Antimicrobial therapy in patients sensitive to penicillin

J. chron. Dis. 1967, Vol. 20, pp. 407- 428. Pergamon Press Ltd. Printed in zyxwvutsrqponmlkjihgfedcbaZ Great Britain ANTIM ICROBIAL THERAPY IN PATIENTS SENSITIVE TO PENICILLIN* zyxwvutsrqponmlkjihgfedcbaZYXWVUTS RICHARD H. WINTERBAUER,M.D., ALLAN R. RONALD, M.D., DONALD W . BELCHER, M .D. and MARVINTURCK, M .D. Department of Medicine,Universityof WashingtonSchool of Medicineand King County Hospital, Seattle, Washington (Received 21 December 1966) THE TREATMENTof infections in patients with suspected allergy to penicillin has become a very common and taxing problem in modern medical practice. [l-3] Unfortunately, the magnitude of this problem probably will increase in the future with the increasing use of semi-synthetic derivatives of 6-amino penicillanic acid, which have continued to make the penicillins the therapy of choice against an ever increasing number of pathogens. It is the purpose of this review to examine critically the currently available methods of treatment in patients sensitive to penicillin who have infections for which penicillin or one of its congeners is the drug of choice. Particular emphasis will be placed on assessing the efficacy of alternative antimicrobials which are not crossallergenic with penicillin. TREATMENT WITH PENICILLIN OR PENICILLIN ANALOGUES The clinical paradox of giving a penicillin to patients with suspected hypersensitivity to penicillin is obvious. However, there are a number of factors which make this a plausible consideration. Firstly, surprisingly few patients, allegedly hypersensitive to penicillin, react adversely when rechallenged with therapeutic doses of penicillin. Secondly, certain tests may be valuable in defining those persons likely to react unfavorably following rechallenge. Thirdly, hypersensitive patients may be “desensitized” to penicillin and finally, certain semi-synthetic penicillins may be less allergenic than others. Value of skin tests in predicting adverse reactions to penicillin It is well known that patients with suspected sensitivity to penicillin may subsequently receive full therapeutic amounts of the drug without untoward effects. This phenomenon was recently quantitated by BROWN,PRICEand MOORE[4] who observed that only 9 of 33 patients (27.3 per cent) with both a history of previous hypersensitivity and a positive penicilloyl-polylysine skin test had a reaction when rechallenged with penicillin. Almost 6 per cent of 344 patients with a negative history but positive skin test and 4 per cent of more than 500 patients with a positive history but negative skin *Supported by a Training Grant AI146-07of the United States Public Health Service. Reprint requests: King County Hospital, 325 9th Avenue, Seattle, Washington,98104(Dr. Turck). 407 408 RI-H. W INTERBAUER, ALLAN R. RONALD, DONALD W. BELCHER and hS.uwmTURCK test reacted unfavorably to rechallenge. However, there was only a 0.5 per cent reaction rate among 11,000 patients with both a negative history and skin test to penicilloyl-polylysine. It is evident from this study that skin testing is helpful in defining a group of patients who have a greater likelihood of developing hypersensitivity reactions. However, for each reactor to penicillin unmasked by skin testing, there will be a large number of “falsely” positive skin tests in persons who would not have an adverse reaction when given penicillin. Therefore, the widespread use of the skin test as a screening procedure would result in excluding from treatment with penicillin, many patients who might benefit from therapy with this drug. Certainly, positive skin tests in persons whose infection can be handled equally well with an alternative antimicrobial, which is not cross-allergenic with penicillin, are indications for use of the alternative agent. However, when patients with a positive skin test are seriously ill with infections best treated with penicillin, such as bacterial endocarditis, the use of this drug is by no means contraindicated. In these instances the necessity for penicillin must be weighed against the possibility of adverse reactions. False negative reactions to penicillin skin testing have been thought to be a much less common problem than false positive reactions. [5] However, a study of zyxwvutsrqponmlkjih IDSOE and WANG [6] in Formosa demonstrated negative scratch or intradermal tests prior to therapy in 16 of 22 patients who had anaphylactoid reactions to penicillin. zyxwvutsrqponmlkji Penicillin desensitization Desensitization to penicillin entails the parenteral injection of small, gradually increasing doses of penicillin at short intervals. Theoretically, this would accomplish gradual neutralization of circulating or cellular antibodies, and persons treated in this fashion could subsequently be given full doses of penicillin without untoward effect. [7-131 The first patients in whom penicillin desensitization was successful were reported by PECK and associates [7, 81 in 1948. Desensitization was accomplished in 6 of 7 patients receiving subcutaneous injections of gradually increasing doses of penicillin and in an eighth patient who received graded doses of oral penicillin. Tolerance to therapeutic doses of penicillin, however, was accomplished only after weeks to months of treatment. In more recent years penicillin desensitization has been completed in 8-24 hr [9, 1l-l 31 and therapeutic doses of penicillin were then given in full dosage. Proper evaluation of penicillin desensitization has been hampered by the small number of patients treated and the marked unpredictability of the natural history of penicillin allergy. Since many patients sensitive to penicillin do not experience adverse reactions when rechallenged without antecedent desensitization, the fallacy of judging the efficacy of desensitization by observing whether adverse effects occur upon rechallenge is obvious. In addition, the procedure is not innocuous and at least one documented case of accelerated serum sickness, laryngeal edema and death during penicillin desensitization [I 31 has been reported. Until desensitization has been shown more clearly to result in a decrease in serum antibody titers or a loss of skin testing reactivity, it remains a procedure of dubious value to ameliorate the allergic state. Administration of antihistamines or steroids The efficacy of antihistamine and/or steriod prophylaxis in penicillin sensitivity is controversial. MASLANSKY and SANGER[14] noted a very low incidence (0.11 per cent) of reactions in 897 patients injected with a combination of 10 mg chlorphenira- Antimicrobial Therapy in Patients Sensitive to Penicillin 409 mine maleate and 400,000 units of aqueous penicillin G. An additional 11 patients with known penicillin sensitivity received similar injections and only one allergic reaction occurred. However, the controlled studies of SCIPLE, KNOX zyxwvutsrqponmlkjihgfedcbaZ and MONTGOMERY[15] and MATTHEWSand associates [16] involving a total of more than 6000 subjects failed to show any protective effect of antihistamines on the incidence of