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Vancomycin and Ristocetin
"'ANCOMY~IN
AND
RISTO~ETIN
HARRIS D. RILEY, JR., M.D.
~ lthough the problem of staphylococcal infections is not a new one, in recent years it has become of increasing concern. In addition to the dramatic epidemics of staphylococcal disease which have occurred in newborn nurseries, some of the most important aspects of this problem relate to diseases occurring principally in infants and children. Although the occurrence of certain clinical types of staphylococcal disease, such as osteomyelitis, has decreased, others, e.g. staphylococcal pneumonia and empyema in infancy, have shown an apparent striking increase. The historical aspects, the fundamental biologic nature of the organism, alterations in host response, the influence of antimicrobial drugs and other factors have been reviewed. 30 , 37, 39, 40, 44 Finland 55 has detailed the circumstances contributing to the increased significance of staphylococcal infections in recent years. Whereas the use of antibiotics in many other infections, such as those caused by pneumococci and hemolytic streptococci, had continued to be effective, antimicrobial therapy of staphylococcal infections, though at first encouraging, was becoming disappointing. One of the main reasons for this was that staphylococci involved in most hospital-acquired infections had shown a pattern of increasing resistance to the generally available antimicrobial agents. 30 , 37, 39, 40, 44, 55 Because of these factors, considerable effort has been directed to the development of newer antimicrobial agents against staphylococcal infections. Vancomycin and ristocetin are two of the newer such agents which have become available.
VANCOMYCIN CHEMICAL AND PHYSICAL PROPERTIES
Vancomycin* is produced by Streptomyces orientalis. The first culture * The trade name of Eli Lilly and Company for vancomycin is Vancocin. From the Department of Pediatrics and the Children's Memorial Hospital, University of Oklahoma School of Medicine, Oklahoma City. 10 73
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VANCOMYCIN AND RISTOCETIN
was obtained from a soil sample obtained by a missionary ill the Indonesian jungles. Vancomycin hydrochloride, which appears to have no significant chemical relation to any other known antibiotic, is a white solid material, and is a large molecule, having a molecular weight of approximately 3300. The ultimate composition and microbial activities of vancomycin are not entirely known at present, since electrophoretic studies have shown that the crystalline substance contains some 20 per cent of a second component, the biological activity of which has not been determined. 21 , 33, 34, 57 ANTIMICROBIAL PROPERTIES
In addition to staphylococci, other organisms usually susceptible to vancomycin include hemolytic streptococci, pneumococci, enterococci, gonococci, cornyebacteria and clostridia. It is not effective against Klebsiella, Brucella, Proteus, Shigella, Salmonella, Pseudomonas, Aerobacter and other coliform organisms, nor Mycobacterium tuberculosis, fungi and yeast 25 (personal communication from R. S. Griffith). Extensive studies by many investigators have shown that pathogenic staphylococci are almost uniformly susceptible to vancomycin in low concentrations (less than 3 micrograms per milliliter). Of the many strains so far studied, only 5 have shown growth in concentrations greater than 10 micrograms per milliliter. l l , 14-16, 25, 26, 43, 56 Vancomycin is bactericidal against multiplying bacteria in a manner similar to penicillin. 57 Bactericidal and bacteriostatic levels are similar, and the action of vancomycin is not greatly affected by the presence of serum.26 , 36 Wise 56 and Kirby and Divelbiss26 have reported vancomycin to have greater activity in vitro than ristocetin and kanamycin. Garrod and Waterworth l l concluded that vancomycin has greater bactericidal activity than seven other antistaphylococcal antibiotics which were studied. Vancomycin does not exhibit cross-resistance with other known antibiotics. Several workers have noted that resistance in vitro of staphylococci to vancomycin rarely develops and then only very slowly and of a small degree even after as many as 28 daily subcultures.14-16,36 Garrod and Waterworth l l feel that resistance to vancomycin of a degree to obviate the therapeutic effect apparently cannot develop in staphylococci. In our laboratory we have not observed staphylococci resistant to vancomycin, nor has resistance developed during rather prolonged treatment of patients with vancomycin. Other workers 14 , 26 have confirmed that staphylococci retain their susceptibility to vancomycin after two to four weeks of vancomycin therapy. ABSORPTION, DISTRIBUTION AND EXCRETION
Lee31 , 32 reported on the absorption, distribution and excretion dogs and other animals.
ill
HARRIS D. RILEY, JR.
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Bactericidal serum concentrations in human beings are readily achieved and maintained by intravenous administration. In 16 children receiving vancomycin in a dose of 20 mg. per kilogram as a single intravenous injection, a peak serum value of 52 micrograms per milliliter was promptly reached at one hour, the concentration slowly falling to a range of 1.6 to 13 micrograms 12 hours after administration. 51 No difference was found in the average values in five patients under the age of two weeks as compared to the older children. In 14 patients receiving 13.3 mg. per kilogram of vancomycin by intramuscular injection the peak concentration occurred 4 hours after administration and averaged approximately 10 micrograms per milliliter. Therapeutic concentrations were maintained for at least eight hours after injection.51 Kirby and Divelbiss26 and Geraci et a1. B reported on serum concentrations in adults following intravenous administration and concluded that 1 gm. every 12 hours was usually the most desirable regimen in this age group. Vancomycin is excreted chiefly through the kidneys, more than 80 per cent of the administered dose within a 24-hour period being recovered from the urine. Considerably higher serum concentrations occur and may persist for long periods in patients with impaired renal function. 26 The half-life of vancomycin in the blood has been estimated to be approximately six hours. 15 Vancomycin diffuses readily into the pleural, ascitic and synovial fluids, but only small amounts are secreted in the bile. It does not diffuse into the spinal fluid through normal meninges even after multiple doses, but may pass the blood-brain barrier in some instances when the meninges are inflamed. 25 ADMINISTRATION AND DOSAGE FORM
Vancomycin is available as 0.5 gm. of vancomycin hydrochloride in 10-m1. rubber-stoppered ampules. At the time of use, 10 m1. of water for injection, U.S.P., is added to the ampule. At present the drug should be administered only by the intravenous route. An intramuscular preparation has also been utilized in experimental studies (unpublished observations), but this product is not commercially available. * Spears and Koch 51 have administered vancomycin intramuscularly after mixing with hydrocortisone to reduce the pain associated with injection. There are several methods of intravenous administration: (a) Intermittent infusion: the desired amount of the drug can be added to 50 to 150 m1. of normal saline or 5 per cent glucose in water and this infusion given rapidly over a period of 20 to 30 minutes at 8- to 12-hour intervals until the total calculated daily dose is administered. (b) Direct injection: one third to one " Personal communication from R. S. Griffith, M.D.
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VANCOMYCIN AND RISTOCETIN
fourth of the total daily dose mixed with 10 m!. of water for injection can be injected directly into a large vein or into the infusion tubing. This injection should be given slowly over at least a five-minute period and can be repeated at 6- to 8-hour intervals until the total daily dose has been administered. (c) Continuous injection: the total daily dose can be added to an appropriate amount of normal saline or 5 per cent glucose (in a ratio of 1 gm. of vancomycin to 1000 m!. of fluid) and the rate of administration of the intravenous infusion adjusted so that the patient receives the total calculated daily dose over a 24-hour period. Continuous intravenous administration may be achieved by means of a venous cutdown or through femoral or caval catheters. If the patient is receiving a continuous infusion of fluids with which vancomycin is not compatible, the infusion bottles can be changed temporarily. All the foregoing methods have been utilized in this Clinic. Methods (a) and (b) have the advantage of allowing a large dose to be given immediately and at frequent intervals in patients with overwhelming infections. The incidence of phlebitis seems to be more frequent with direct injection than with other methods. Although intermittent infusion is probably the easiest method, we feel that the method of administration should be individualized. In children a total daily dose of 20 mg. per pound of body weight per day divided into equal aliquots and administered intermittently at 8- or 12-hour intervals or given by continuous drip as described above is usually satisfactory. In serious, overwhelming infection we have used doses as high as 68 mg. initially without significant untoward effects. For premature and full-term newborn infants a dose of 6 mg. per pound pe~ day has proved satisfactory and safe,2 though others38 have recommended a dose of 15 mg. Until more experience has been accumulated, it is probably desirable to use the drug in this age group with caution and to adjust dosage on the basis of serial determinations of serum concentration. The usual adult dose is 2 gm. daily, and doses larger than this should be avoided except occasionally for initiating therapy in a severely ill patient with normal renal function. Vancomycin should be used cautiously in patients with reduced renal function, the dosage being titrated according to serum levels. The oral administration of vancomycin has been used in the management of enterocolitis caused by penicillin-resistant staphylococci and also in conjunction with systemic therapy in some patients.21 . 26. 34 TOXICITY AND SIDE EFFECTS
Vancomycin has a low order of toxicity in experimental mice, rats and other animals. In monkeys and dogs, daily intravenous dosage of 25 to 50 m!;. per kilogram for 3 months or longer produced no signs of toxicity.2
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Further purification of the antibiotic has reduced the incidence of chemical phlebitis, and pain at the site of intravenous injection, which was a common occurrence with the initial lots of vancomycin available for clinical investigation, so that with the relatively pure material which has been available more recently untoward effects of these types have presented little difficulty. Phlebitis can be minimized by using dilute solutions and alternating the sites of injection. Rapid intravenous injection of vancomycin may cause a feeling of warmth, generalized tingling and nausea, but this may be avoided by slowing the rate of injection and usually does not occur when the dose is given over a period of 20 to 30 minutes. On occasion, chills, fever, slight renal irritation, urticaria and macular rashes have occurred during or after the administration of vancomycin in some patients, as is true with other compounds of high molecular weight. Such reactions have sometimes occurred in a non predictable fashion, beginning with the first dose of vancomycin; in other patients, vancomycin was tolerated without reaction several months later. The febrile reaction occurring with some of the earlier lots often made clinical evaluation of therapeutic response difficult.43 If these reactions are severe, the drug should be discontinued. These manifestations may be minimized by the concurrent administration of antihistamine or hydrocortisone. 13. 27. 51 Although these untoward effects were common with early lots, they are much less frequent with the more purified material. Three instances of possible cross-sensitization between vancomycin and other antibiotics such as streptomycin have been reported. 7 Though this is extremely rare, precaution should be observed against anaphylaxis. 49 . 51 Hearing loss has been reported in a few patients when excessively high serum levels-levels 5 to 10 greater than the necessary therapeutic concentration-were present. 13 . 25 In certain patients the deafness has been temporary and reversible when therapy was discontinued. 43 Because of these observations vancomycin should be used cautiously in patients with reduced renal function, and when long-term administration is planned, tests of auditory acuity along with serial measurements of renal function should be performed before starting therapy and at frequent intervals during and after the course of therapy. Hematopoietic disturbances have not been a problem with the use of vancomycin, only two cases of transient leukopenia having been observed. 3 Hepatic toxicity has not been reported. Nevertheless, as with the prolonged intravenous administration of any drug, it is suggested that appropriate hematologic studies, urinalysis and liver and renal function tests be performed periodically, especially if the medication is to be used in a dosage larger than 20 mg. per pound per day in a child or more than 2 gm. per day in adults over a period longer than 2 weeks.
