.3 citrate buffer was the least stable and those in pH 7.0 and pH 8.0 phosphate buffer were intermediate.

STABILITY IN I N T R A V E N O U S SOLUTIONS

Results of our studies of ticarcillin and carbenicillin stabilities in a range of intravenous so lu t ions a r e p r e s e n t e d in T a b l e s 5 a n d 6, r e spe c t i ve ly . T h e a n t i b i o t i c s we re a s sa ye d m i c r o - b i o l o g i c a l l y , a n d the f igures for r e s i d u a l p o t e n c y a re a v e r a g e v a l u e s o b t a i n e d f r o m a n u m b e r o f s e p a r a t e d e t e r m i n a t i o n s .

Bo th c o m p o u n d s a r e l eas t s t a b l e in s o d i u m l a c t a t e so lu t ion , b u t g e n e r a l l y s p e a k i n g t h e y h a v e g o o d s t ab i l i t i e s in t he f luids tes ted .

Effect of buffer solutions on the stability of 10% w/v disodium carbenicillin at 23°C

Residual potency (%)

Days stored No buffer Citrate buffer Phosphate buffer Phosphate buffer at 23°C pH 7.3 pH 6-3 pH 7.0 pH 8'0

1 102 99 101 1 0 0 3 99 97 99 98 8 93 80 88 86

Table 5. Stability of disodium tacarcillin, equivalent to 2 . 0 ~ w/v free acid, in four intravenous fluids at 25°C

pH values Residual potency (%) Initial 4 hr 24 hr 4 hr 24 hr

Sodium chloride 0.9% 6.85 6'7 6.1 98 94 Dextrose 5°o 6.9 6-6 5"95 99 97 Dextrose 4'3% with

sodium chloride 0-18% 6"8 6"6 6-0 101 101 Sodium lactate M/6 5.0 5.0 5.1 101 89

Table 6. Stability of disodium carbenicillin in intravenous fluids at 23°C

pH values Residual potency (%) Concentration* Initial 6 hr 24 hr 6 hr 24 hr

Sodium chloride 0"9% Dextrose 5% Dextrose 4.3% with

sodium chloride 0' 18% Sodium lactate M/6 Ringer's solution Sodium bicarbonate 1"4% Dextran 40 (Rheomacrodex) 10%

in sodium chloride 0-9% Dextran 40 (Rheomacrodex) 10%

in dextrose 5%

2.0% w/v 6-5 6"4 5'9 96 96 2'0% w/v 6.7 6.4 6-3 97 95

2.0% w/v 6.5 6.3 6.0 99 96 2'0% w/v 6-7 6"7 6"5 91 88 0"2% w/v 97 96 3.0% w/v 8"I 8"1 8"1 96 94

2"0% w/v 6"55 6"35 6-0 96 92

2.0% w/v 6.6 6"5 6" 1 97 91

*Expressed in terms of the free acid.

428 Brian Lynn

Stability is therefore not a critical factor, and the method of intravenous administration is determined solely by the necessity of achieving very high serum levels in the treatment of infections caused by Pseudomonas aeruginosa.

I N C O M P A T I B I L I T I E S A N D D R U G I N T E R A C T I O N S

With the increasing complexity of modern therapeutics, problems of drug interaction, both chemical and pharmacological are becoming more frequent. I shall confine myself to the question of physical or chemical incompati- b i l i ty-par t icu lar ly in intravenous infusions, where the majority of drug mixtures occur. Unfortunately, only a limited amount of factual information is available on the compatibility and stability of drug mixtures, and provision of such data is urgently required. Experimental assessment of all the possible combinations of therapeutic agents (and of the variations of concentration and conditions which are encountered) is clearly impossible, but it is important that systematic investigation of the more commonly encountered mixtures should be carried out.

In addition, I believe that where possible we should exploit ways of preventing or mini- mising drug contact, when there is reason to doubt compatibility or where relevant information is not available. This is often possible, even when a patient is receiving several drugs, by making use of an infusion set which in- corporates a Y-tube, a burette, or a special drug injection site, or by injecting the agents alter- nately into the drip tubing. Those agents which can not be administered by intravenous bolus or those, like heparin, which are often required by continuous infusion, may cause special difficulties.