penicillin reactions. The protective effect of glucocorticoids has been reported by several authors. [13, 17-191 This evidence consists almost entirely of a number of isolated case reports and is subject to the criticisms and reservations mentioned previously with regard to desensitization. The ability of glucocorticoids, however, to control delayed type hypersensitivity reactions such as urticaria and erythematous maculopapular cutaneous reactions appears well documented in these reports. zyxwvutsrqponmlkjihgfedcbaZYX [l 1, zyxwvutsrqponmlkjihgfedcbaZ 12, 18, 191 However, the value of glucocorticoids as prophylaxis against anaphylactic reactions remains dubious. Animal experiments indicate that steroids have no protective affect against anaphylaxis [20] and, in addition, BERNSTEINand LUSTBERG[21] have reported a patient with penicillin induced anaphylaxis who was taking 15 mg/day of prednisolone for rheumatoid arthritis. The paucity of information available allows few conclusions to be drawn. However, at this time, reliance on either antihistamines or steroids to prevent severe penicillin reactions in patients sensitive to penicillin is untenable, and like desensitization, this manoeuver should be used only in the rare instance in which no adequate alternative antimicrobial is available. Treatment with semi-synthetic penicillins Modification of the side chain attached to the 6-amino penicillanic acid nucleus has produced multiple new semi-synthetic penicillins. The appearance of each new penicillin has served to rekindle the hope for finding a penicillanic acid derivative which is not cross-allergenic with penicillin. However, the sensitizing antigen of benzylpenicillin appears to be penicillanic acid and/or penicilloyl which are breakdown products of the 6-amino penicillanic acid nucleus. [22, 231 Therefore, variation in the side chain would be expected to have little effect on decreasing the cross-allergenicity between benzylpenicillin and other derivatives containing the 6-amino penicillanic acid nucleus. [23, 241 VANARSDELand O’ROURKE [25] studied the in vitro cross-reactivity between benzylpenicillin, methicillin and oxacillin by measuring the ability of sera from penicillin sensitive patients to agglutinate erythrocytes sensitized with methicillin and oxacillin. Of the nine sera tested, eight reacted with oxacillin and seven with methicillin. SCHWARTZand VAUGHAN[24] reported that 28 of 41 sera from patients sensitive to penicillin G reacted with erythrocytes sensitized to methicillin. In addition, crossreactivity has been shown by positive skin testing to methicillin, phenethicillin, and penicillin 0 in patients sensitive only to penicillin G. [23, 24, 26, 271 Ampicillin also causes cross-reacting positive skin tests in patients sensitive to penicillin G. [26, 281 Additional evidence for cross-reaction among the penicillins comes from reported cases of drug allergy in patients sensitive to penicillin when they were given phenethicillin or methicillin. [29, 301 BUNN [31] has shown that determining the titers of circulating antibodies by hemagglutination tests has been of no practical clinical value and the mere presence of circulating antibody to penicillin G does not predict the development of a reaction to another penicillin. Although cross-allergenicity between 410 RICHARD H. WINTERBAUER, ALLANR. RONALD, DONALD W. BELCHBR and MARVINTURCK 6-amino penicillanic acid derivatives appears well established, the actual frequency of adverse reactions developing when semi-synthetic penicillins are given to a patient sensitive to penicillin G remains to be clarified. LUTON [31, 321 reported 8 patients, each with a history of penicillin induced anaphylaxis, positive penicillin skin test, and negative methicillin skin tests, who had no reactions when challenged with 1 g of methicillin intramuscularly. This study indicated that some fraction of patients sensitive to penicillin could safely be treated with semi-synthetic penicillins and that skin testing might be an effective tool for delineating these individuals. However, until these issues are more clearly resolved it seems wise to regard the administration of semi-synthetic penicillins to patients sensitive to penicillin as potentially as dangerous as giving benzylpenicillin zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF per se. ALTERNATIVE ANTIMICROBIAL THERAPY In general, then, substitution of an equally effective antimicrobial, which is presumably not cross-allergenic with penicillin, is the recommended treatment for infection in patients sensitive to penicillin. The discussion to follow lists the infections commonly treated with penicillin and analyzes the therapeutic efficacy of alternative antimicrobials. With the possible exception of cephalothin, all antibiotics to be discussed do not share cross-sensitization with penicillin. Whether cross-sensitization exists between cephalothin and penicillin is unresolved at present. Cephalothin is a semi-synthetic derivative of cephalosporin C which has a chemical structure similar to the penicillins. However, cephalothin has a 6-membered dihydrothiazine ring in place of the 5-membered thiazolidine ring in the penicillins. It was hoped that the chemical dissimilarity between the two antibiotics would preclude cross-sensitization. Preliminary reports by GRIFFITHand BLACK [33] and WEINSTEIN,KAPLANand CHANG [34] indicated that cephalothin could be given to patients sensitive to penicillin without adverse reaction. However, subsequently 2 case reports have appeared of anaphylactic reactions in patients sensitive to penicillin following their initial exposure to cephalothin. [35, 361 MERRILL and co-workers [37] observed 9 hypersensitivity reactions among 22 patients sensitive to penicillin treated with cephalothin, in contrast to 5 reactions in 34 patients zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE with no history of penicillin allergy who were given the drug. Transient eosinophilia was the most common reaction. PERKINSand SASLAW[38] treated 12 patients allergic to penicillin with cephalothin and one developed a diffuse maculopapular eruption on the second day of therapy. Skin testing of 30 patients with documented penicillin sensitivity revealed cross-reactivity to cephalothin in only one instance. However, animal experimentation by BATCHELOR and associates [39] showed that antibodies produced in response to cephalothin bovine gamma globulin conjugates cross-reacted with benzylpenicillin. In addition, anaphylactic shock was elicited by the intravenous injection of a cephalothin polylysine conjugate into guinea pigs sensitized to benzylpenicillin. For the purpose of this review, cephalothin is discussed as an alternative antimicrobial for patients sensitive to penicillin but it should be emphasized that some patients sensitive to penicillin are also likely to have adverse reactions with cephalothin. The magnitude and severity of this problem remains to be defined. Pneumococcal infections Tetracycline, chloramphenicol, lincomycin, erthromycin and cephalothin have all Antimicrobial Therapy in