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VANCOMYCIN AND RISTOCETIN
INDICATIONS AND CLINICAL USE
The principal clinical indication for the use of vancomycin lies in the treatment of severe infections due to pathogenic staphylococcI. Vancomycin is not indicated for treatment of comparatively mild staphylococcal infections, but may be the drug of choice when patients have failed to respond to the commonly used antimicrobial agents or when the causative strain is resistant to other antibiotics. It may be used in patients seriously ill with infections caused by other gram-positive organisms;28 however, infections due to streptococci and pneumococci usually respond well to more easily administered agents such as penicillin, and its use in such infection will not be reviewed here. A significant experience with the use of vancomycin in serious staphylococcal infections has now accumulated. STAPHYLOCOCCAL PNEUMONIA AND EMPYEMA. In 1959 Riley and Ryan 43 reported that 5 infants and children critically ill with staphylococcal pneumonia responded satisfactorily to vancomycin. Since this report a much larger experience with the use of vancomycin has been accumulated in this Clinic. The initial impression of excellent results in serious staphylococcal pneumonia, many cases of which had been unsuccessfully previously treated with other antibiotics, has been confirmed. Spears and Koch 51 also reported good results in several children with staphylococcal pneumonia. Kirby et aP8 and Ehrenkranz 7 found vancomycin effective in several cases of staphylococcal pneumonia in adults in many of whom previous antibiotic therapy had failed. The role of vancomycin therapy in treatment of staphylococcal empyema is I,msettled. Geraci et aU4 could not demonstrate any concentration of the drug in empyema fluid after four doses. Spears and Koch 51 feel that vancomycin should be used in conjunction with another antibiotic in situations in which the antibiotic must cross tissue barriers, as in meningitis and empyema pockets. On the other hand, Ehrenkranz 7 has reported success with vancomycin in staphylococcal empyema after catheter drainage and therapy with other drugs had apparently failed. Our experience with vancomycin in staphylococcal empyema has been satisfactory. STAPHYLOCOCCAL INFECTIONS OF SKIN AND SOFT TISSUES. In several infants and children with severe, life-threatening soft tissue infections treated with vancomycin in this Clinic, the results have been good. 42 . 43 Other workers have observed a satisfactory response to vancomycin in patients with cellulitis, recurrent furunculosis, carbuncles and deep postoperative wound infections, the latter due for the most part to antibiotic-resistant staphylococci. 14 . 25. 26. 28 The role of surgical drainage as an adjunct to therapy should not be neglected. Here vancomycin, because of difficulties in administration, should be reserved for patients in whom there has been a failure to respond to other antibiotics, those
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with lesions caused by antibiotic-resistant organisms or those with lesions that are potentially life-threatening, such as cellulitis about the face and deep-seated wound infections, especially if there is a possibility of hematogenous dissemination. SEPTICEMIA AND ENDOCARDITIS. Promising results in the treatment of these conditions with vancomycin have been reported by several investigators. Many of the reported patients had serious, usually fatal underlying diseases complicated by septicemia due to antibiotic-resistant staphylococci. Riley and Ryan 43 reported a satisfactory response in eight of nine children with staphylococcal septicemia treated with vancomycin; since that report several additional patients have been treated successfully.42 Three of four children with staphylococcal septicemia treated with vancomycin by Spears and Koch 5 ! were cured. Kirby and co-workers27 have recently reported the treatment with vancomycin of 33 adults with staphylococcal septicemia. Of these, most of whom were in the older age groups and had serious underlying illnesses, 20 were cured, a number of whom had failed to improve with other antibiotics to which the causative organism was susceptible, 6 were improved, but died of underlying diseases, and 7 were classified as treatment failures, although most of these last had overwhelming infections and died shortly after therapy was initiated. Blood cultures may remain positive for three to four days after initiation of vancomycin therapy in some patients who obtain a satisfactory response. 25 A lO-year-old boy with staphylococcal septicemia and septic arthritis who also had renal failure due to pyelonephritis exhibited dramatic improvement and a prompt bacteriologic response with no worsening of his renal status after treatment with vancomycin. 54 Dosage was governed by the results of serial determinations of the serum levels of vancomycin. Of four children with staphylococcal endocarditis treated with vancomycin, Spears and Koch 5! considered one cured, one improved, and one unimproved; one with uremia died of his infection after four days of therapy. The infection was promptly eradicated in two children with staphylococcal endocarditis treated with vancomycin by Riley and Ryan. 43 Geraci et alP reported the successful treatment of four of six adults with acute staphylococcal endocarditis with vancomycin, no patients with this type of acute endocarditis having been cured previously in his clinic. Of the two remaining patients, the infection was not controlled by vancomycin in one, and the other died two weeks after therapy was terminated of his primary disease, the infection having been eradicated. Since the four successfully treated patients received vancomycin for 28, 20, 18 and 28 days respectively, and the results of the serum bactericidal tests were satisfactory, these workers suggested that short-term (2 weeks) treatment with vancomycin alone might be satisfactory in staphylococcal endocarditis.
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VANCOMYCIN AND RISTOCETIN
OSTEOMYELITIS. We have treated a small number of patients with staphylococcal osteomyelitis with vancomycin with good results.42,43 Other workers 7 , 14, 26, 28 have also reported satisfactory results in several patients with osteomyelitis and septic arthritis. STAPHYLOCOCCAL ENTEROCOLITIS. Because of the high concentration in the stools after oral administration, it has been speculated that vancomycin administered orally might be useful in the treatment of staphylococcal enterocolitis.14 In our hands a satisfactory treatment regimen in patients with severe staphylococcal disease requiring long-term therapy, such as staphylococcal pneumonia, has been to use vancomycin during the initial period, for perhaps 7 to 10 days, and then complete the course of treatment with a more easily administered antistaphylococcal agent or agents. Waisbren et aJ.53 concluded that vancomycin did not show any clinical superiority over ristocetin and kanamycin in their experience with the treatment of staphylococcal infections. In a panel discussion on the use of various antibiotics in staphylococcal infections there was general agreement that vancomycin and ristocetin were two of the most effective antistaphylococcal agents, the majority of the panelists regarding vancomycin as the more potent of the two. 9 RISTOCETIN
Ristocetin * was first isolated by Grundy and co-workers18 from cultures of Nocardia lurida, an actinomycete, which was first recovered from a soil sample from the Garden of the Gods, Colorado Springs, Colorado. To date, no other culture which produces ristocetin has been found. CHEMICAL AND PHYSICAL PROPERTIES
Two related substances, ristocetins A and B, which are large molecules, have been isolated. Although the chemical characteristics are not completely defined, ristocetin B is 3 to 4 times as active as ristocetin A, which has an arbitrarily assigned potency of 1000 units per milligram. 19 Body fluids containing ristocetin may be stored at 10° C. for at least 5 days without deterioration. 47 ANTIMICROBIAL PROPERTIES
Ristocetin has activity against gram-positive bacteria, including staphylococci, pneumococci, streptococci and mycobacteria, but is not active against gram-negative bacteria, including Hemophilus influenzae and Neisseria species as well as yeast and a few protozoa which have been studied. Although most strains of Staphylococcus aureus, including * The trade name of Abbott Laboratories for ristocetin is Spontin.
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1081
many which are resistant to many other antimicrobial agents, are susceptible to ristocetin, some strains require a concentration somewhat higher than the minimum inhibitory concentration for a bactericidal effect.1 Grundy and co-workers 18 and Romansky et a1. 48 outlined in detail the antimicrobial spectrum in vitro of ristocetin. Cross-resistance among ristocetin, vancomycin, kanamycin and other antibiotics reportedly does not occur. 48 , 50 Early studies revealed a narrow range between bacteriostatic and bactericidal effects against streptococci, pneumococci and staphylococci, but with the accumulation of additional laboratory data, some strains have shown a greater variability in this range. 12, 17, 47, 50 The bactericidal activity of ristocetin is apparently not restricted to actively dividing cells.17 Several workers have reported that ristocetin has less activity in vitro than vancomycin. 28 , 50, 56 Wise 56 found that vancomycin was bactericidal against 12 of 13 strains of staphylococci, whereas ristocetin exhibited bactericidal action against only one of th~ thirteen. Grundy and co-workers17 reported that none of more than 400 cultures of streptococci, pneumococci and staphylococci were naturally resistant to ristocetin and that bacteria do not readily acquire resistance in vitro to the drug. Romansky, Limson and Hawkins 48 observed no development of resistance in 2 strains of Staphylococcus aureus isolated from purulent exudates after 45 subcultures. These workers reported that all of 35 strains of hemolytic Staphylococcus aureus were susceptible to less than 5 micrograms per milliliter of ristocetin, all of 74 strains of pneumococci were susceptible to 3 micrograms or less, and more than 70 per cent of 90 strains of streptococci were susceptible to 5 micrograms. Hsie et aJ.22 reported that staphylococci slowly developed a low order of resistance to ristocetin as measured by the agar gradient technique. The bactericidal properties of ristocetin have been emphasized by the manufacturers, and some investigators have referred to its bactericidal characteristics. Other workers, however,35,50 have reported it to be primarily bacteriostatic for staphylococci. Rantz35 found that the bactericidal concentration of ristocetin for 42 strains of Staphylococcus aureus was threefold to more than tenfold greater than the 24-hour inhibitory concentration and was often 2 to 4 times, or more, greater than the 48-hour inhibitory concentration. ABSORPTION, DISTRIBUTION AND EXCRETION
Hwang et aJ.23 studied the pharmacologic properties and toxicity of ristocetin in animals. Dries, Asay and Koch 6 and Dries and Koch 4 studied both the intravenous and intramuscular administration of ristocetin in children ranging in age from 2 days to 15 years. Two hours
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VANCOMYCIN AND RISTOCETIN
after a dose of 12.5 mg. per kilogram was administered rapidly intravenously in 8 children, serum levels varied from 1.3 to 10.6 micrograms per milliliter. Thereafter the level declined gradually to less than 0.7 microgram at 12 hours. After the intravenous administration of 25 mg. per kilogram in 13 children, the ristocetin content of the serum averaged approximately 18 micrograms per milliliter for 4 hours after injection and then gradually decreased to an average of 2.5 micrograms per milliliter at 12 hours. In 6 children receiving 50 mg. per kilogram per day as a 24-hour continuous intravenous infusion, the serum content ranged between 2.6 and 21.1 micrograms per milliliter during the infusion. When the drug was administered intramuscularly to 14 children in a dosage of 12.5 mg. per kilogram with hydrocortisone added in a ratio of 1 mg. to each 100 mg. of antibiotic, serum concentrations at 2 hours averaged 5.3 micrograms per milliliter and decreased to less than 0.7 microgram 12 hours after administration. Satisfactory serum levels, comparable to those obtained with intravenous administration, were obtained in 8 children who received 25 mg. per kilogram per day intramuscularly. Romansky and 01son 47 have reported on serum concentrations in adults. Intramuscular ~dministration of ristocetin in doses of 200 to 500 mg. in adults was painful, and blood levels obtained by this route of administration were generally less than 5 micrograms per milliliter. 48 Ristocetin diffuses freely into pleural and ascitic fluid; levels at 2 to 4 hours approximate those in the blood when 1 to 2 gm. is administered rapidly intravenously.47 Ristocetin does not readily pass the blood-brain barrier. In one pediatric patient with meningitis and 12 without meningitis, the spinal fluid content' of ristocetin remained less than 0.7 microgram per milliliter, regardless of route of administration or dosage. 4 Spinal fluid concentrations in another study were less than 0.625 microgram per milliliter 3 hours after a I-gm. dose despite concentrations in the blood at the same time between 5 and 20 micrograms per milliliter. 45 ,48 Excretion studies revealed that 40 to 50 per cent of a 1- to 2-gm. dose is recoverable in the urine in 24 hours. 47 Further studies are needed to ascertain whether transplacental diffusion occurs and whether the drug passes into bile, milk or seminal fluid. Oral ristocetin in doses of 2 to 4 gm. does not reduce the total bacterial count in the stools, but does reduce the number of enterococci and staphylococci. Ristocetin solutions containing 1 mg. per milliliter of antibiotic are apparently well tolerated by the tracheobronchial tree when used for nebulization therapy.47 DOSAGE AND ROUTES OF ADMINISTRATION