Penicillin/aminoglycoside interactions

Interactions between penicillins and aminoglycosides are of particular interest and importance because of the frequency with which antibiotics of these two groups are used in combination for severe infections. The use ofbenzyl- penicillin or ampicillin with streptomycin or kanamycin against Streptococcus faecalis (the enteroccus); of carbenicillin with gentamicin against Pseudomonas aeruginosa ; and ofmethicillin or cloxacillin with kanamycin or gentamicin against Staphylococcus aureus, are all examples of potentially synergistic combinations.

The first indication of adverse interactions between penicillins and aminoglycosides was the report in 1967 of mutual inactivation

between methicillin and kanamycin when mixed at intramuscular concentrations [34]. This was not followed up at the time, but sub- sequent clinical observations suggested that gentamicin may have been inactivated in vivo by concurrently administered carbenicillin [35, 36]. This raises the intriguing general question of interactions between antibiotics in the body, which needs to be further explored. Slow iu vitro inactivation of gentamicin was demon- strated by the same workers: using typical therapeutic concentrations of the two antibiotics, the gentamicin half-life was about 40 hr at 35°C [35]. It should be noted, however, that a very high ratio of penicillin to aminoglycoside is necessary to bring about significant inactivation of the latter [36-38]. Two points are therefore worth stressing:

1. The clinical significance of penicillin/aminoglycoside interactions would seem to be con- fined to patients in renal failure, where excretion would be delayed, dosage would be less frequent, and the agents would be in contact in the body for relatively prolonged periods. Gentamicin inactivation is too slow to be of clinical importance in patients with normal renal function.

2. For all practical purposes, the in vivo effect is limited to penicillins which are given in very high intravenous dosage, that is, essen- tially to carbenicillin (which is used at a dosage of 30 g per day) and occasionally benzylpenicillin (which may sometimes be used at dosages of 60 mega-units per day or more). Other semi-synthetic penicillins are rarely given in dosages of this order. Ticarcillin will also be used in fairly high dosage and, in the absence of information to the contrary, it is advisable to assume that it may be capable of interacting with gentamicin, and possibly with other aminoglycosides.

Very marked inactivation of gentamicin by carbenicillin or ampicillin has been reported at the concentrations likely to be added to intravenous infusion bottles [38]. Gentamicin 160/*g/ ml was mixed with carbenicillin 20 mg/ml in 0 .9~ sodium chloride, sodium chloride/ dextrose and 5 ~ dextrose solutions at room temperature, and 50% of the gentamicin activity was lost in 8-12 hr. In the presence of 8 mg/ml ampicillin, 50~o of the gentamicin was lost in 2 hr and no gentamicin activity remained at 24 hr. We ourselves have found that interactions may take place within 15-30 min in mixed intramuscular solutions of penicillins and aminoglycosides, often

Administration of Carbenicillin and Ticarcillin--Pharmaceutical Aspects 429

with significant loss of activity of one or both components [39].

To summarize, therefore, there is no contra- indication to concurrent therapy with gentamicin and carbenicillin, provided that they are not mixed in the syringe or in the infusion bottle. In patients with renal impairment, however, it would be advisable to monitor gentamicin serum levels, to ensure that they are adequate.

Penicillins with heparin

In collaboration with colleagues in hospital pharmacy, we are at present engaged in an investigation of possible interactions between penicillins and heparin in intravenous solutions at room temperature. So far, it has been found that 10 mega units per 500 ml of benzylpenicillin and 5g/500 ml of ampicillin or methicillin have no effect on the stability or anticoagulant activity of heparin sodium (10,000 U/500 ml). Nor was the stability of the penicillins adversely affected by the presence of heparin. Study of individual stabilities, however, led to some interesting findings. Heparin remained stable and active for 24 hr in normal saline, but there was a rapid inactivation of 40-55% in solutions containing dextrose or lactate. Ampicillin was shown to be unstable in dextrose solutions, and it would be preferable for it not to be added to intravenous dextrose, unless the solution can be infused within 1-2 hr (preferably within 1 hr) of preparation.