Patients Sensitive to Penicillin 411 been shown to be effective in the treatment of pneumococcal infections. The availability of several alternative antimicrobials permits considerable leeway in making a selection, and the reported experience with each drug, the incidence of toxic side effects and ease of administration should be considered in arriving at a decision. On the basis of clinical trails and in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA vitro laboratory tests, erythromycin and cephalothin are acceptable alternative antimicrobials for treatment of pneumococcal infections in patients sensitive to penicillin. Oral erythromycin is a well absorbed bacteriostatic antibiotic with minimal toxic side effects. One-half gram taken by mouth yields serum levels between 5 and 20 ug/ml. [40] Most strains of pneumococci are inhibitied by 0.1 ug/ml. [41] Cephalothin on the other hand, is a bactericidal antibiotic which must be given parenterally. In dosage of 1 .O g, peak blood levels of 10-20 ug/ml are achieved, an ample excess because the pneumococci are inhibited by concentrations of 0.1 ug/ml or less. [42-44] The advantages of high blood levels, bactericidal action, and lack of dose related toxicity, make cephalothin the drug of choice in severe pneumococcal infections. In 1964 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI KIRBY [44] reviewed the clinical experience with cephalothin. Included in the 484 infections treated with cephalothin, were 76 patients with pneumococcal pneumonia. Seventy-four of the 76 were cured. More recently TURCKand associates [43] reported 26 cases of pneumococcal pneumonia treated with cephalothin. Twenty-one of the 26 patients improved and failure was not related to the drug’s inability to eradicate the organism but was due to associated illnesses, such as pulmonary malignancy. The reported clinical experience with cephalothin in pneumococcal pneumonia currently totals over 100 patients; good therapeutic results accompanied by relatively few serious side effects have been observed consistently. The drug however, causes considerable irritation at the site of injection and a predisposition to gram-negative bacterial superinfection has been noted by several authors. [37, 431 There have been multiple clinical trials and considerable experience with erythromycin in the treatment of pneumococcal pneumonia. In 1953 AUSTRIAN and ROSENBLUM [45] reported 50 patients with pneumococcal pneumonia who were treated with 1.6 g/day of oral erythromycin. The authors concluded that in these patients oral erythromycin was as effective as parenteral penicillin. WADDINGTON, MAPLE and KIRBY [41] reported a prompt therapeutic response to oral erythromycin in 80 per cent of 75 patients with pneumococcal pneumonia, 11 of whom had a concomitant bacteremia. Only one death was actually attributable to the infection, and toxic side effects of erythromycin in this series consisted of gastrointestinal irritation in only one patient. HILL and associates [46] reported 64 patients moderately to severely ill with pneumococcal pneumonia who were treated with oral erythromycin. Therapy was judged successful in 62 patients. There were no deaths and no toxic side effects were attributable to the drug. ROMANSKY and co-workers [47] reported a favorable clinical response to erythromycin in 199 of 213 patients with pneumococcal pneumonia. These studies clearly indicate erythromycin’s excellent therapeutic effect and low incidence of toxic side reactions in patients treated for pneumococcal pneumonia. Lincomycin is another adequate alternative to penicillin for the treatment of pneumococcal pneumonia. Thirty-six of 40 patients with uncomplicated pneumonia reported by HOLLOWAYand SCOTT [48] responded well to 500 mg of lincomycin given orally or parenterally every 6 hr. TURCK and PETERSDORF[49] treated 20 patients with pneumococcal pneumonia, three of whom had concomitant bacteremia, with 2 g/day 412 RICHARDH. WINTERBAUER, ALLAN R. RONALD, DONALD W. BELCHER and MARVIN TURCK of oral lincomycin. Eighteen of 20 patients showed rapid clinical improvement and prompt defervescence. Under most circumstances one of the tetracyclines has provided adequate therapy for pneumococcal pneumonia. [50, 511 However, there have been recent reports of treatment failures in patients with infections caused by pneumococci resistant to tetracycline. [52-551 In addition, JACKSONand associates [50] noted a significant incidence of staphylococcal intestinal superinfection in patients with pneumococcal pneumonia treated with oxytetracycline. Although the occurrence of either tetracycline induced superinfection or primary infection with pneumococci resistant to tetracycline is relatively unusual, safer, more reliable therapy for pneumococcal infection is available. Chloramphenicol also has been effective in the treatment of pneumococcal infections. However, the attendant risk of bone marrow depression and irreversible aplastic anemia or pancytopenia would seem unwarranted when several other, equally efficacious, agents are available. [56] Considerable clinical experience has been accumulated with chloramphenicol in patients with pneumococcal meningitis. In this infection, the life-threatening character of the infection as well as lack of sufficient clinical trials with tetracycline, lincomycin, erythromycin or cephalothin make chloramphenicol an acceptable alternative to penicillin. PARKERand associates [57] reported a mortality rate of only 18 per cent in 17 patients with pneumococcal meningitis treated with chloramphenicol. An additional 19 patients have been treated subsequently with only one reported fatality. [58] The clinical experience with erythromycin in pneumococcal meningitis consists of 14 patients, [47, 59, 601 only five of whom responded favorably to the drug. The experience with cephalothin in pneumoccocal meningitis is even more limited. PERKINSand SASLAW[38] recently reported a patient with pneumococcal pneumonia, bacteremia and meningitis who responded dramatically to cephalothin therapy. Simultaneous serum and spinal fluid levels obtained 30 min after a 1 g intramuscular dose were 20.7 and 1.75 pg/ml respectively. The minimum bactericidal concentration for the infecting pneumococcus was 0.19 pg/ml. However, TURCKand co-workers have reported a patient with pneumococcal pneumonia, and bacteremia who developed pneumococcal meningitis after 36 hr of therapy with cephalothin. [43] Until more clinical data with cephalothin becomes available, chloramphenicol probably will remain the most reasonable alternative for penicillin in the treatment of pneumococcal meningitis. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC Streptococcal infections The treatment of streptococcal pharyngitis with oral penicillin results in eradication of streptococci in 85-90 per cent of patients, and retreatment of therapeutic failures will increase the cure rate to over 95 per cent. [61] Therapeutic trials with oral erythromycin, or lincomycin have produced results similar to those seen in patients treated with penicillin. In a series of 208 patients with scarlet fever, HAIGHT [62] reported identical clinical responses in groups receiving 1.2 g of oral erythromycin or 600,000 units of parenteral procaine penicillin daily. The antistreptolysin 0 titer rose in 14 per cent of patients treated with erythromycin and 10 per cent treated with penicillin while 60 per cent in the placebo group had elevations in antistreptolysin 0 titers. STILLERMAN and associates [63] have demonstrated in vitro that 98 per cent of group A beta hemolytic streptococci were inhibited by 0.012 pg/ml of penicillin V AntimicrobialTherapy in Patients Sensitiveto Penicillin 413 while only 61 per cent were sensitive to a similar concentration of erythromycin. However, even with erythromycin the minimal inhibitory concentration of all strains was less than 0.1 pg/ml, and eradication of the organism from the nasopharynx was accomplished in 78 per cent of 86 patients with streptoccocal pharyngitis treated with erythromycin propionate in dosage of 30 mg/kg/day. A dose of 750 mg/day of oral penicillin V, resulted in a bacterial cure rate of 88 per cent in 73 patients. With erythromycin estolate, which is absorbed better than the propionate, MOFFETand co-workers [64] demonstrated that erythromycin and phenoxymethyl penicillin (penicillin V) were equally effective in the treatment of streptococcal pharyngitis. Indeed, second episodes occurring within 60 days were more common after phenoxymethyl penicillin than erythromycin therapy. A limiting factor with erythromycin., however, is lack of a suitable injectable preparation which is free from severe discomfort and irritation. Lincomycin has been effective in zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJI vitro against streptococci and a recent large study showed that the organisms were eradicated from the throats of 93 per cent of patients treated with this drug. [65, 661 The only side effect was mild diarrhea in 10 per cent of patients treated with lincomycin. The results suggest that lincomycin is an acceptable alternative to erythromycin for patients sensitive to penicillin who can be treated with an oral preparation. Furthermore, the parenteral preparation of lincomycin appears to be tolerated well. [65] Tetracycline is therapeutically inferior to both erthyromycin and lincomycin in the treatment of streptococcal infections. KUHARIC,ROBERTSand KIRBY[67] reported that 20 per cent of hospital isolates of group A streptococci were resistant to tetracycline. It has been suggested that prolonged usage of tetracycline, particularly in hospitalized patients, may be important in inducing these tetracycline resistant strains. [68, 691 Even when used against susceptible strains, tetracycline fails to eradicate the organisms from the nasopharynx in 50 per cent of patients with streptococcal pharyngitis. [61] In severe streptococcal infections requiring parenteral therapy either cephalotin or lincomycin should give excellent results. [43, 44, 651 Prophylaxis against streptococcal pharyngitis in patients with rheumatic fever requires that any alternative to penicillin be well tolerated for prolonged periods. STAHLMANand DENNY [70] followed 50 patients who were taking either 0.5 g of sulfadiazine or 100 mg of erythromycin twice daily prophylactically for an average of 19 months. Only one patient receiving erythromycin developed a positive culture for group A beta hemolytic streptococci while seven of the patients given prophylactic sulfadiazine had positive cultures and one developed a recurrence of rheumatic fever. zyxwvutsrqp WOOD and associates [71] compared the efficacy of three different prophylactic programs used against streptococcal infections in 431 patients who were observed for a total of 1681 patient-years. Benzathine penicillin in dosage of 1.2 million units IM every 4 weeks was the most effective regimen. However, 1 g/day of oral sulfadiazine was as effective as 200,000 units/day of oral penicillin G in preventing streptococcal infections and recurrences of acute rheumatic fever. Erythromycin and sulfonamides are both tolerated well for prolonged periods. The rare instance of intraphepatic cholestatic jaundice in association with erythromycin estolate appears to be a hypersensitivity phenomenon and is not related to prolonged use of the drug. [72] Both erythromycin and sulfadiazine provide equally potent antistreptococcal prophylaxis H. 414 RICHARD WINTERBA~ER, ALLANR. RONALD, DONALD W. BELCHER and ~~ARVIN TURCK but sulfadiazine has the important advantage of being much cheaper. Lincomycin has not been evaluated in long term prophylaxis of streptococcal infections. Lancefield group D streptococci (enterococci) are common pathogens in urinary tract infections and bacterial endocarditis. These organisms may be resistant to multiple antimicrobials and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIH in vitro sensitivity tests should be used to select the appropriate drug. Both chloramphenicol and erythromycin are often suitable alternatives to penicillin or ampicillin for most enterococcal urinary tract infections. Enterococcal endocarditis will be discussed separately. Streptococci, other than group A or D, have been associated with meningitis, urinary tract infection, bacterial endocarditis and a variety of localized suppurative processes. [73] The majority are susceptible to erythromycin. [73, 741 Staphy lococcal infections The majority of staphylococcal infections consist of minor illnesses such as carbuncles, paronychia, and other skin and soft-tissue infections. These are usually acquired outside the hospital environment, and the organisms are sensitive to multiple antibiotics. [75] For example, over 90 per cent are sensitive to erythromycin and extensive clinical trials have demonstrated this drug to be quite effective in the treatment of staphylococcal infections. [47, 72, 75-781 SMITH and SODERSTROM [78] obtained a good therapeutic response in 43 of 46 patients with staphylococcal pustular acne, furuncles, carbuncles and pyodermas, who received erythromycin propionate in dosages of l-l .5 g/day. KIRBY, FORLANDand MAPLE [76] reported excellent clinical results in 22 patients treated with erythromycin for staphylococcal soft tissue infections. More recently lincomycin also has been demonstrated to be an effective antistaphylococcal drug. [48, 65,791 Of particular interest is the report by MACLEODand associates [81] that 95.2 per cent of 1055 hospital staphylococcal isolates were susceptible to lincomycin while only 43.1 per cent were susceptible to erythromycin. However, staphylococci made resistant to erythromycin in vitro may simultaneously become resistant to lincomycin and the degree of cross-resistance between the two drugs needs further clarification. [82] Sensitivity testing may be necessary, even for the proper management of minor staphylococcal infections, since some organisms will be resistant to either or both erythromycin and lincomycin. More severe staphylococcal infections arising in patients sensitive to the penicillins, such as pneumonia, meningitis, acute osteomyelitis or bacteremia