Ristocetin is available as a sterile, lyophilized powder in vials containing a mixture of ristocetins A and B, representing 500 mg. of ristocetin
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A activity. Sterile solutions of ristocetin may be stored under refrigeration for one month without significant loss of potency. Most investigators recommend a dose of 25 to 50 mg. per kilogram per day, depending on the type of infecting organism and severity of the disease, in both children and adults. Dries and Koch 5 recommend a dose of 50 mg. per kilogram per day intravenously or intramuscularly in children. A maximum dosage of 25 mg. per kilogram per day is usually adequate in pneumococcal and streptococcal infections. The majority of staphylococcal infections are controlled by 25 to 50 mg. per kilogram per day, but in severe infections, including bacterial endocarditis, a larger dose is often desirable during the early stages of the disease. Larger dosages should be reduced to 25 mg. per kilogram per day after clinical response. Since ristocetin is excreted by the kidney, dosage should be considerably reduced (to approximately half) in patients with renal impairment, to prevent excessive serum accumulation. A dose of 15 mg. per kilogram per day has been recommended for premature and newborn infants. 38 Ristocetin should be administered by the intravenous route. A 0.5 to 1 per cent solution should be prepared, using approximately 100 m!. of 5 per cent glucose or normal or hypotonic saline. Solutions should be prepared so that the maximum concentration of antibiotic does not exceed 25 mg. per milliliter. The solution may be given by the drip technique over 35 to 40 minutes, or may be injected directly into the tubing of an intravenous infusion used for fluid therapy or into a large vein, making certain that the time of administration is at least 5 minutes. Generally, the total daily dose is divided into 2 portions and administered at 12-hour intervals. In more severe infections, particularly those caused by the Staphylococcus, an eight-hour schedule may be used. When doses of 50 mg. per kilogram per day or more are used, the total daily dose should be divided into 3 equal parts. The duration of therapy must be determined by the kind of infection and the clinical course of the disease. Dries and Koch 5 report that the intravenous preparation of ristocetin can be safely administered intramuscularly by adding 1 mg. of hydrocortisone to each 100 mg. of antibiotic to decrease the inflammatory response at the site of injection. TOXICITY AND SIDE EFFECTS
Side effects associated with the use of ristocetin are not uncommon, having been noted in 29, or 20.8 per cent, of one series of 139 patients 47 and in 29 per cent of another series of 76 patients in the pediatric age group.5 In certain of the cases toxic effects could not be attributed solely to ristocetin, since the patients had received other potentially
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VANCOMYCIN AND RISTOCETIN
toxic drugs also. One of the more serious and unfortunately more common untoward effect is that affecting the hematopoietic system. Romansky and 01son 47 reported that varying degrees of leukopenia, neutropenia, thrombocytopenia and eosinophilia, either alone or in combination, occurred in 12.9 per cent of a series of 139 patients treated with ristocetin. Leukopenia or neutropenia occurred in six, and eosinophilia, which may presage the development of neutropenia or leukopenia, in 10 of 76 pediatric patients. 5 Thrombocytopenia, although less common than neutropenia, may occur even with currently recommended therapeutic regimens.lO Bone marrow examination and other studies suggest that ristocetin exerts its effect on the circulatory blood elements rather than on the bone marrow.lO, 47 To date, the side effects appear reversible on reduction of dosage or discontinuance of the drug, and all reported patients have recovered from the various degrees of leukopenia and thrombocytopenia. It is recommended that a complete hemogram, including hemoglobin determination, leukocyte, differential and platelet counts, be done on alternate days in children receiving more than 25 mg. per kilogram per day or in adults receiving more than 2 gm. a day and twice a week in patients receiving lower dosages. In general, the drug should be withdrawn if the total white cell count falls below 5000 cells per cubic millimeter or if the neutrophile count falls to less than 50 per cent of the total leukocytes even if the total white cell count exceeds 5000 cells per cubic millimeter. Phlebitis due to chemical irritation of the vein may occur at the site of injection, but can usually be controlled by reducing the volume of antibiotic solution. Drug fever, and a maculopapular rash associated with ristocetin administration, as well as instances of deafness and nephrotoxicity possibly related to ristocetin, have been reported. 47 ,53 It seems clear that the occurrence of toxicity is directly related to the size of dose of ristocetin, the incidence rising steeply when the recommended daily dose is exceeded. A similar relation between the total dosage of ristocetin administered and the incidence of side effects can be demonstrated. In a review of 333 cases the incidence of side effects rose in a stepwise fashion from 9.4 per cent with a maximum daily dose of between 1 and 1.9 gm. to 41 per cent with a daily dose of 4 to 4.9 gm. 20 With improved methods of manufacture and a more purified material, there has been a decline in the incidence of side effects, lllcluding those affecting the hematopoietic system. INDICATIONS AND CLINICAL USE
Although ristocetin may be effective in the treatment of streptococcal, pneumococcal and other infections due to gram-positive bacteria, it has found its greatest use in the management of staphylococcal and enterococcal infections. Six cases of pneumococcal pneumonia treated with
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HARRIS D. RILEY, JR.
ristocetin exhibited a rapid defervescence. 48 Romansky and Holmes 46 have reported the successful short-term (13 to 24 days) treatment of 6 patients with enterococcal endocarditis. Since that time other reports of the successful treatment of enterococcal endocarditis with ristocetin have appeared. The largest reported experience in the use of ristocetin in infancy and childhood has come from the group at the Los Angeles Childrens HospitaJ.4, 5, 6 Seventy-six hospitalized infants and children, 27 of whom were considered severely ill, were treated for pyogenic infections with ristocetin administered both intravenously and intramuscularly. Fortyseven had infections due to coagulase-positive staphylococci, of which 19 were resistant to penicillin and 16 to tetracycline, and the majority of the remainder pneumococcal, hemolytic streptococcal and enterococcal infections. As shown in Table 13, of the 76 patients, 87 per cent were considered improved after treatment with ristocetin. Twenty-seven of the children with severe staphylococcal infections received other drugs in addition to ristocetin. All of 5 patients with staphylococcal septicemia and II of 13 patients with staphylococcal pneumonia and empyema were considered cured. Of four patients with staphylococcal endocarditis, two were cured and two were unimproved. There was no improvement in two children with staphylococcal meningitis. Of the 19 patients with staphylococcal infections resistant to penicillin, 6 failed to respond to ristocetin, including 2 with bacterial endocarditis, 2 with meningitis and 2 with pneumonia and empyema. The data of these workers suggest a relation between dosage and TABLE
13. Clinical Effectiveness of Ristocetin in 76 Patients
DIAGNOSIS
NUMBER
ORGANISM
CLINICAL RESULTS
Cured Unim- Died proved Septicemia ...................... . Septicemia ...................... . Acute bacterial pericarditis. . ..... . Subacute bacterial endocarditis .... . Meningitis ...................... . Cellulitis and/or abscess .......... . Osteomyelitis .................... . Pneumonia and empyema ......... . Pneumonia and empyema ......... . Bronchopneumonia .............. . Respiratory tract infections ........ . Enterocolitis ..................... . Bronchiectasis due to fibrocystic disease ........................ . Disseminated moniliasis ...... .
5 StaphylococcuS * 1 Enterococcus 1 Staphylococcus * 4 Staphylococcus* 2 Staphylococcus * 12 Staphylococcus 1 H. influenzae B* 13 Staphylococcus * 1 Pneumococcus 18 Various 15 Various 1 Staphylococcus
Totals ............................ 76 al. 6
From Dries et * Received additional antibiotics.
5 1
2
2 2
12 1
11
2 1
18 15 1
Staphylococcus Candida and staphylococcus 2
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VANCOMYCIN AND RISTOCETIN
clinical result. Of the 35 patients treated with 25 mg. per kilogram per day, 8 failed to improve, and one death occurred in this group. Only 4 of 38 patients treated with 50 mg. per kilogram per day failed to respond. Of 5 patients treated with 75 mg. per kilogram per day, 4 were considered cured, and one, a child with fulminating staphylococcal bacteremia and pericarditis following cardiotomy, expired. Three of the 4 patients considered cured had not responded previously to 25 or 50 mg. per kilogram per day. Of the total 76 patients, 29 per cent showed some sort of side effects to ristocetin; severe toxic reaction such as leukopenia and neutropenia occurred in 7.6 per cent of the patients. All subsided promptly, however, with discontinuance of the antibiotic. Romansky and Olson47 reviewed 139 cases of infections collected from the literature, mostly in adult patients, treated with ristocetin and considered 89 to have a clearly established staphylococcal etiology. The number and types of cases and these workers' interpretation of the results of therapy are shown in Table 14. Fifty-seven patients (63.9 per cent) were regarded as cured, and 19 (21.3 per cent) improved. There were 6 failures (6.7 per cent), and 7 (7.8 per cent) patients died of unrelated causes or before ristocetin therapy could be evaluated. In 40 staphylococcal pulmonary infections, 33 of which had previously been treated with other antibiotics without apparent effect, ristocetin was considered to have a curative effect in 30, or 75 per cent. Romansky and Olson47 consider that ristocetin can be used as the sole agent in the treatment of staphylococcal pulmonary infections. Ristocetin was considered to have cured 13 of 19 patients with skin and soft tissue infections, including patients with widespread furunculosis and multiple abscesses. Of the 11 patients with staphylococcal osteomyelitis and arthritis, 9 of whom had not responded to other antibiotics, 3 were considered cured, and the remaining 8 improved after the use of ristocetin in conjunction with surgery. An initial dose of 50 to 75 mg. per kilogram per day folTABLE
14. Ristocetin-Results of Therapy in Staphylococcal Infections NUMBER
CURED
IMPROVED
FAILED
OTHER OUTCOME
Pneumonia, lung abscess ........... Skin and soft tissues ............... Osteomyelitis, arthritis ............. Endocarditis ...................... Septicemia .......... ............. Meningitis, brain abscess .......... Visceral .......................... Totals .......
40 19 11 7 8
30 13 3 5 3
2 2
2
89
1 57
2 6
2
6
8 2
2 2
19
6
Modified from Romansky and Olson. 47 * Died of unrelated causes or befbre therapy could be evaluated.
7
*
HARRIS D. RILEY, JR.
