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Infectious Disease Emergencies
Infectious Disease Emergencies SOL KATZ, M.D., F.A.C.P. Chief, Medical Service, Mt. Alto Veterans Administration Hospital, Washington, D.C.; Associate Professor of Medicine, Georgetown University School of Medicine; Professorial Lecturer in Medicine, George Waskington University School of Medicine
THERE ARE many infectious diseases whose usual course is calm and uncomplicated yet in which occasionally imperative complications occur. Other rare contagious diseases are seen that present pressing clinical problems. There are also common infectious diseases that are therapeutically troublesome and demand exacting attention. They require careful appraisal because specific agents for their management are available. This essay will be concerned only with several entities in the last category. BACTERIAL ENDOCARDITIS
Under most circumstances the treatment of bacterial endocarditis is urgent but not emergent. That is, the importance of establishing the precise etiologic identification of the causative agent is so great that therapy in most situations can be withheld until adequate blood cultures have been obtained. This becomes apparent when it is appreciated that the major attack in this disease is the proper application of antibiotics. This means isolation of the responsible organism and the determination of its sensitivity to a variety of antimicrobial substances. Only in this way can one make an intelligent selection of the appropriate agent or combination of agents including dosage and duration of treatment. Diagnosis The best results in the management of bacterial endocarditis are obtained when the diagnosis is made early and treatment instituted promptly. This means that unnecessary delay in diagnosis while awaiting the classical clinical syndrome to develop cannot be condoned, nor can the diagnosis be eliminated because blood cultures are negative. Rather, the most sensible approach should be based on the acceptance of minimal clinical diagnostic criteria, proper performance of blood cultures and establishment of treatment before the valvular infection becomes firmly established or serious complications ensue. This means that bacterial
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endocarditis is the primary consideration in the patient with an organic heart murmur and unexplained fever whether or not embolic phenomena, enlarged spleen, anemia, microscopic hematuria, clubbing, etc., are present. Similarly the diagnosis is paramount in a patient with known rheumatic heart disease or a congenital cardiac lesion with unexplained fever especially with a history of recent dental manipulation, urologic procedures or intestinal surgery. Blood cultures made under these circumstances will be rewarding, for the commonest reason for delay in the diagnosis of bacterial endocarditis is failure to obtain blood cultures early in the course of the disease when the clinical manifestations are subtle. 5 In most cases positive blood cultures are either obtained on the first few attempts or not at all. 6 At least four cultures daily at different times of the day for two to five days will provide a higher yield than many cultures throughout a single day. In patients who are very seriously ill because of marked toxicity, congestive heart failure, or widespread embolization especially to the central nervous system therapy even though it is vital, can usually await several blood cultures obtained during a period of several hours. Attempts to increase the blood culture yield by either an increase in the number of daily cultures or extending the collection beyond several days is unsound and do not justify a delay in the decision regarding therapy. About an hour elapses between the sudden entrance of bacteria into the blood stream and the onset of a chill or temperature spike. Thus, in patients with intermittent chills or peaks in temperature, blood cultures should be obtained about an hour before thc anticipated rigor or tempcrature rise whenever possible.! Blood for cultures should be adequate in amount (20 to 30 cc.) and inoculated into aerobic and anaerobic media. It is desirable to incubate a few cultures under increased carbon dioxide tension. Most positive cultures are obtained with routine enriched laboratory mediums. However, special mediums and growth requirements may be necessary when infections due to "finicky" organisms are suspected. Although growth usually occurs in a few days, cultures should not be discarded before three weeks because growth may be delayed when the number of organisms is small, the bacteria slow-growing or in the presence of suppressive substances in the blood. Arterial blood offers no superiority for culture over venous blood, for insignificant numbers of organisms are sequestered in an extremity. Bone marrow culture may be advantageous, however, for granulomatous infections. At times in patients recently receiving antibiotics, bone marrow cultures may be positive when routine blood cultures are negative. 4 False-negative blood cultures occur not infrequently in patients receiving or recently treated with antibiotics. Whenever possible such antimicrobial therapy should be suspended for several days to