must be treated immediately with an antibiotic to which the organisms are predictably sensitive, such as vancomycin and cephalothin. Both agents have been studied extensively in the laboratory and clinically. Virtually all staphylococci are sensitive to 5 pg/ml or less of vancomycin and to 2 pg/ml or less of cephalothin [43, 831. Peak blood levels of 10-20 pg are usually attained following 1 g of either drug. [42, 841 KIRBY,PERRYand BAUER[85] reported a 60 per cent survival in 33 patients with staphylococcal bacteremia treated with vancomycin; these results are comparable with the 70 per cent survival rate in patients with severe staphylococcal infections treated with methicillin. [86, 871 Other investigators also have found vancomycin to be effective in severe staphylococcal infections. [88,89] In a review of 65 cases of staphylococcal pneumonia or bacteremia treated with cephalothin, KIRBYreported a mortality rate of 34per cent. [44] Three more recent reports have described a total of 59 patients treated with cephalothin for severe staphylococcal infections. [37, 38,431 There was a 19 per cent Antimicrobial Therapy in Patients Sensitive to Penicillin 415 mortality rate in this group. The recommended dose of cephalothin for serious infections is 1 g every 4 hr. Vancomycin is administered as an intravenous infusion over a period of 30 min in 1 g doses every 12 hr diluted in 100 ml of 5 per cent dextrose in water. The dose and duration between administrations should be reduced in the presence of renal insufficiency. Side effects include phlebitis at the site of injection, urticaria, chills and fever, and rashes. These can be managed symptomatically and usually do not make it necessary to discontinue the drug. However, the difficulties associated with the administration of vancomycin have made cephalothin the preferred drug in serious staphylococcal infections in patients who cannot be given a penicillin. Staphylococcal enterocolitis and chronic osteomyelitis deserve special mention. zyxwvutsrqp KIRBY and associates [76] reported nine patients with chronic osteomyelitis, eight of whom responded promptly to oral erythromycin. The single therapeutic failure was attributed to the development of resistance to erythromycin. Erythromycin was used in four additional patients with osteomyelitis. [77] Two of the patients were cured, and again one of the failures was associated with the development of resistance to erythromycin by the infecting organism. Lincomycin reportedly has been particularly effective in chronic staphylococcal osteomyelitis. [48,80, 811 This drug has an affinity for bone and for this reason may be peculiarly suitable for the treatment of osteomyelitis. In addition, it may be effective against staphylococcal L forms and protoplasts which have been incriminated as possible pathogenetic determinants in persistent staphylococcal infection. [90] Staphylococcal enterocolitis may be adequately managed with oral erythromycin, neomycin, kanamycin or vancomycin. One half gram of vancomycin diluted in 30 ml of fruit juice administered every 6 hr will cure most cases of staphylococcal enterocolitis in 48-72 hr. [91] zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Bacterial endocarditis The penicillins are superior to all antimicrobials in the treatment of endocarditis caused by organisms sensitive to penicillin. Experience with other antibiotics is quite limited and the guidelines for alternative therapy are poorly defined. In this situation, disc diffusion sensitivity tests must not be used to select alternative antimicrobials. The alternative drug should be bactericidal at blood levels which can be readily achieved in vivo, and ideally the serum bactericidal activity should be measured during therapy. [92] In selecting alternative drugs for patients with endocarditis, it is important to emphasize that the response of individual patients with this infection is not applicable in general terms, and that the antibiotics selected must be tailored zyxwvutsrqponm to fit both the organism and patient. It is equally important to be aware of the fact that the initial clinical response in patients with bacterial endocarditis may not be used to prognosticate the outcome. Not infrequently patients with endocarditis will improve and blood cultures will become sterile while organisms persist in the vegetations and. valve destruction occurs. Bacteriostatic drugs such as erythromycin, chloramphenicol, or the tetracyclines should never be used alone in the treatment of endocarditis because many patients relapse when therapy is discontinued. [93-951 Combinations of these drugs sometimes produce a synergistic bactericidal effect and have been used successfully in several small series. JAWETZ and BRAINERD [96] cured three patients with staphylococcal 416 RICHARDH. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA WINI-ERBAUER,ALLAN R. RONALD, DONALD W. BELCHERand MARVIN TURCK endocarditis with various combinations of bacitracin, chloramphenicol, streptomycin, tetracycline and erythromycin. JONESand Yow [97] successfully treated five of six patients with zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Streptococcus viridans endocarditis with streptomycin and erythromycin. At present vancomycin appears to be the drug of choice in the treatment of staphylococcal endocarditis in patients who are unable to tolerate methicillin. GERACI, NICHOLSand WELLMAN[98] reported a cure rate of 74 per cent in 19 patients with staphylococcal endocarditis, results comparable to those attained with methicillin. [86] To date there are only limited reports on the use of vancomycin in the successful treatment of Streptococcus viridans or enterococcal endocarditis and no reports of its use in pneumococcal endocarditis. [99] However, on the basis of in vitro bactericidal sensitivity tests, this drug should provide effective therapy. HERRELL,BALOWSand BECKER[lOO] have compared the antibacterial activity of streptomycin in combination with either cephalothin or penicillin against viridans streptococci. They found that cephalothin and streptomycin had bactericidal activity equal to penicillin and streptomycin. In a recent review of the literature, KIRBY [44] reported cures of four patients with Streptococcal viridans endocarditis and six patients with staphylococcal endocarditis who were treated with cephalothin. The only two patients with enterococcal endocarditis treated with this drug failed to respond. In addition in subsequent reports, cephalothin was used in two patients with staphylococcal endocarditis, one of whom was cured, and in single patients with Streptococcal viridans and microaerophilic streptococcal endocarditis both of whom were cured. [37] While vancomycin and cephalothin are satisfactory alternatives for penicillin in the treatment of endocarditis due to Streptococcus viridans, microaerophilic streptococci and staphylococci, treatment of enterococcal endocarditis in patients sensitive to penicillin and ampicillin is much more difficult. The only reported cure of enterococcal endocarditis using alternative therapy