T H E R A P E U T I C U S E O F C A R B E N I C I L L I N A N D T I C A R C I L L I N

Antibacterial activity

Sutherland et al. measured the activity of ticarcillin and carbenicillin against 74 clinical isolates of Pseudomonas aeruginosa, and found that ticarcillin was at least twice as active as carbenicillin [23]. Their results were as follows :

were inhibited by 100 pg/ml or less ofticarcillin and 72 7o by 50 #g/ml or less [22]. Bodey and Deerhake stated that 80~/o of Pseudomonas isolates were sensitive to 50 pg/ml or less of ticarcillin, compared with under 30~o for carbenicillin [24].

Very high intravenous dosage ofcarbenicillin is needed to achieve the requisite serum and tissue levels, and the increased activity of ticarcillin should therefore be of clinical importance. Bearing in mind that a higher concentration than the MIC may be required to produce a good bactericidal effect; that, like carbenicillin and benzylpenicillin, ticarcillin is reversibly bound to serum albumin to an extent of approximately 50 per cent; and that the concentration at the site of infection may sometimes be lower than that in the blood, it appears that therapeutically we need to achieve serum levels in excess of 125 pg/ml ticarcillin, and with carbenicillin even higher.

Principles of intravenous administration

A substantial body of opinion has always advocated that during penicillin therapy, con- tinuously inhibitory levels of the antibiotic should, as far as possible, be maintained at the site of infection. An opposing viewpoint is that intermittent bolus administration, giving high peak concentrations alternating with periods where serum levels may be sub-inhibitory, could well be more effective. The theory behind this is based on the well-known fact that penicillins act only against growing bacterial cells. It is suggested that bacteria which have escaped the effect of one dose by being a resting phase should be allowed to resume active growth in the absence of penicillin, so that they will then be susceptible to the next dose. This is an attrac- tive, though perhaps oversimplified, concept, and the truth may lie somewhere between the two approaches. As far as intravenous therapy is concerned, the danger of continuous, slow in-

Cumulative % strains inhibited by: 12-5 gg/ml 25 pg/ml 50 pg/ml 125 gg/ml 250 pg/ml

Ticarcillin 26 80 95 100 100 Carbenicillin 8 20 79 95 100

It can be seen that the minimum inhibitory concentration for the majority of strains is in the 12.5-25 #g/ml range for ticarcillin and in the 25-50 #g/ml range for carbenicillin. This agrees broadly with the findings of Adler et al. in 162 strains [21]. Neu and Winshell also found ticarcillin to be consistently twofold more active than carbenicillin against Pseudo- monas, and reported that 8 9 ~ of strains

fusion is that serum, and hence tissue, levels of penicillin may be inadequate. With intermittent, rapid infusion, on the other hand, it is obviously vital that the penicillin-free intervals should not be so prolonged as to allow a significant amount of bacterial growth and multipli- cation to take place, otherwise the patient's condition would deteriorate. One of the key factors here is the time taken for bacterial cells

430 Brian Lynn

which have been exposed to penicillin to "recover" and move once more into a phase of normal growth and division.

Investigations of the antibacterial effect of penicillins in vitro, carried out by my colleagues in the microbiology department at Beecham Research Laboratories, have thrown some light on this question of bacterial recovery times [40]. The data available so far suggest a marked difference between Gram-positive bacteria and Gram-negative bacilli in their response to removal of penicillin by penicillinase after varying periods of exposure. It has been found that exposure of Staphylococcus aureus, Bacillus subtilis and Streptococcusfaecalis to benzylpenicillin or ampicillin is followed by an interval during which the viable count ceases to fall and remains almost constant, before growth is resumed at a normal rate. This "recovery period" is commonly 1½-2 hr, but may be as long as 4½ hr, depending upon the concentration of penicillin and the exposure time. In contrast, exposure of Escherichia coli or Proteus mirabilis to ampicillin, and Pseudomonas aeruginosa to carbenicillin, is followed by resumption of growth as soon as the penicillin is removed.