1087
lowed by 25 to 50 mg. per kilogram per day is recommended by Terry and Bradley52 in the treatment of osteomyelitis and suppurative arthritis in childhood. Five of seven patients with staphylococcal endocarditis were considered cured with ristocetin therapy. All the patients had been treated with one or more antibiotics before ristocetin therapy was instituted and had positive blood cultures when ristocetin was begun. Four of the five successfully treated patients were adults and received 1.5 to 2 gm. every 8 hours for 12 to 18 days. Dries and co-workers 6 successfully treated an ll-year-old girl with 75 mg. per kilogram per day for 35 days after 25 mg. per kilogram per day had failed to produce improvement. Ristocetin was considered curative in three of eight patients with septicemia and is credited with producing improvement in two additional patients. Rantz and Jawetz 35 reported failures with ristocetin in three cases of sepsis with bacteremia due to Staphylococcus aureus. Bacteremia persisted in each patient during therapy, and there was no clinical improvement. Romansky and 0lson 47 are of the opinion that these failures may well be related to insufficient dose of the drug and the fact that it was given by constant intravenous drip, precluding the attainment of peak concentrations. A patient with staphylococcal septicemia while under treatment with adrenal steroids, reported by Knight,29 did not respond to 6 gm. per day. Two patients with staphylococcal meningitis obtained a good result with ristocetin therapy.12,24 Of particular interest is the fact that studies of the spinal fluid in one of the cases24 revealed that ristocetin had crossed the blood-brain barrier. Herting and co-workers20 of Abbott Laboratories surveyed 333 cases treated with ristocetin, including those published in the literature as well as reports submitted directly by clinicians to the manufacturer. On the basis of "an analysis conducted entirely by machine methods to minimize personal factors in the evaluation," 60 per cent of the patients treated were considered cured and a further 17 per cent "improved," while 23 per cent demonstrated no response. Waisbren and co-workers53 administered ristocetin, vancomycin and kanamycin alternately to 131 patients with severe staphylococcal infections or bacterial endocarditis. They concluded that no one of the three antibiotics showed clinical superiority over the others. Although significant ototoxicity and nephrotoxicity were found with all three, ristocetin, in addition, caused a high incidence of skin reactions and depression of the granulocytic series of the white blood cells in some patients. SUMMARY
Vancomycin, a bactericidal antibiotic, is a valuable drug for the treatment of staphylococcal infections. Because it must be administered
1088
VANCOMYCIN AND RISTOCETIN
intravenously, it should be used chiefly for severe infections unlikely to respond to other antibiotics. Staphylococci resistant to vancomycin have not been encountered, and effective serum concentrations are readily obtained. With further purification of the drug, side effects have been much less common. The antibiotic should be used cautiously in the presence of renal insufficiency, since excessive serum concentrations may produce deafness. Ristocetin is an effective agent in the management of staphylococcal infections. Because of difficulties in administration and untoward reactions, it should be reserved for severe infections not expected to be improved by more conventional antimicrobials. Its action is apparently not consistently bactericidal. Side effects, the most serious of which is hematopoietic depression, are not infrequent, but are usually reversible and can be reduced by adherence to recommended dosage schedules. Preliminary data suggest that it may be used effectively in the shortterm therapy of enterococcal endocarditis. The assistance of Sue Fuller in preparation of the manuscript is acknowledged. REFERENCES
1. Abbott Laboratories: Spontin (Ristocetin, Abbott), 1958. 2. Anderson, R. C., Worth, H. M., Harris, P. N., and Chen, K. K.: Vancomycin, a New Antibiotic. IV. Pharmacologic and Toxicologic Studies; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 75-81. 3. Dangerfield, H. C., and others: Clinical Use of Vancomycin. Presented at Con· ference on Anti-Microbial Agents, Washington, D.C., October 27, 1960. 4. Dries, C. P., and Koch, R.: Ristocetin, a Laboratory and Clinical Evaluation in Children. 1- Pediat., 56:498, 1960. 5. Idem: Clinical Evaluation of Ristocetin in Children. A.M.A. J. Dis. Child., 99: 752, 1960. 6. Dries, C. P., Asay, L. D., and Koch, R.: Ristocetin in Serum Levels in Children; in Antibiotics Annual, 1958~1959. New York, Medical Encyclopedia, Inc., 1959, pp. 428, 431. 7. Ehrenkranz, N. J.: The Clinical Evaluation of Vancomycin in Treatment of Multi-antibiotic Refractory Staphylococcal Infections; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 587-94. 8. Finegold, S. M., and Gaylor, D. W.: Enterocolitis Due to Phage Type 54 Staphylococci Resistant to Kanamycin, Neomycin, Paromomycin, and Chloramphenicol. New England 1- Med., 263:1110, 1960. 9. Finland, M., and others: Panel Discussion: The Current Status of Erythromycin, Kanamycin, Novobiocin, Oleandomycin, Ristocetin, and Vancomycin, with Particular Reference to Their Use in Staphylococcal Disease; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 1051-72. 10. Gangarosa, E. J., Johnson, T. R., and Ramos, H. S.: Ristocetin-Induced Thrombocytopenia: Site and Mechanism of Action. A.M.A. Arch. Int. Med., 105:83, 1960. II. Garrod, L. P., and Waterworth, P. M.: Behaviour in Vitro of Some New An· tistaphylococcal Antibiotics. Brit. MI, 2:61, 1956. 12. Geraci, J. E.: The Antibiotic Therapy of Bacterial Endocarditis. M. Clin. North America, 42:1101, 1958. 13. Geraci, J. E., Heilman, F. R., Nichols, D. R., and Wellman, W. E.: Antibiotic Therapy of Bacterial Endocarditis. VII. Vancomycin for Acute Micrococcal 1<:ndocarditis: Preliminary Report. Proc. Staff Meet., Mayo Glin., 33:172, 1958
HARRIS D. RILEY, JR.
1089
14. Geraci, J. E., Heilman, F. R., Nichols, D. R., Wellman, W. E., and Ross, G. T.: Some Laboratory and Clinical Experiences with a New Antibiotic, Vancomycin. Proc. Staff Meet., Mayo Clin., 31:564, 1956. 15. Idem: Some Laboratory and Clinical Experiences with a New Antibiotic, Van· comycin; in Antibiotics Annual, 195()""1957. New York, Medical Encyclopedia, Inc., 1957, pp. 90-106. 16. Griffith, R. S., and Peck, F. B., Jr.: Vancomycin, a New Antibiotic. III. Pre· liminary Clinical and Laboratory Studies; in Antibiotics Annual, 1955-1956. New York, Medical Encyclopedia, Inc., 1956, pp. 619-22. 17. Grundy, W. E., Alford, E. F., Rdzok, E. J., and Sylvester, 1. C.: Ristocetin, the Development of Resistance and Bactericidal Activity; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 693~8. 18. Grundy, W. E., and others: Ristocetin, Microbiologic Properties; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 687-92. 19. Idem: Ristocetin, a Microbiological Comparison of Ristocetins A and B; in Anti· biotics Annual, 1957-1958. New York, Medical Encyclopedia, Inc., 1958, pp. 15~62. 20. Herting, R. L., Lees, B., Zimmermann, A. J., and Berryman, G. H.: Ristocetin: A Statistical Review of Three Hundred Thirty-Three Cases. l.A.M.A., 170: 176, 1959. 21. Higgins, H. M., Harrison, W. H., Wild, G. M., Bungay, H. R., and McCormick, M_ H.: Vancomycin, a New Antibiotic. VI. Purification and Properties of Vancomycin; in Antibiotics Annual, 1957-1958. New York, Medical Encyclopedia, Inc., 1958, pp. 906-14. 22. Hsie, J. Y., Nusser, W., Epstein, S., Van Maren, H., and Oxog, S.: Resistance to Ristocetin, Oleandomycin, and Novobiocin. Antibiotics 6 Chemother., 8:607, 1958. 23. Hwang, K., Primach, N., Stein, R. J., and Richards, R. K.: Pharmacological and Toxicological Properties of Ristocetins A and B; in Antibiotics Annual, 19571958. New York, Medical Encyclopedia, Inc., 1958, p. 163. 24. Kanner, I. F.: Ristocetin in the Cerebrospinal Fluid during Staphylococcal Meningitis; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 432~6. 25. Kirby, W. M. M.: Vancomycin; in H. Welch and M. Finland. 55 26. Kirby, W. M. M., and Divelbiss, C. L.: Vancomycin; Clinical and Laboratory Studies; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 107-17. 27. Kirby, W. M. M., Perry, D. M., and Bauer, A. W.: Treatment of Staphylococcal Septicemia with Vancomycin. New England J. Med., 262:49, 1960. 28. Kirby, W. M. M., Perry, D. M., and Lane, J. L.: Present Status of Vancomycin Therapy of Staphylococcal and Streptococcal Infections; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 580-86. 29. Knight, V.: The Staphylococcal Problem Today. J. Kentucky M.A., 56:1110, 1958. 30. Knight, V., White, A., and Hemmerly, H.: The Effect of Antibiotics on Staphy· lococci of Hospital Patients. Proceedings, National Conference on HospitalAcquired Staphylococcal Disease, Atlanta, Communicable Disease Center, U.S. Public Health Service, 1958. 31. Lee, C. C., Anderson, R. C., and Chen, K. K.: Tissue Distribution of Erythromycin in Rats. Antibiotics 6 Chemother., 3:920, 1953. 32. Idem: Vancomycin, a New Antibiotic. V. Distribution, Excretion, and Renal Clearance; in Antibiotics Annual, 19 56~ 1957. New York, Medical Encyclo· pedia, Inc., 1957, pp. 82-9. 33. McCormick, M. H., Stark, W_ M., Pittenger, G. E., Pittenger, R. C., and McGuire,1. M.: Vancomycin, a New Antibiotic. I. Chemical and Biologic Properties; in Antibiotics Annual, 1955~1956. New York, Medical Encyclopedia, Inc., 1956, pp. 606-11. 34. Pittenger, R. C., and Brigham, R. B.: Streptomyces Orientalis, n. sp., the Source of Vancomycin. Antibiotics 6 Chemother., 6:624, 1956.
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VANCOMYCIN AND RISTOCETIN
35. Rantz, L. A., and Jawetz, E.: Failure of Ristocetin Therapy in Three Cases of Staphylococcal Sepsis with Bacteremia. New England J. Med., 259:963, 1958; 260:144,1959. 36. Rantz, L. A., Randall, E., Thurn, L., and Barker, L. F.: The Effects of Vanco· mycin, Oleandomycin, and Novobiocin on Staphylococci in Vitro. Antibiotics & Chemother., 7:399, 1957. 37. Ravenholt, R. T., and Ravenholt, O. H.: Staphylococcal Infections in the Hospital and Community, Hospital Environment and Staphylococcal Disease. Am. J. Pub. Health, 48:277, 1958. 38. Report of the Committee on the Control of Infectious Diseases. Evanston, Ill., American Academy of Pediatrics, 1961. 39. Riley, H. D., Jr.: A Review: Staphylococcal Disease in Infancy. Med. Times, 88: 177,1960. 40. Idem: Recent Advances in Antimicrobial Therapy, with Particular Reference to Staphylococcal Infections. J. Arkansas M. Soc., 57:59, 1960. 41. Idem: Neonatal Pediatrics. V. The Role of Infection. Am. Pract. & Digest. Treat., 11:465,1960. 42. Idem: Management of Severe Staphylococcal Infections in Infants and Children. To be published. 43. Riley, H. D., Jr., and Ryan, N. 1.: Treatment of Severe Staphylococcal Infections in Infancy and Childhood with Vancomycin; in Antibiotics Annual, 1959-1960. New York, Medical Encyclopedia, Inc., 1960, p. 908. H. Rogers, D. E.: The Current Problem of Staphylococcal Infections. Ann. Int. Med., 45:738,1956. 45. Romansky, M. J.: Panel Discussion: The Current Status of Erythromycin, Kana· mycin, Novobiocin, Oleandomycin, Ristocetin, and Vancomycin, with Partic· ular Reference to Their Use in Staphylococcal Disease; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 1051-72. 46. Romansky, M. 1., and Holmes, J. R.: Successful Short-Term Therapy of Enterococcal and Staphylococcal Endocarditis with Ristocetin-Seven Patients; in Antibiotics Annual, 1957-1958. New York, Medical Encyclopedia, Inc., 1958, p.187. 47. Romansky, M. 1., and Olson, R. A.: Ristocetin; in H. Welch and M. Finland. 55 48. Romansky, M. J., Limson, B. M., and Hawkins, 1. E.: Ristocetin: A New Antibiotic-Laboratory and Clinical Studies. Preliminary Report; in Antibiotics Annual,J95~1957. New York, Medical Encyclopedia, Inc., 1957, pp. 706-15. 49. Rothenberg, H. J.: Anaphylactoid Reaction to Vancomycin. J.A.M.A., 171:1101, 1959. 50. Schneierson, S. S., Amsterdam, D., and Bryer, M. S.: Bacterial Sensitivity to Ristocetin. Antibiotics & Chemother., 8:204,1958. 51. Spears, R. L., and Koch, R.: The Use of Vancomycin in Pediatrics; in Antibiotics Annual, 1959-1960. New York, Medical Encyclopedia, Inc., 1960, p. 908. 52. Terry, R. B., and Bradley, L. F.: Ristocetin in Adults and Children; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, p. 458. 53. Waisbren, B. A., and others: Comparative Clinical Effectiveness and Toxicity of Vancomycin, Ristocetin, and Kanamycin. Arch. Int. Med., 106:179, 1960. 54. Wallace, 1. R., and Carson, N. A. J.: Staphylococcal Septicaemia Treated with Vancomycin in the Presence of Chronic Renal Failure. Lancet, 1:519, 1960. 55. Welch, H., and Finland, M.: Antibiotic Therapy for Staphylococcal Diseases. New York, Medical Encyclopedia, Inc., 1959. 56. Wise, R. 1.: Principles of Management of Staphylococcic Infections. J.A.M.A., 166:1178, 1958. 57. Ziegler, D. W., Wolfe, R. N., and McGuire, 1. M.: Vancomycin, a New Antibiotic. II. In Vitro Antibacterial Studies; in Antibiotics Annual, 1955-1956. New York, Medical Encyclopedia, Inc., 1956, pp. 612-18. 800 N.E. 13th St. Oklahoma City 4, Okla.