consists of a single patient treated with vancomycin. [99] While ristocetin has been used successfully, this drug has not been consistently effective, is quite toxic and is no longer commercially available in this country. [IOI, 1021 Effective and safe alternative antimicrobials are so sparse, that in enterococcal endocarditis, penicillin “desensitization”, or administration of steroids concomitantly with a penicillin, should be undertaken, Syphilis Erythromycin, tetracycline and chloramphenicol have all been effective in the treatment of syphilis but optimal dosage schedules particularly for therapy of latent, cardiovascular and central nervous system syphilis have not been established. This is related in part to the fact that assessment of therapeutic efficacy in syphilis requires prolonged follow-up with multiple serologic and cerebrospinal fluid examinations. [IO31 This type of study is difficult to institute because most patients attending city venereal disease clinics are notoriously unreliable. Indeed the instability of the patient population with venereal disease is an important reason for selecting penicillin as the drug of choice for syphilis and gonorrhea. Erythromycin has a marked treponemicidal effect and has been used successfully in treating early syphilis when given orally in a total dosage of 15-20 g over a IO-day period. [104-1901 Patients with darkfield positive lesions regularly convert to a darkfield negative state within 2448 hr after treatment is instituted. In 1961 MONTGOMERY Antimicrobial Therapy in Patients Sensitive to Penicillin 417 and associates [105] reported the results of erythromycin therapy in 148 darkfield positive patients with primary and secondary syphilis. Varying doses of erythromycin were used and the authors found that 2 g/day of erythromycin for 10 days resulted in only 5 per cent of the group requiring retreatment at the end of 6 months. These results compare with those obtained with penicillin. [ 1031 BROWNand associates [ 1071 noted a 12.5 per cent retreatment rate in 313 patients with darkfield positive syphilis treated with 15-20 g of erythromycin, compared to a 48 per cent retreatment rate in patients who received only 10 g of the drug. Patients with seropositive early syphilis have been shown by CORDERO[106] to convert to seronegativity with 6 months after therapy with erythromycin. Syphilis treated during pregnancy requires a total dose of at least 30 g of erythromycin given over a 15-day period. SOUTH,SHORTand KNOX [l IO] recently reported a case of congenital syphilis occurring in the fetus of a mother with secondary syphilis who received a total of only 15 g of erythromycin. The higher dosage necessary to protect the fetus reflects the drug’s poor penetration across the placenta. Three successfully treated cases of syphilis in pregnancy have been reported when 30 g of erythromycin were used. [ 1061 The infants appeared normal at birth and showed no evidence of active prenatal syphilis. There is no valid reason why erythromycin would not be adequate therapy for latent and tertiary lues, but clinical trials are virtually non-existent and dosage schedules are necessarily arbitrary. zyxwvutsrqponmlkjih [l 1 zyxwvutsrqponmlk l] With tetracyclines, darkfield negativity can be achieved within 2448 hr after administration and patients with early syphilis regularly become seronegative within one year’s time after treatment with at least 30 g given for 10 days. [104, 112-I 161 RODRIQUEZand co-workers [113] found that 66 per cent of 101 cases of secondary syphilis treated with 70 g of chlortetracycline, administered over a 1Zday period were seronegative 15 months after treatment. Seven patients became pregnant after treatment and none delivered a fetus with active luetic infection. Over-all, 76 per cent of patients treated with chlortetracycline had a satisfactory therapeutic response compared to an 86 per cent cure rate in 159 patients treated with 4.8 million units of penicillin parenterally. [113] TAGGART,ROMANSKYand LANDMAN[114] treated 85 patients with primary or secondary syphilis and 43 with early latent syphilis with different dosages of chlortetracycline. It was concluded that 60 mg/kg/day of chlortetracycline for 8 days produced therapeutic results similar to those following the use of intramuscular penicillin. There is a total of 21 reported patients with neurosyphilis who have been treated with tetracycline. [I 13, 1171 Eighteen of the 21 have shown an excellent response to 60-70 g of oral chlortetracycline given for 2-3 weeks. Chloramphenicol in a dose of at least 60 mg/kg/day for 8 days also constitutes effective therapy for early syphilis. [114, 1161 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSR Gonococcal infections Erythromycin in dosage of 0.5 g orally every 6 hr for 24 hr has been reported curative in 85-90 per cent of patients with gonococcal urethritis. [ 1181 More refractory infections such as the gonococcal carrier state and gonococcal prostatitis require at least a 3-day course of 2 g of erythromycin daily. Patients who cannot be relied upon to take medication can be given 2 g of erythromycin orally as a single dose at the time of diagnosis. Over 90 per cent of patients with acute gonococcal urethritis are cured with this regimen. [119] However, there is a significant incidence of severe gastrointestinal symptoms after such a large single dose. Clinical trials with tetracycline have shown it to be a suitable alternative for penicillin in the treatment of gonococcal infections. [118] However, THAYERand associates [120] have recently reported the development of increased gonococcal resistance to tetracycline and only 50 per cent of the strains tested were sensitive to less than 1 .O pg/m.l. In contrast, gonococci resistant to erythromycin have not been observed as yet and gonococci are uniformly susceptible to less than 0.05 pg/ml of this drug. [120-1223 For this reason, ery~romy~n is presently the number one alternative to penicillin in the treatment of these infections. Cephalothin is bactericidal for gonococci in concentration easily obtained with standard dosage but the drug is excreted rapidly and measurable blood levels are not found after 4 hr. 1431 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE LUCASand associates 11231obtained a very poor thera~utic response in 56 patients with gonococcal urethritis treated with a single 2 g injection of cephalothin. The rapid excretion of the drug probably accounted for the poor results because it has been shown in vitro that sterilization of gonococcal cultures requires m~ntenan~ of the antibiotic concentration above the org~isms’ bactericidal level for at least 30 hr. [124] Cephalothin, however, would be an excellent alternative for gonococcal arthritis and endocarditis which require continued parenteral therapy. More recently, cephaloridine, another cephalosporin C derivative, which is excreted more slowly than cephalothin, has appeared promising in the treatment of gonorrhea in out-patients. [125] Chloramphenicol is also effective but should be reserved for more serious gonococcal infections. ~enin~ococcul infections In view of the rising incidence of meningococci resistant to sulfonamides, these drugs no longer can be considered acceptable substitutes for treatment of meningococcal infections. 