In vivo studies with the mouse thigh lesion test, using Pseudomonas aeruginosa strain 44 as the infecting organism and carbenicillin as therapy are also in progress [40]. The work is concerned with the xelationship between carbenicillin dosage, concentrations of antibiotic in vivo, antibacterial effect and overall therapeutic response. Although it would be dangerous to draw too close a parallel between experimental and human infections, particularly on the evidence of a single model, a few relevant points have emerged:

1. I f the dosage interval was lengthened beyond the optimum, resumption of bacterial growth between doses coincided with the fall in serum concentrations of carbenicillin to low levels, and took place without any recovery period. This agrees with the in vitro findings and indicates the importance of the dosage interval.

2. Serum levels which correspond closely with the MIC in vitro resulted in a rapid bactericidal effect in vivo over the first few hours.

3. Quite low serum concentrations of carbenicillin often had a marked bactericidal effect, but bacterial growth resumed soon after dosage ceased, and the overall therapeutic effect was not comparable to that given by higher dosage. In contrast, therapeutically effective regimes brought about a steady fall in the number of viable bacteria, and this

continued after the end of treatment (pre- sumably due to normal body defence mechanisms).

4. Provided that the dosage interval did not allow significant resumption of bacterial growth, it appeared that less frequent higher dosage had a better therapeutic effect than more frequent lower dosage.

Serum concentrations after intravenous infusion

My colleague Dr. Lees has recently carried out a cross-over study to determine the serum levels achieved in healthy adult male volunteers who received 5 g carbenicillin and ticarcillin, either by rapid intravenous infusion over 30 min or by slow infusion over 4 hr, both with and without concurrent oral probenecid [41]. The complete data are to be published in due course, but it would be useful to summarise the essential findings.

(a) Carbenicillin. (Fig. 2) With infusion of 5 g over 30 min, mean peak serum concentrations of approximately 500/lg/ml were obtained at the end of the infusion and concentrations remained above 100/~g/ml for the first 3 hr. Probenecid led to some prolongation of serum levels, but did not enhance the peak value.

60C

---615| infused O--30min (withou~ Probenecid)

IEOC ~ -"~S| infused O--30min (with Probenecld)

4 0 0 ~ . - '0 51~ in[used O--4hr (wilchout Probenecld)

S:rrUm I I I .-ClS, ...... d O--4hr (w,th Prob . . . . . d) (.ug/ml) 3 0 0 \

¢:::: ~[~" ~ " . . .

, o o . . . . . o

. 4 ° . . . . . . . . . . . .

1 2 g 4 ~ 6 ~' 8 H o u r s

Fig. 2. Intravenous infusion of carbenicillin.

With infusion of 5 g over 4 hr, peak concentrations were again reached at the end of the infusion period, and averaged 170/~g/ml. The mean peak serum concentration was 230 ~g/ml with concurrent probenecid, and excretion was also delayed. In the probenecid study, serum levels were in excess of 100/~g/ml between 2 and 5 hr.

(b) Ticarcillin. (Fig. 3). By rapid infusion, mean peak serum concentrations of 350-400 ~ug/ ml were achieved at 30 min, falling to below 100/~g/ml at about 2½ hr. As with carbenicillin, probenecid had little effect on the peak concentration, though there was slight prolongation of levels from 2½ hr onwards.

Slow infusion of ticarcillin over a 4-hr period gave peak serum concentrations of 250-300/~g/


400

30C

Serum cohen

~g /m l ) 200

100

Fig. 3.

~ , - ' l $ l Infused O-30mln (without Probene¢id)

"~l~S| infuled O--]Omln ~ (with Probene¢id)

.~ - ' . . ".. ."~*'*. - -e$| infused ~ 4 h r

\ ~ : / \ ' . . (w~t~o.t P~ob,.,c~d) : - / ~ - ~ " . , : / \ " . "'aS, ,nfused O--4hr

" ."] ~' ~ (with Probcntcld) ...-/ "\ "'"..

. . .~ '~ / ~_ '~-. "= ....

| ~ 3 4 5 6 7 S

Hours

Intravenous infusion of ticarcillin.

ml at 4 hr. These were somewhat higher than the corresponding carbenicillin levels. There was some enhancement of levels with probenecid, both at peak and at earlier and later measurements. For subjects who received probenecid, levels were above 100/ag/ml between approximately 2½ and 5½ hr.