AND
RISTO~ETIN
HARRIS D. RILEY, JR., M.D.
~ lthough the problem of staphylococcal infections is not a new one, in recent years it has become of increasing concern. In addition to the dramatic epidemics of staphylococcal disease which have occurred in newborn nurseries, some of the most important aspects of this problem relate to diseases occurring principally in infants and children. Although the occurrence of certain clinical types of staphylococcal disease, such as osteomyelitis, has decreased, others, e.g. staphylococcal pneumonia and empyema in infancy, have shown an apparent striking increase. The historical aspects, the fundamental biologic nature of the organism, alterations in host response, the influence of antimicrobial drugs and other factors have been reviewed. 30 , 37, 39, 40, 44 Finland 55 has detailed the circumstances contributing to the increased significance of staphylococcal infections in recent years. Whereas the use of antibiotics in many other infections, such as those caused by pneumococci and hemolytic streptococci, had continued to be effective, antimicrobial therapy of staphylococcal infections, though at first encouraging, was becoming disappointing. One of the main reasons for this was that staphylococci involved in most hospital-acquired infections had shown a pattern of increasing resistance to the generally available antimicrobial agents. 30 , 37, 39, 40, 44, 55 Because of these factors, considerable effort has been directed to the development of newer antimicrobial agents against staphylococcal infections. Vancomycin and ristocetin are two of the newer such agents which have become available.
VANCOMYCIN CHEMICAL AND PHYSICAL PROPERTIES
Vancomycin* is produced by Streptomyces orientalis. The first culture * The trade name of Eli Lilly and Company for vancomycin is Vancocin. From the Department of Pediatrics and the Children's Memorial Hospital, University of Oklahoma School of Medicine, Oklahoma City. 10 73
1074
VANCOMYCIN AND RISTOCETIN
was obtained from a soil sample obtained by a missionary ill the Indonesian jungles. Vancomycin hydrochloride, which appears to have no significant chemical relation to any other known antibiotic, is a white solid material, and is a large molecule, having a molecular weight of approximately 3300. The ultimate composition and microbial activities of vancomycin are not entirely known at present, since electrophoretic studies have shown that the crystalline substance contains some 20 per cent of a second component, the biological activity of which has not been determined. 21 , 33, 34, 57 ANTIMICROBIAL PROPERTIES
In addition to staphylococci, other organisms usually susceptible to vancomycin include hemolytic streptococci, pneumococci, enterococci, gonococci, cornyebacteria and clostridia. It is not effective against Klebsiella, Brucella, Proteus, Shigella, Salmonella, Pseudomonas, Aerobacter and other coliform organisms, nor Mycobacterium tuberculosis, fungi and yeast 25 (personal communication from R. S. Griffith). Extensive studies by many investigators have shown that pathogenic staphylococci are almost uniformly susceptible to vancomycin in low concentrations (less than 3 micrograms per milliliter). Of the many strains so far studied, only 5 have shown growth in concentrations greater than 10 micrograms per milliliter. l l , 14-16, 25, 26, 43, 56 Vancomycin is bactericidal against multiplying bacteria in a manner similar to penicillin. 57 Bactericidal and bacteriostatic levels are similar, and the action of vancomycin is not greatly affected by the presence of serum.26 , 36 Wise 56 and Kirby and Divelbiss26 have reported vancomycin to have greater activity in vitro than ristocetin and kanamycin. Garrod and Waterworth l l concluded that vancomycin has greater bactericidal activity than seven other antistaphylococcal antibiotics which were studied. Vancomycin does not exhibit cross-resistance with other known antibiotics. Several workers have noted that resistance in vitro of staphylococci to vancomycin rarely develops and then only very slowly and of a small degree even after as many as 28 daily subcultures.14-16,36 Garrod and Waterworth l l feel that resistance to vancomycin of a degree to obviate the therapeutic effect apparently cannot develop in staphylococci. In our laboratory we have not observed staphylococci resistant to vancomycin, nor has resistance developed during rather prolonged treatment of patients with vancomycin. Other workers 14 , 26 have confirmed that staphylococci retain their susceptibility to vancomycin after two to four weeks of vancomycin therapy. ABSORPTION, DISTRIBUTION AND EXCRETION
Lee31 , 32 reported on the absorption, distribution and excretion dogs and other animals.
ill
HARRIS D. RILEY, JR.
1075
Bactericidal serum concentrations in human beings are readily achieved and maintained by intravenous administration. In 16 children receiving vancomycin in a dose of 20 mg. per kilogram as a single intravenous injection, a peak serum value of 52 micrograms per milliliter was promptly reached at one hour, the concentration slowly falling to a range of 1.6 to 13 micrograms 12 hours after administration. 51 No difference was found in the average values in five patients under the age of two weeks as compared to the older children. In 14 patients receiving 13.3 mg. per kilogram of vancomycin by intramuscular injection the peak concentration occurred 4 hours after administration and averaged approximately 10 micrograms per milliliter. Therapeutic concentrations were maintained for at least eight hours after injection.51 Kirby and Divelbiss26 and Geraci et a1. B reported on serum concentrations in adults following intravenous administration and concluded that 1 gm. every 12 hours was usually the most desirable regimen in this age group. Vancomycin is excreted chiefly through the kidneys, more than 80 per cent of the administered dose within a 24-hour period being recovered from the urine. Considerably higher serum concentrations occur and may persist for long periods in patients with impaired renal function. 26 The half-life of vancomycin in the blood has been estimated to be approximately six hours. 15 Vancomycin diffuses readily into the pleural, ascitic and synovial fluids, but only small amounts are secreted in the bile. It does not diffuse into the spinal fluid through normal meninges even after multiple doses, but may pass the blood-brain barrier in some instances when the meninges are inflamed. 25 ADMINISTRATION AND DOSAGE FORM
Vancomycin is available as 0.5 gm. of vancomycin hydrochloride in 10-m1. rubber-stoppered ampules. At the time of use, 10 m1. of water for injection, U.S.P., is added to the ampule. At present the drug should be administered only by the intravenous route. An intramuscular preparation has also been utilized in experimental studies (unpublished observations), but this product is not commercially available. * Spears and Koch 51 have administered vancomycin intramuscularly after mixing with hydrocortisone to reduce the pain associated with injection. There are several methods of intravenous administration: (a) Intermittent infusion: the desired amount of the drug can be added to 50 to 150 m1. of normal saline or 5 per cent glucose in water and this infusion given rapidly over a period of 20 to 30 minutes at 8- to 12-hour intervals until the total calculated daily dose is administered. (b) Direct injection: one third to one " Personal communication from R. S. Griffith, M.D.
1076
VANCOMYCIN AND RISTOCETIN
fourth of the total daily dose mixed with 10 m!. of water for injection can be injected directly into a large vein or into the infusion tubing. This injection should be given slowly over at least a five-minute period and can be repeated at 6- to 8-hour intervals until the total daily dose has been administered. (c) Continuous injection: the total daily dose can be added to an appropriate amount of normal saline or 5 per cent glucose (in a ratio of 1 gm. of vancomycin to 1000 m!. of fluid) and the rate of administration of the intravenous infusion adjusted so that the patient receives the total calculated daily dose over a 24-hour period. Continuous intravenous administration may be achieved by means of a venous cutdown or through femoral or caval catheters. If the patient is receiving a continuous infusion of fluids with which vancomycin is not compatible, the infusion bottles can be changed temporarily. All the foregoing methods have been utilized in this Clinic. Methods (a) and (b) have the advantage of allowing a large dose to be given immediately and at frequent intervals in patients with overwhelming infections. The incidence of phlebitis seems to be more frequent with direct injection than with other methods. Although intermittent infusion is probably the easiest method, we feel that the method of administration should be individualized. In children a total daily dose of 20 mg. per pound of body weight per day divided into equal aliquots and administered intermittently at 8- or 12-hour intervals or given by continuous drip as described above is usually satisfactory. In serious, overwhelming infection we have used doses as high as 68 mg. initially without significant untoward effects. For premature and full-term newborn infants a dose of 6 mg. per pound pe~ day has proved satisfactory and safe,2 though others38 have recommended a dose of 15 mg. Until more experience has been accumulated, it is probably desirable to use the drug in this age group with caution and to adjust dosage on the basis of serial determinations of serum concentration. The usual adult dose is 2 gm. daily, and doses larger than this should be avoided except occasionally for initiating therapy in a severely ill patient with normal renal function. Vancomycin should be used cautiously in patients with reduced renal function, the dosage being titrated according to serum levels. The oral administration of vancomycin has been used in the management of enterocolitis caused by penicillin-resistant staphylococci and also in conjunction with systemic therapy in some patients.21 . 26. 34 TOXICITY AND SIDE EFFECTS
Vancomycin has a low order of toxicity in experimental mice, rats and other animals. In monkeys and dogs, daily intravenous dosage of 25 to 50 m!;. per kilogram for 3 months or longer produced no signs of toxicity.2
HARRIS D. RILEY, JR.