11261281 ~hloramphe~col and tetmcycline both have antibacterial activity in v&o against all strains of meningococci. [126, 1291 PARKERand associates effected cures in 48 of 49 patients with meningococcal meningitis treated with chloramphenicol. [57] Chloramphenicol in a dose of 1 g every 6 hr will provide adequate therapy for meningococc~ infection in patients sensitive to ~~cillin. The treatment ofasymptomatic meningococcal carriers and prophylaxis of contacts, poses a more diflicult problem. Sulfadiazine in a dose of 2 g/day for 3 days eradicates sensitive meningococci from the nasopharynx 90 per cent of the time. However, there is no known etfective drug prophyl~is for treatment of contacts or carriers when outbreaks are due to meningococci resistant to sulfonamides. [130, 1311 Prophylactic sulfonamides should, therefore, be reserved for outbreaks due to sensitive organisms but may be used as interim prophylaxis until the antibiotic susceptibility of the infecting meningoco~us has been determined. Clostridial infections Antibiotic therapy in clostridial infections serves the dual role of eradicating the bacilli and preventing further production of toxin. In 1950 BLISS, WARTH and CHANDLER [132] demonstrated the antibacterial potency of tetracycline against Clostridium tetani in vitro. Mice injected subcutaneously with a 100 lethal doses of ~~ostridi~ tetani spores had zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE 100per cent survival rates when given oxytetracycline, in dosage of IO mgfkg, as late as 6 hr after bacterial challenge while chloramphenicol in a dosage of 25 mg/kg conferred only 80 per cent protection. [132] Subsequently, Antimicrobial Therapy in Patients Sensitive to Penicillin 419 zyxwvutsr KISER and associates [133] and ANWAR and TURNER [ 1341 have substantiated the efficacy of tetracyclines against zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF Clostridium tetani and, in particular, have pointed out the greater bacteriostatic activity of tetracycline when compared to chloramphenicol. Although there has been no clear-cut substantiation of tetracycline’s efficacy in clinical tetanus, it is not really clear whether any antibiotic including penicillin effects the prognosis of this disease favorably. [135, 1361 However, the experimental evidence suggests that a tetracycline in dosage of 2 g/day will give comparable results to penicillin in the treatment of clinical tetanus and it is certainly reasonable to employ the drug in patients who give a history of penicillin allergy. The same dose of tetracycline for 5 days also should provide effective antimicrobial prophylaxis against clostridial infection in non-immunized patients with a traumatic injury. These patients should also be given human antitoxin and should be immunized actively at a later date. The use of antibiotics without tetanus antitoxin has been advocated but should be avoided unless there is evidence of hypersensitization to antitoxin. [137, 1381 Other infections due to clostridial species, which require prompt administration of an effective antimicrobial include cellulitis, myonecrosis, gas gangrene, uterine infections, usually following septic criminal abortion, cholecystitis and septicemia. [139] Penicillin is preferable but if an allergic history interdicts its use, other agents should be selected. Clinical experience is scanty and most data consists of in vitro tests and animal experimentation. In 1950, ALTEMEIER[140] demonstrated that eight strains of Clostridium welchii were sensitive to chlortetracycline in vitro: three of these strains were resistant to chloramphenicol. The protective action of chloramphenicol and tetracycline in guinea pigs injected with varying amounts of Clostridium welchii was identical and both were as effective as penicillin. The susceptibility of Cfostridium welchii, septicum, and novyi to tetracycline in vitro, and the drug’s value in the prophylaxis of these infections, has been documented in several studies. [132, 133, 141, 1421 In 1954, LINDBERGand NEWTON[143] reported the antibiotic sensitivity of 507 strains of clostridia isolated from Korean war casualties. Tetracycline was found to be a more effective inhibitor of clostridial growth than either penicillin or chloramphenicol. Eighty-four per cent of strains isolated from wounds and 18.5 per cent of strains cultured from soil and clothing were inhibited by 0.35 ug/ml of chlortetracycline. Lincomycin, erythromycin and cephalothin have not been evaluated adequately in the treatment of histotoxic clostridial infections. Listeriosis Listeria monocytogenes has become a well recognized human pathogen causing meningitis, bacteremia, granulomatosis infantiseptica, conjunctivitis and, rarely, endocarditis. [144-1461 In the antibiotic era virtually all patients with listeriosis have been treated with penicillin alone or a combination of antimicrobials including penicillin. [144, 146-1521 On the basis of these clinical trials penicillin is listed in medical textbooks as the drug of choice in the treatment of listeria infections despite the fact that the mortality from these infections is almost 40 per cent, and that considerable evidence exists indicating considerable in vitro resistance to penicillin of many Listeria monocytogenes. [145, 151, 153, 1541 In 1944 FOLEY, EPSTEINand LEE [I531 reported the in vitro susceptibility of seven strains of listeria to penicillin and found the minimal inhibitory concentration of these organisms to be 40 times that of streptococci and staphylococci. HOOD [154] found 420 RICHARD H. WINTERBAUER, ALLANR. RONALD, DONALD W. BELCHER and MARVIN TURCK that eight of ten listeria isolated from human infections were resistant to penicillin in a concentration of 10 units/ml. All isolates, however, were inhibited by 2 ug/ml of erythromycin or 5 ug/ml of tetracycline. Half of these strains were resistant to 10 ug/ml of chloramphenicol. NYSTROMand KARLSSON[155] tested 86 strains of zyxwvutsrqponmlk Listeriu monocy togenes of animal origin against 14 different antibiotics. The tetracyclines and erythromycin were clearly superior to the other antibiotics including penicillin and chloramphenicol. Other in vitro studies with listeria isolated from human infections have shown consistent sensitivity to tetracycline with occasional instances of resistance to erythromycin, penicillin or chloramphenicol. [146, 149, 1501 Reports of listeria infections treated with antibiotic regimens which did not include penicillin are quite rare. FINEGOLDand associates [148] described a patient with listeria meningitis who failed to improve with penicillin and sulfonamides. This patient improved dramatically when given chlortetracycline intravenously and although he received concomitant dihydrostreptomycin, the chlortetracycline was thought to be the decisive factor in his recovery. DEDRICK[ 1491 observed