Conclusions

From the data presented, it is doubtful whether serum and tissue levels of carbenicillin adequate for less sensitive strains of Pseudomonas would be achieved by infusion of the antibiotic over a 4 hour period. However, a regime of 5 g in 100 ml of water, infused over 30 min at four-hour intervals, would seem to meet the necessary criteria for both height and duration of levels.

Some clinicians, whilst using the same total daily amount of carbenicillin, modify the regime to 10 g given at 8-hourly intervals. The first 5 g is infused over 30 min, rapidly achieving peak serum concentrations of some 500/ag/ml, and the second 5 g is infused more slowly over a further 90 rain, to sustain these peak levels. This form of administration might be expected to result in a rather longer period of relatively

low concentrations, before the next intravenous bolus is given. Infusion of the second 5 g over 3-4 hr instead of over 90 min might overcome this. In any case, clinical results using this regime appear to have been quite satisfactory, which is the most important criterion.

Rapid infusion of 10 g carbenicillin gives very high peak serum concentrations, but if this is administered at 8-hour intervals the question arises as to whether concentrations would be sustained at a sufficiently high level during this period. Klastersky and his colleagues have studied serum concentrations following 5, 10 and 15 g carbenicillin infused over 45 rain [8]. Levels of antipseudomonas activity in the serum, measured 15min after the infusion, corre- sponded to 1000, 250 and 125 ~g/ml following the 15, 10 and 5 g doses, respectively. A level of inhibitory activity equivalent to 125 ~g/ml remained at 7 hr after the onset of the 15 g infusion and at 6 hr in the case of the 10 g infusion. The authors suggest that the effectiveness of 10 g carbenicillin given three or four times daily should be assessed in severe Pseudo- monas infections. In addition, it would be valuable to have comparative clinical data for the various alternative regimes.

On the basis of the in vitro antibacterial activities and comparative pharmacological data referred to, it would seem that equivalent effectiveness would be obtained using a lower dosage of ticarcillin, for example 3-4 g by rapid infusion over 30 min, six times daily, or 5 g four times daily. Alternatively, use of the same dosage as carbenicillin would give a greater therapeutic margin, which would be particularly valuable against strains of marginal sensitivity to carbenicillin. Ticarcillin promises to be a valuable addition to our limited but growing range of antipseudomonas drugs, and every effort should be made to determine the most effective means of using this new antibiotic.

RKFERKNCES

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2. E .T . KNUDSEN, D. M. BROWN and G. N. ROLINSON, A new orally effective penicillinase-stable penicillin-BRL 1621. Lancet 2, 632 (1962).

3. R. SUTHERLAND, E. A. P. CROYDON and G. N. ROLINSON, Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin. Brit. med. J. 4, 455 (1970).

4. W. BRUMFITT, A. PERCIVAL and D. A. LEXGH, Clinical and laboratory studies with carbenicillin. A new penicillin active against Pseudomonas pyocyanea. Lancet 1, 1289 (1967).

5. P. ACRED, D. M. BROWN, E. T. KNUDSEN, G. N. ROLINSON and R. SUTHER- LAND, New semi-synthetic penicillin active against Pseudomonas pyocyanea. Nature (Lond.) 215, 25 (1967).

432 Brian Lynn

6. E .T . KNUDSEN, G. N. ROLINSON and R. SUTHERLAND, Carbenicillin: a new semi-synthetic penicillin active against Pseudomonas pyocyanea. Brit. reed. J. 3, 75 (1967).

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9. Advances in the Management of Pseudomonas and Proteus Infections. New York 1969, (Publ. Excerpta Medica Foundation 1970).

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11. "Colloque Pyopen," Paris 1971. (Laboratoires Beecham--Sdvign6). 12. Int. Z. klin. Pharmakol. Ther. Toxikol. (1972), 5, suppl. Pyopen Symposium

1969. 13. G . N . ROLINSON and R. SUTHERLAND, Carbenicillin, a new semi-synthetic

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administration of carbenicillin and ticarcillin—pharmaceutical aspects

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