1077
Further purification of the antibiotic has reduced the incidence of chemical phlebitis, and pain at the site of intravenous injection, which was a common occurrence with the initial lots of vancomycin available for clinical investigation, so that with the relatively pure material which has been available more recently untoward effects of these types have presented little difficulty. Phlebitis can be minimized by using dilute solutions and alternating the sites of injection. Rapid intravenous injection of vancomycin may cause a feeling of warmth, generalized tingling and nausea, but this may be avoided by slowing the rate of injection and usually does not occur when the dose is given over a period of 20 to 30 minutes. On occasion, chills, fever, slight renal irritation, urticaria and macular rashes have occurred during or after the administration of vancomycin in some patients, as is true with other compounds of high molecular weight. Such reactions have sometimes occurred in a non predictable fashion, beginning with the first dose of vancomycin; in other patients, vancomycin was tolerated without reaction several months later. The febrile reaction occurring with some of the earlier lots often made clinical evaluation of therapeutic response difficult.43 If these reactions are severe, the drug should be discontinued. These manifestations may be minimized by the concurrent administration of antihistamine or hydrocortisone. 13. 27. 51 Although these untoward effects were common with early lots, they are much less frequent with the more purified material. Three instances of possible cross-sensitization between vancomycin and other antibiotics such as streptomycin have been reported. 7 Though this is extremely rare, precaution should be observed against anaphylaxis. 49 . 51 Hearing loss has been reported in a few patients when excessively high serum levels-levels 5 to 10 greater than the necessary therapeutic concentration-were present. 13 . 25 In certain patients the deafness has been temporary and reversible when therapy was discontinued. 43 Because of these observations vancomycin should be used cautiously in patients with reduced renal function, and when long-term administration is planned, tests of auditory acuity along with serial measurements of renal function should be performed before starting therapy and at frequent intervals during and after the course of therapy. Hematopoietic disturbances have not been a problem with the use of vancomycin, only two cases of transient leukopenia having been observed. 3 Hepatic toxicity has not been reported. Nevertheless, as with the prolonged intravenous administration of any drug, it is suggested that appropriate hematologic studies, urinalysis and liver and renal function tests be performed periodically, especially if the medication is to be used in a dosage larger than 20 mg. per pound per day in a child or more than 2 gm. per day in adults over a period longer than 2 weeks.
1078
VANCOMYCIN AND RISTOCETIN
INDICATIONS AND CLINICAL USE
The principal clinical indication for the use of vancomycin lies in the treatment of severe infections due to pathogenic staphylococcI. Vancomycin is not indicated for treatment of comparatively mild staphylococcal infections, but may be the drug of choice when patients have failed to respond to the commonly used antimicrobial agents or when the causative strain is resistant to other antibiotics. It may be used in patients seriously ill with infections caused by other gram-positive organisms;28 however, infections due to streptococci and pneumococci usually respond well to more easily administered agents such as penicillin, and its use in such infection will not be reviewed here. A significant experience with the use of vancomycin in serious staphylococcal infections has now accumulated. STAPHYLOCOCCAL PNEUMONIA AND EMPYEMA. In 1959 Riley and Ryan 43 reported that 5 infants and children critically ill with staphylococcal pneumonia responded satisfactorily to vancomycin. Since this report a much larger experience with the use of vancomycin has been accumulated in this Clinic. The initial impression of excellent results in serious staphylococcal pneumonia, many cases of which had been unsuccessfully previously treated with other antibiotics, has been confirmed. Spears and Koch 51 also reported good results in several children with staphylococcal pneumonia. Kirby et aP8 and Ehrenkranz 7 found vancomycin effective in several cases of staphylococcal pneumonia in adults in many of whom previous antibiotic therapy had failed. The role of vancomycin therapy in treatment of staphylococcal empyema is I,msettled. Geraci et aU4 could not demonstrate any concentration of the drug in empyema fluid after four doses. Spears and Koch 51 feel that vancomycin should be used in conjunction with another antibiotic in situations in which the antibiotic must cross tissue barriers, as in meningitis and empyema pockets. On the other hand, Ehrenkranz 7 has reported success with vancomycin in staphylococcal empyema after catheter drainage and therapy with other drugs had apparently failed. Our experience with vancomycin in staphylococcal empyema has been satisfactory. STAPHYLOCOCCAL INFECTIONS OF SKIN AND SOFT TISSUES. In several infants and children with severe, life-threatening soft tissue infections treated with vancomycin in this Clinic, the results have been good. 42 . 43 Other workers have observed a satisfactory response to vancomycin in patients with cellulitis, recurrent furunculosis, carbuncles and deep postoperative wound infections, the latter due for the most part to antibiotic-resistant staphylococci. 14 . 25. 26. 28 The role of surgical drainage as an adjunct to therapy should not be neglected. Here vancomycin, because of difficulties in administration, should be reserved for patients in whom there has been a failure to respond to other antibiotics, those
HARRIS D. RILEY, JR.
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with lesions caused by antibiotic-resistant organisms or those with lesions that are potentially life-threatening, such as cellulitis about the face and deep-seated wound infections, especially if there is a possibility of hematogenous dissemination. SEPTICEMIA AND ENDOCARDITIS. Promising results in the treatment of these conditions with vancomycin have been reported by several investigators. Many of the reported patients had serious, usually fatal underlying diseases complicated by septicemia due to antibiotic-resistant staphylococci. Riley and Ryan 43 reported a satisfactory response in eight of nine children with staphylococcal septicemia treated with vancomycin; since that report several additional patients have been treated successfully.42 Three of four children with staphylococcal septicemia treated with vancomycin by Spears and Koch 5 ! were cured. Kirby and co-workers27 have recently reported the treatment with vancomycin of 33 adults with staphylococcal septicemia. Of these, most of whom were in the older age groups and had serious underlying illnesses, 20 were cured, a number of whom had failed to improve with other antibiotics to which the causative organism was susceptible, 6 were improved, but died of underlying diseases, and 7 were classified as treatment failures, although most of these last had overwhelming infections and died shortly after therapy was initiated. Blood cultures may remain positive for three to four days after initiation of vancomycin therapy in some patients who obtain a satisfactory response. 25 A lO-year-old boy with staphylococcal septicemia and septic arthritis who also had renal failure due to pyelonephritis exhibited dramatic improvement and a prompt bacteriologic response with no worsening of his renal status after treatment with vancomycin. 54 Dosage was governed by the results of serial determinations of the serum levels of vancomycin. Of four children with staphylococcal endocarditis treated with vancomycin, Spears and Koch 5! considered one cured, one improved, and one unimproved; one with uremia died of his infection after four days of therapy. The infection was promptly eradicated in two children with staphylococcal endocarditis treated with vancomycin by Riley and Ryan. 43 Geraci et alP reported the successful treatment of four of six adults with acute staphylococcal endocarditis with vancomycin, no patients with this type of acute endocarditis having been cured previously in his clinic. Of the two remaining patients, the infection was not controlled by vancomycin in one, and the other died two weeks after therapy was terminated of his primary disease, the infection having been eradicated. Since the four successfully treated patients received vancomycin for 28, 20, 18 and 28 days respectively, and the results of the serum bactericidal tests were satisfactory, these workers suggested that short-term (2 weeks) treatment with vancomycin alone might be satisfactory in staphylococcal endocarditis.
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VANCOMYCIN AND RISTOCETIN
OSTEOMYELITIS. We have treated a small number of patients with staphylococcal osteomyelitis with vancomycin with good results.42,43 Other workers 7 , 14, 26, 28 have also reported satisfactory results in several patients with osteomyelitis and septic arthritis. STAPHYLOCOCCAL ENTEROCOLITIS. Because of the high concentration in the stools after oral administration, it has been speculated that vancomycin administered orally might be useful in the treatment of staphylococcal enterocolitis.14 In our hands a satisfactory treatment regimen in patients with severe staphylococcal disease requiring long-term therapy, such as staphylococcal pneumonia, has been to use vancomycin during the initial period, for perhaps 7 to 10 days, and then complete the course of treatment with a more easily administered antistaphylococcal agent or agents. Waisbren et aJ.53 concluded that vancomycin did not show any clinical superiority over ristocetin and kanamycin in their experience with the treatment of staphylococcal infections. In a panel discussion on the use of various antibiotics in staphylococcal infections there was general agreement that vancomycin and ristocetin were two of the most effective antistaphylococcal agents, the majority of the panelists regarding vancomycin as the more potent of the two. 9 RISTOCETIN
Ristocetin * was first isolated by Grundy and co-workers18 from cultures of Nocardia lurida, an actinomycete, which was first recovered from a soil sample from the Garden of the Gods, Colorado Springs, Colorado. To date, no other culture which produces ristocetin has been found. CHEMICAL AND PHYSICAL PROPERTIES
Two related substances, ristocetins A and B, which are large molecules, have been isolated. Although the chemical characteristics are not completely defined, ristocetin B is 3 to 4 times as active as ristocetin A, which has an arbitrarily assigned potency of 1000 units per milligram. 19 Body fluids containing ristocetin may be stored at 10° C. for at least 5 days without deterioration. 47 ANTIMICROBIAL PROPERTIES
Ristocetin has activity against gram-positive bacteria, including staphylococci, pneumococci, streptococci and mycobacteria, but is not active against gram-negative bacteria, including Hemophilus influenzae and Neisseria species as well as yeast and a few protozoa which have been studied. Although most strains of Staphylococcus aureus, including * The trade name of Abbott Laboratories for ristocetin is Spontin.
HARRIS D. RILEY, JR.