a child with listeria meningitis who failed to respond to penicillin and streptomycin but recovered promptly when oxytetracycline was used in place of the streptomycin. Another patient in this series did not become afebrile until penicillin and chloramphenicol were discontinued and the patient was treated only with oxytetracycline. Hook [154] reported a young woman with listeria bacteremia following a premature delivery who was treated successfully with only tetracycline. Erythromycin has been used in a single neonate with listeria meningitis, bacteremia, and multiple liver abscesses. [ 1541 This child died following 48 hr of therapy with erythromycin and chloramphenicol. Diphtheria Antibiotics are advocated as an adjunct and never as a substitute for antitoxin in the treatment of acute diphtheria. However, the rapid eradication of all Cory nebacterium diphtheriae is desirable both for the patient to remove a continuing source of toxin, and for the community to eliminate a potential source of new cases. Cory nebacterium diphtheriae are very susceptible to erythromycin and all strains are inhibited by less than 0.02 ug/ml of the drug. [156, 1571 In two clinical studies all 46 patients with acute diphtheria achieved bacteriological cures, usually within 24 hr of beginning treatment with erythromycin. [158, 1591 There were no immediate deaths in the patients treated with erythromycin and only one late death. The latter patient died of diphtheritic myocarditis on the thirteenth day of illness after successful eradication of diphtheria organisms from the oropharynx. Based on these uniformly excellent experiences, KEMPE[160] recommended erythromycin as the antimicrobial agent of choice in acute diphtheria. Antibiotic treatment is also necessary for the chronic carrier of virulent Cory neAll 26 patients who were chronic diphtheria carriers were cured of their carrier state with erythromycin therapy. [158, 161-1631 There were no recorded relapses. Eighteen of these 26 patients had previously demonstrated persistence of virulent organisms during one or more courses of peniclliin therapy. The experience with other antimicrobials is at present too meager to evaluate their use in the treatment of acute diphtheria. bacterium diphtheriae. Antimicrobial Therapy in Patients Sensitive to Penicillin 421 zyxwvutsrq Actinomy cosis There have been major discrepancies in testing the in vitro sensitivity of actinomyces. This is probably due to the increased resistance to clumped organisms when compared with the resistance of a fine homogeneous suspension of actinomyces. [ 1641 However, when sensitivity testing is done under standard conditions all isolates of actinomyces pathogenic for man are inhibited by penicillin as well as the tetracyclines, chloramphenicol and erythromycin. [165-1701 Streptomycin, at levels feasible in man, is less bacteriostatic in vitro and resistance quickly develops with some strains. [ 168, 17I] In one study chlortetracycline and penicillin were equally effective in preventing progression of disease in mice infected with actinomyces. [172] One of the tetracyclines is the drug of choice for patients with actinomycosis who are allergic to penicillin. One author has even suggested that the tetracyclines be used routinely in this disease. [173] MCVAY and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQ SPRUNT[166] reported cures in seven of eight patients, including one with generalized actinomycosis and an hepatic abscess, who were treated with tetracycline. Another seven patients with cervicofacial actinomycosis were successfully treated with 2-6 week courses of oxytetracycline. [174] PEABODYand SEABURYinclude in their review isolated case reports of patients with actinomycosis cured with tetracycline. [175] Erythromycin is a suitable alternative in patients unable to tolerate one of the tetracyclines. HERRELL,BALOWSand DAILEYsuccessfully treated three of four patients with actinomycosis with 1.2 g/day of erythromycin for 3-7 weeks. [176] One patient relapsed 4 months following an apparently successful 4 weeks course of erythromycin. Although in vitro testing indicates that actinomyces are susceptible, the necessity for prolonged therapy is a relative contraindication to chloramphenicol. M iscellaneous infections Penicillin G and more recently ampicillin (alpha-aminobenzyl penicillin) have been shown to possess a broad spectrum of activity against many strains of Proteus mirabilis, Escherichia coli and Hemophilus influenzae. [176] The efficacy of penicillin in certain gram-negative infections was first hinted by HELMHOLZand SUNG [177] in 1944 when they demonstrated antibacterial activity in vitro against several strains of proteus and commented “that the high concentrations of penicillin obtainable in the urine made it an ideal urinary antiseptic”. Actually, ampicillin probably has no more antibacterial activity than is afforded by very high doses of penicillin G. [178] For example, it has been shown that infections with Proteus mirabilis can be handled with 10-20 million units of penicillin G per day. [ 179, 1801 Comparable antibacterial activity in the serum can be achieved with 4-6 g of ampicillin. Since other drugs such as cephalothin, tetracycline, chloramphenicol and kanamycin cover essentially the same gram-negative microbial spectrum as either high doses of penicillin G or ampicillin, there is no difficulty in choosing an alternative drug in the patient hypersensitive to penicillin. CONCLUSIONS Although the various penicillins differ in their absorption, solubility and antibacterial activity, they probably share a common characteristic of invoking hypersensitivity reactions. Most of these allergic reactions are more of a nuisance than a hazard and consist of urticaria or other erythematous skin eruptions. Anaphylaxis is encountered most frequently after parenteral administration of drug, particularly in 422 RICHARDH. WINTERBAUBR, ALLAN R. RONALD,I)~NALD W. BELCHERand zyxwvutsrqponmlkjihgfed MAROONTURCK patients with a previous history of penicillin allergy. There is lack of agreement regarding the clinical usefulness of screening tests in predicting hypersensitivity to the penicillins. Since allergic reactions to penicillin have been attributed largely to degradation products of its 6-amino penicillanic acid nucleus, it is not surprising that cross reactions occur among the various members of the family. Although there are numerous patients with alleged hypersensitivity to penicillin who have subsequently been challenged with one of its newer semi-synthetic congeners without incident, this practice is not recommended. Since other drugs not cross-allergenic withthe penicillins are available for the treatment of most infections, it is best not to use penicillin at all in patients with clear-cut history of penicillin hypersensitivity. This stand occasionally may have to be modified when dealing with severe life-threatening infections in which there is no satisfactory substitute for the penicillins, that is, enterococcal endocarditis. 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