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many which are resistant to many other antimicrobial agents, are susceptible to ristocetin, some strains require a concentration somewhat higher than the minimum inhibitory concentration for a bactericidal effect.1 Grundy and co-workers 18 and Romansky et a1. 48 outlined in detail the antimicrobial spectrum in vitro of ristocetin. Cross-resistance among ristocetin, vancomycin, kanamycin and other antibiotics reportedly does not occur. 48 , 50 Early studies revealed a narrow range between bacteriostatic and bactericidal effects against streptococci, pneumococci and staphylococci, but with the accumulation of additional laboratory data, some strains have shown a greater variability in this range. 12, 17, 47, 50 The bactericidal activity of ristocetin is apparently not restricted to actively dividing cells.17 Several workers have reported that ristocetin has less activity in vitro than vancomycin. 28 , 50, 56 Wise 56 found that vancomycin was bactericidal against 12 of 13 strains of staphylococci, whereas ristocetin exhibited bactericidal action against only one of th~ thirteen. Grundy and co-workers17 reported that none of more than 400 cultures of streptococci, pneumococci and staphylococci were naturally resistant to ristocetin and that bacteria do not readily acquire resistance in vitro to the drug. Romansky, Limson and Hawkins 48 observed no development of resistance in 2 strains of Staphylococcus aureus isolated from purulent exudates after 45 subcultures. These workers reported that all of 35 strains of hemolytic Staphylococcus aureus were susceptible to less than 5 micrograms per milliliter of ristocetin, all of 74 strains of pneumococci were susceptible to 3 micrograms or less, and more than 70 per cent of 90 strains of streptococci were susceptible to 5 micrograms. Hsie et aJ.22 reported that staphylococci slowly developed a low order of resistance to ristocetin as measured by the agar gradient technique. The bactericidal properties of ristocetin have been emphasized by the manufacturers, and some investigators have referred to its bactericidal characteristics. Other workers, however,35,50 have reported it to be primarily bacteriostatic for staphylococci. Rantz35 found that the bactericidal concentration of ristocetin for 42 strains of Staphylococcus aureus was threefold to more than tenfold greater than the 24-hour inhibitory concentration and was often 2 to 4 times, or more, greater than the 48-hour inhibitory concentration. ABSORPTION, DISTRIBUTION AND EXCRETION
Hwang et aJ.23 studied the pharmacologic properties and toxicity of ristocetin in animals. Dries, Asay and Koch 6 and Dries and Koch 4 studied both the intravenous and intramuscular administration of ristocetin in children ranging in age from 2 days to 15 years. Two hours
1082
VANCOMYCIN AND RISTOCETIN
after a dose of 12.5 mg. per kilogram was administered rapidly intravenously in 8 children, serum levels varied from 1.3 to 10.6 micrograms per milliliter. Thereafter the level declined gradually to less than 0.7 microgram at 12 hours. After the intravenous administration of 25 mg. per kilogram in 13 children, the ristocetin content of the serum averaged approximately 18 micrograms per milliliter for 4 hours after injection and then gradually decreased to an average of 2.5 micrograms per milliliter at 12 hours. In 6 children receiving 50 mg. per kilogram per day as a 24-hour continuous intravenous infusion, the serum content ranged between 2.6 and 21.1 micrograms per milliliter during the infusion. When the drug was administered intramuscularly to 14 children in a dosage of 12.5 mg. per kilogram with hydrocortisone added in a ratio of 1 mg. to each 100 mg. of antibiotic, serum concentrations at 2 hours averaged 5.3 micrograms per milliliter and decreased to less than 0.7 microgram 12 hours after administration. Satisfactory serum levels, comparable to those obtained with intravenous administration, were obtained in 8 children who received 25 mg. per kilogram per day intramuscularly. Romansky and 01son 47 have reported on serum concentrations in adults. Intramuscular ~dministration of ristocetin in doses of 200 to 500 mg. in adults was painful, and blood levels obtained by this route of administration were generally less than 5 micrograms per milliliter. 48 Ristocetin diffuses freely into pleural and ascitic fluid; levels at 2 to 4 hours approximate those in the blood when 1 to 2 gm. is administered rapidly intravenously.47 Ristocetin does not readily pass the blood-brain barrier. In one pediatric patient with meningitis and 12 without meningitis, the spinal fluid content' of ristocetin remained less than 0.7 microgram per milliliter, regardless of route of administration or dosage. 4 Spinal fluid concentrations in another study were less than 0.625 microgram per milliliter 3 hours after a I-gm. dose despite concentrations in the blood at the same time between 5 and 20 micrograms per milliliter. 45 ,48 Excretion studies revealed that 40 to 50 per cent of a 1- to 2-gm. dose is recoverable in the urine in 24 hours. 47 Further studies are needed to ascertain whether transplacental diffusion occurs and whether the drug passes into bile, milk or seminal fluid. Oral ristocetin in doses of 2 to 4 gm. does not reduce the total bacterial count in the stools, but does reduce the number of enterococci and staphylococci. Ristocetin solutions containing 1 mg. per milliliter of antibiotic are apparently well tolerated by the tracheobronchial tree when used for nebulization therapy.47 DOSAGE AND ROUTES OF ADMINISTRATION
Ristocetin is available as a sterile, lyophilized powder in vials containing a mixture of ristocetins A and B, representing 500 mg. of ristocetin
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1083
A activity. Sterile solutions of ristocetin may be stored under refrigeration for one month without significant loss of potency. Most investigators recommend a dose of 25 to 50 mg. per kilogram per day, depending on the type of infecting organism and severity of the disease, in both children and adults. Dries and Koch 5 recommend a dose of 50 mg. per kilogram per day intravenously or intramuscularly in children. A maximum dosage of 25 mg. per kilogram per day is usually adequate in pneumococcal and streptococcal infections. The majority of staphylococcal infections are controlled by 25 to 50 mg. per kilogram per day, but in severe infections, including bacterial endocarditis, a larger dose is often desirable during the early stages of the disease. Larger dosages should be reduced to 25 mg. per kilogram per day after clinical response. Since ristocetin is excreted by the kidney, dosage should be considerably reduced (to approximately half) in patients with renal impairment, to prevent excessive serum accumulation. A dose of 15 mg. per kilogram per day has been recommended for premature and newborn infants. 38 Ristocetin should be administered by the intravenous route. A 0.5 to 1 per cent solution should be prepared, using approximately 100 m!. of 5 per cent glucose or normal or hypotonic saline. Solutions should be prepared so that the maximum concentration of antibiotic does not exceed 25 mg. per milliliter. The solution may be given by the drip technique over 35 to 40 minutes, or may be injected directly into the tubing of an intravenous infusion used for fluid therapy or into a large vein, making certain that the time of administration is at least 5 minutes. Generally, the total daily dose is divided into 2 portions and administered at 12-hour intervals. In more severe infections, particularly those caused by the Staphylococcus, an eight-hour schedule may be used. When doses of 50 mg. per kilogram per day or more are used, the total daily dose should be divided into 3 equal parts. The duration of therapy must be determined by the kind of infection and the clinical course of the disease. Dries and Koch 5 report that the intravenous preparation of ristocetin can be safely administered intramuscularly by adding 1 mg. of hydrocortisone to each 100 mg. of antibiotic to decrease the inflammatory response at the site of injection. TOXICITY AND SIDE EFFECTS
Side effects associated with the use of ristocetin are not uncommon, having been noted in 29, or 20.8 per cent, of one series of 139 patients 47 and in 29 per cent of another series of 76 patients in the pediatric age group.5 In certain of the cases toxic effects could not be attributed solely to ristocetin, since the patients had received other potentially
1084
VANCOMYCIN AND RISTOCETIN
toxic drugs also. One of the more serious and unfortunately more common untoward effect is that affecting the hematopoietic system. Romansky and 01son 47 reported that varying degrees of leukopenia, neutropenia, thrombocytopenia and eosinophilia, either alone or in combination, occurred in 12.9 per cent of a series of 139 patients treated with ristocetin. Leukopenia or neutropenia occurred in six, and eosinophilia, which may presage the development of neutropenia or leukopenia, in 10 of 76 pediatric patients. 5 Thrombocytopenia, although less common than neutropenia, may occur even with currently recommended therapeutic regimens.lO Bone marrow examination and other studies suggest that ristocetin exerts its effect on the circulatory blood elements rather than on the bone marrow.lO, 47 To date, the side effects appear reversible on reduction of dosage or discontinuance of the drug, and all reported patients have recovered from the various degrees of leukopenia and thrombocytopenia. It is recommended that a complete hemogram, including hemoglobin determination, leukocyte, differential and platelet counts, be done on alternate days in children receiving more than 25 mg. per kilogram per day or in adults receiving more than 2 gm. a day and twice a week in patients receiving lower dosages. In general, the drug should be withdrawn if the total white cell count falls below 5000 cells per cubic millimeter or if the neutrophile count falls to less than 50 per cent of the total leukocytes even if the total white cell count exceeds 5000 cells per cubic millimeter. Phlebitis due to chemical irritation of the vein may occur at the site of injection, but can usually be controlled by reducing the volume of antibiotic solution. Drug fever, and a maculopapular rash associated with ristocetin administration, as well as instances of deafness and nephrotoxicity possibly related to ristocetin, have been reported. 47 ,53 It seems clear that the occurrence of toxicity is directly related to the size of dose of ristocetin, the incidence rising steeply when the recommended daily dose is exceeded. A similar relation between the total dosage of ristocetin administered and the incidence of side effects can be demonstrated. In a review of 333 cases the incidence of side effects rose in a stepwise fashion from 9.4 per cent with a maximum daily dose of between 1 and 1.9 gm. to 41 per cent with a daily dose of 4 to 4.9 gm. 20 With improved methods of manufacture and a more purified material, there has been a decline in the incidence of side effects, lllcluding those affecting the hematopoietic system. INDICATIONS AND CLINICAL USE
Although ristocetin may be effective in the treatment of streptococcal, pneumococcal and other infections due to gram-positive bacteria, it has found its greatest use in the management of staphylococcal and enterococcal infections. Six cases of pneumococcal pneumonia treated with
1085
HARRIS D. RILEY, JR.
ristocetin exhibited a rapid defervescence. 48 Romansky and Holmes 46 have reported the successful short-term (13 to 24 days) treatment of 6 patients with enterococcal endocarditis. Since that time other reports of the successful treatment of enterococcal endocarditis with ristocetin have appeared. The largest reported experience in the use of ristocetin in infancy and childhood has come from the group at the Los Angeles Childrens HospitaJ.4, 5, 6 Seventy-six hospitalized infants and children, 27 of whom were considered severely ill, were treated for pyogenic infections with ristocetin administered both intravenously and intramuscularly. Fortyseven had infections due to coagulase-positive staphylococci, of which 19 were resistant to penicillin and 16 to tetracycline, and the majority of the remainder pneumococcal, hemolytic streptococcal and enterococcal infections. As shown in Table 13, of the 76 patients, 87 per cent were considered improved after treatment with ristocetin. Twenty-seven of the children with severe staphylococcal infections received other drugs in addition to ristocetin. All of 5 patients with staphylococcal septicemia and II of 13 patients with staphylococcal pneumonia and empyema were considered cured. Of four patients with staphylococcal endocarditis, two were cured and two were unimproved. There was no improvement in two children with staphylococcal meningitis. Of the 19 patients with staphylococcal infections resistant to penicillin, 6 failed to respond to ristocetin, including 2 with bacterial endocarditis, 2 with meningitis and 2 with pneumonia and empyema. The data of these workers suggest a relation between dosage and TABLE
13. Clinical Effectiveness of Ristocetin in 76 Patients
DIAGNOSIS
NUMBER
ORGANISM
CLINICAL RESULTS
Cured Unim- Died proved Septicemia ...................... . Septicemia ...................... . Acute bacterial pericarditis. . ..... . Subacute bacterial endocarditis .... . Meningitis ...................... . Cellulitis and/or abscess .......... . Osteomyelitis .................... . Pneumonia and empyema ......... . Pneumonia and empyema ......... . Bronchopneumonia .............. . Respiratory tract infections ........ . Enterocolitis ..................... . Bronchiectasis due to fibrocystic disease ........................ . Disseminated moniliasis ...... .
5 StaphylococcuS * 1 Enterococcus 1 Staphylococcus * 4 Staphylococcus* 2 Staphylococcus * 12 Staphylococcus 1 H. influenzae B* 13 Staphylococcus * 1 Pneumococcus 18 Various 15 Various 1 Staphylococcus
Totals ............................ 76 al. 6
From Dries et * Received additional antibiotics.
5 1
2
2 2
12 1
11
2 1
18 15 1
Staphylococcus Candida and staphylococcus 2
1086
VANCOMYCIN AND RISTOCETIN
clinical result. Of the 35 patients treated with 25 mg. per kilogram per day, 8 failed to improve, and one death occurred in this group. Only 4 of 38 patients treated with 50 mg. per kilogram per day failed to respond. Of 5 patients treated with 75 mg. per kilogram per day, 4 were considered cured, and one, a child with fulminating staphylococcal bacteremia and pericarditis following cardiotomy, expired. Three of the 4 patients considered cured had not responded previously to 25 or 50 mg. per kilogram per day. Of the total 76 patients, 29 per cent showed some sort of side effects to ristocetin; severe toxic reaction such as leukopenia and neutropenia occurred in 7.6 per cent of the patients. All subsided promptly, however, with discontinuance of the antibiotic. Romansky and Olson47 reviewed 139 cases of infections collected from the literature, mostly in adult patients, treated with ristocetin and considered 89 to have a clearly established staphylococcal etiology. The number and types of cases and these workers' interpretation of the results of therapy are shown in Table 14. Fifty-seven patients (63.9 per cent) were regarded as cured, and 19 (21.3 per cent) improved. There were 6 failures (6.7 per cent), and 7 (7.8 per cent) patients died of unrelated causes or before ristocetin therapy could be evaluated. In 40 staphylococcal pulmonary infections, 33 of which had previously been treated with other antibiotics without apparent effect, ristocetin was considered to have a curative effect in 30, or 75 per cent. Romansky and Olson47 consider that ristocetin can be used as the sole agent in the treatment of staphylococcal pulmonary infections. Ristocetin was considered to have cured 13 of 19 patients with skin and soft tissue infections, including patients with widespread furunculosis and multiple abscesses. Of the 11 patients with staphylococcal osteomyelitis and arthritis, 9 of whom had not responded to other antibiotics, 3 were considered cured, and the remaining 8 improved after the use of ristocetin in conjunction with surgery. An initial dose of 50 to 75 mg. per kilogram per day folTABLE
14. Ristocetin-Results of Therapy in Staphylococcal Infections NUMBER
CURED
IMPROVED
FAILED
OTHER OUTCOME
Pneumonia, lung abscess ........... Skin and soft tissues ............... Osteomyelitis, arthritis ............. Endocarditis ...................... Septicemia .......... ............. Meningitis, brain abscess .......... Visceral .......................... Totals .......
40 19 11 7 8
30 13 3 5 3
2 2
2
89
1 57
2 6
2
6
8 2
2 2
19
6
Modified from Romansky and Olson. 47 * Died of unrelated causes or befbre therapy could be evaluated.
7
*
HARRIS D. RILEY, JR.
1087
lowed by 25 to 50 mg. per kilogram per day is recommended by Terry and Bradley52 in the treatment of osteomyelitis and suppurative arthritis in childhood. Five of seven patients with staphylococcal endocarditis were considered cured with ristocetin therapy. All the patients had been treated with one or more antibiotics before ristocetin therapy was instituted and had positive blood cultures when ristocetin was begun. Four of the five successfully treated patients were adults and received 1.5 to 2 gm. every 8 hours for 12 to 18 days. Dries and co-workers 6 successfully treated an ll-year-old girl with 75 mg. per kilogram per day for 35 days after 25 mg. per kilogram per day had failed to produce improvement. Ristocetin was considered curative in three of eight patients with septicemia and is credited with producing improvement in two additional patients. Rantz and Jawetz 35 reported failures with ristocetin in three cases of sepsis with bacteremia due to Staphylococcus aureus. Bacteremia persisted in each patient during therapy, and there was no clinical improvement. Romansky and 0lson 47 are of the opinion that these failures may well be related to insufficient dose of the drug and the fact that it was given by constant intravenous drip, precluding the attainment of peak concentrations. A patient with staphylococcal septicemia while under treatment with adrenal steroids, reported by Knight,29 did not respond to 6 gm. per day. Two patients with staphylococcal meningitis obtained a good result with ristocetin therapy.12,24 Of particular interest is the fact that studies of the spinal fluid in one of the cases24 revealed that ristocetin had crossed the blood-brain barrier. Herting and co-workers20 of Abbott Laboratories surveyed 333 cases treated with ristocetin, including those published in the literature as well as reports submitted directly by clinicians to the manufacturer. On the basis of "an analysis conducted entirely by machine methods to minimize personal factors in the evaluation," 60 per cent of the patients treated were considered cured and a further 17 per cent "improved," while 23 per cent demonstrated no response. Waisbren and co-workers53 administered ristocetin, vancomycin and kanamycin alternately to 131 patients with severe staphylococcal infections or bacterial endocarditis. They concluded that no one of the three antibiotics showed clinical superiority over the others. Although significant ototoxicity and nephrotoxicity were found with all three, ristocetin, in addition, caused a high incidence of skin reactions and depression of the granulocytic series of the white blood cells in some patients. SUMMARY
Vancomycin, a bactericidal antibiotic, is a valuable drug for the treatment of staphylococcal infections. Because it must be administered
1088
VANCOMYCIN AND RISTOCETIN
intravenously, it should be used chiefly for severe infections unlikely to respond to other antibiotics. Staphylococci resistant to vancomycin have not been encountered, and effective serum concentrations are readily obtained. With further purification of the drug, side effects have been much less common. The antibiotic should be used cautiously in the presence of renal insufficiency, since excessive serum concentrations may produce deafness. Ristocetin is an effective agent in the management of staphylococcal infections. Because of difficulties in administration and untoward reactions, it should be reserved for severe infections not expected to be improved by more conventional antimicrobials. Its action is apparently not consistently bactericidal. Side effects, the most serious of which is hematopoietic depression, are not infrequent, but are usually reversible and can be reduced by adherence to recommended dosage schedules. Preliminary data suggest that it may be used effectively in the shortterm therapy of enterococcal endocarditis. The assistance of Sue Fuller in preparation of the manuscript is acknowledged. REFERENCES
1. Abbott Laboratories: Spontin (Ristocetin, Abbott), 1958. 2. Anderson, R. C., Worth, H. M., Harris, P. N., and Chen, K. K.: Vancomycin, a New Antibiotic. IV. Pharmacologic and Toxicologic Studies; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 75-81. 3. Dangerfield, H. C., and others: Clinical Use of Vancomycin. Presented at Con· ference on Anti-Microbial Agents, Washington, D.C., October 27, 1960. 4. Dries, C. P., and Koch, R.: Ristocetin, a Laboratory and Clinical Evaluation in Children. 1- Pediat., 56:498, 1960. 5. Idem: Clinical Evaluation of Ristocetin in Children. A.M.A. J. Dis. Child., 99: 752, 1960. 6. Dries, C. P., Asay, L. D., and Koch, R.: Ristocetin in Serum Levels in Children; in Antibiotics Annual, 1958~1959. New York, Medical Encyclopedia, Inc., 1959, pp. 428, 431. 7. Ehrenkranz, N. J.: The Clinical Evaluation of Vancomycin in Treatment of Multi-antibiotic Refractory Staphylococcal Infections; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 587-94. 8. Finegold, S. M., and Gaylor, D. W.: Enterocolitis Due to Phage Type 54 Staphylococci Resistant to Kanamycin, Neomycin, Paromomycin, and Chloramphenicol. New England 1- Med., 263:1110, 1960. 9. Finland, M., and others: Panel Discussion: The Current Status of Erythromycin, Kanamycin, Novobiocin, Oleandomycin, Ristocetin, and Vancomycin, with Particular Reference to Their Use in Staphylococcal Disease; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 1051-72. 10. Gangarosa, E. J., Johnson, T. R., and Ramos, H. S.: Ristocetin-Induced Thrombocytopenia: Site and Mechanism of Action. A.M.A. Arch. Int. Med., 105:83, 1960. II. Garrod, L. P., and Waterworth, P. M.: Behaviour in Vitro of Some New An· tistaphylococcal Antibiotics. Brit. MI, 2:61, 1956. 12. Geraci, J. E.: The Antibiotic Therapy of Bacterial Endocarditis. M. Clin. North America, 42:1101, 1958. 13. Geraci, J. E., Heilman, F. R., Nichols, D. R., and Wellman, W. E.: Antibiotic Therapy of Bacterial Endocarditis. VII. Vancomycin for Acute Micrococcal 1<:ndocarditis: Preliminary Report. Proc. Staff Meet., Mayo Glin., 33:172, 1958
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14. Geraci, J. E., Heilman, F. R., Nichols, D. R., Wellman, W. E., and Ross, G. T.: Some Laboratory and Clinical Experiences with a New Antibiotic, Vancomycin. Proc. Staff Meet., Mayo Clin., 31:564, 1956. 15. Idem: Some Laboratory and Clinical Experiences with a New Antibiotic, Van· comycin; in Antibiotics Annual, 195()""1957. New York, Medical Encyclopedia, Inc., 1957, pp. 90-106. 16. Griffith, R. S., and Peck, F. B., Jr.: Vancomycin, a New Antibiotic. III. Pre· liminary Clinical and Laboratory Studies; in Antibiotics Annual, 1955-1956. New York, Medical Encyclopedia, Inc., 1956, pp. 619-22. 17. Grundy, W. E., Alford, E. F., Rdzok, E. J., and Sylvester, 1. C.: Ristocetin, the Development of Resistance and Bactericidal Activity; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 693~8. 18. Grundy, W. E., and others: Ristocetin, Microbiologic Properties; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 687-92. 19. Idem: Ristocetin, a Microbiological Comparison of Ristocetins A and B; in Anti· biotics Annual, 1957-1958. New York, Medical Encyclopedia, Inc., 1958, pp. 15~62. 20. Herting, R. L., Lees, B., Zimmermann, A. J., and Berryman, G. H.: Ristocetin: A Statistical Review of Three Hundred Thirty-Three Cases. l.A.M.A., 170: 176, 1959. 21. Higgins, H. M., Harrison, W. H., Wild, G. M., Bungay, H. R., and McCormick, M_ H.: Vancomycin, a New Antibiotic. VI. Purification and Properties of Vancomycin; in Antibiotics Annual, 1957-1958. New York, Medical Encyclopedia, Inc., 1958, pp. 906-14. 22. Hsie, J. Y., Nusser, W., Epstein, S., Van Maren, H., and Oxog, S.: Resistance to Ristocetin, Oleandomycin, and Novobiocin. Antibiotics 6 Chemother., 8:607, 1958. 23. Hwang, K., Primach, N., Stein, R. J., and Richards, R. K.: Pharmacological and Toxicological Properties of Ristocetins A and B; in Antibiotics Annual, 19571958. New York, Medical Encyclopedia, Inc., 1958, p. 163. 24. Kanner, I. F.: Ristocetin in the Cerebrospinal Fluid during Staphylococcal Meningitis; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 432~6. 25. Kirby, W. M. M.: Vancomycin; in H. Welch and M. Finland. 55 26. Kirby, W. M. M., and Divelbiss, C. L.: Vancomycin; Clinical and Laboratory Studies; in Antibiotics Annual, 1956-1957. New York, Medical Encyclopedia, Inc., 1957, pp. 107-17. 27. Kirby, W. M. M., Perry, D. M., and Bauer, A. W.: Treatment of Staphylococcal Septicemia with Vancomycin. New England J. Med., 262:49, 1960. 28. Kirby, W. M. M., Perry, D. M., and Lane, J. L.: Present Status of Vancomycin Therapy of Staphylococcal and Streptococcal Infections; in Antibiotics Annual, 1958-1959. New York, Medical Encyclopedia, Inc., 1959, pp. 580-86. 29. Knight, V.: The Staphylococcal Problem Today. J. Kentucky M.A., 56:1110, 1958. 30. Knight, V., White, A., and Hemmerly, H.: The Effect of Antibiotics on Staphy· lococci of Hospital Patients. Proceedings, National Conference on HospitalAcquired Staphylococcal Disease, Atlanta, Communicable Disease Center, U.S. Public Health Service, 1958. 31. Lee, C. C., Anderson, R. C., and Chen, K. K.: Tissue Distribution of Erythromycin in Rats. Antibiotics 6 Chemother., 3:920, 1953. 32. Idem: Vancomycin, a New Antibiotic. V. Distribution, Excretion, and Renal Clearance; in Antibiotics Annual, 19 56~ 1957. New York, Medical Encyclo· pedia, Inc., 1957, pp. 82-9. 33. McCormick, M. H., Stark, W_ M., Pittenger, G. E., Pittenger, R. C., and McGuire,1. M.: Vancomycin, a New Antibiotic. I. Chemical and Biologic Properties; in Antibiotics Annual, 1955~1956. New York, Medical Encyclopedia, Inc., 1956, pp. 606-11. 34. Pittenger, R. C., and Brigham, R. B.: Streptomyces Orientalis, n. sp., the Source of Vancomycin. Antibiotics 6 Chemother., 6:624, 1956.
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