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permit its elimination before blood cultures are procured. In the presence of antimicrobial agents in the blood, inhibitory substances may be added to the culture mediums in an attempt to increase the culture yield. Thus, para-aminobenzoic acid may be used to inactivate sulfonamides, penicillinase to oppose penicillin and magnesium sulfate to eounteract the tetracyclines. These culture methods, although of some usefulness, are not preferred over the technique of interrupting antibacterial therapy before obtaining blood cultures. 3 In many situations, following the identification of the responsible organism its susceptibility to antibacterial agents should be determined. This technique need not be a routine procedure, for eertain organisms such as pneumococci and group A hemolytic streptoeocci are never resistant to penicillin. Tube dilution sensitivity determinations are most useful in testing organisms that vary in their degree of sensitivity to penicillin such as streptocoeci of the viridans group, enterocoeei and micrococei pyogenes var. aureus (Staphylococcus aureus), sinee the selected dose of penieillin will be appreciably influenced by the degree of susceptibility of these organisms. Sensitivity studies are also necessary for organisms that vary in their sensitivity to various antibiotics, for the choice of the proper antibiotic is thus determined. Treatment
In the selection of therapeutic agents bacterieidal antibiotics (penicillin, streptomycin, vancomycin, ristocetin, dimethoxyphenyl penicillin (methecillin) are always given preference over bacteriostatic drugs (tetracyclines and chloramphenicol). Streptomycin should never be used alone but it is an important adjunctive antibiotic to be used concomitantly with other agents. Proper diagnostic measures having been instituted, therapy should be begun before the results of blood cultures are known, for early treatment bears the best results. Since the great majority of organisms causing bacterial endocarditis are penicillin-susceptible to a greater or lesser degree, this agent becomes the logical choice during this temporary period in which one is "flying blind" while anxiously awaiting the laboratory results. Large doses of penicillin are more rational during this temporary trial in order that infections due to relatively penicillinresistant organisms such as enterococci will be adequately managed. For this purpose 20 million units of potassium or sodium penicillin G in 1 or 2 liters of 5 per cent glucose in water or saline is administered daily by continuous slow intravenous infusion. Instead of the continuous intravenous route, one to two million units of penicillin G may be given intramuscularly every two or three hours for a total minimum daily dose of 12 million units. With either regimen 1 gram of streptomycin every 12 hours is given intramuscularly. Probenecid, 0.5 gm. orally every six hours, is a useful adjuvant in intermittent intramuscular treat~
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ment since it permits the use of smaller and therefore better tolerated doses, provides about a twofold increase in penicillin blood levels, and allows a longer interval between injections. With the concomitant use of probenecid, many prefer the intermittent intramuscular route for penicillin administration except when extremely massive doses are required. Because of the statistical likelihood of bacterial endocarditis being due to streptococci of the viridans group and therefore penicillin sensitive, the use of one million units of aqueous procaine penicillin and 1 gram of streptomycin intramuscularly twice daily is recommended by some in this phase before cultures are reported. When the blood culture is reported and sensitivities are determined, the choice and dosage of antibiotics may be altered as indicated. If the blood cultures are negative the regimen is continued if there is a favorable response, or it is altered by increasing the amount of penicillin or changing antibiotics if the response is inadequate. TREATMENT REGIMENS FOR SPECIFIC VARIETIES OF BACTERIAL ENDOCARDITIS. Streptococcus viridans. Endocarditis due to streptococci of the viridans group is the most common variety, occurring in 75 to 85 per cent of all cases. The organisms of this group are quite sensitive to penicillin at an in vitro level readily attained. However, elimination of bacteria from vegetations requires larger amounts of an effective antibiotic than is indicated bythe in vitro bactericidal level. For this reason, larger doses of penicillin are used than are required to reach this bactericidallevel. Most streptococci of the viridans group are sensitive to 0.1 mcg. of penicillin or less per cubic centimeter. Bacterial endocarditis of this variety is usually effectively treated by one million units of aqueous procaine penicillin and 1 gram of streptomycin intramuscularly twice a day for two weeks. Because higher peak levels are attained with sodium penicillin G, some clinicians prefer this variety administered at a dose of 500,000 to one million units intramuscularly every six hours plus 1 gram of streptomycin twice daily. Less sensitive strains of streptococcus viridans are inhibited by 0.2 mcg. of penicillin of more per cubic centimeter. These infections are treated with the same regimen used for enterococcal endocarditis (see below). Oral penicillin may be substituted in the management of highly susceptible strains of streptococci provided facilities are available for penicillin level estimations. As an alternative one may determine by serial dilution the bactericidal effect of the patient's serum on the causative organism. The serum should be bactericidal when diluted to 1:4 or greater. Enterococci. Enterococci are nonhemolytic streptococci commonly found in the intestinal tract and hence the group is often called Strep-
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tococcus fecalis. Enterococcal endoearditis now comprises 5 to 20 per cent of all cases of endocarditis. This variety is important not only because its incidence is increasing but also because enterococci possess a relative or absolute resistance to penicillin. Enterococcal endocarditis occurs most often after disease or instrumentation of the genitourinary tract. Although most enterococci are inhibited by 1 to 10 units of penicillin per cubic centimeter (levels attainable with high penieillin dosage), clinical experience attests to the inadequacy of penicillin alone in the management of enterococcal endocarditis. Similarly, streptomycin alone is deficient therapy in this form of endocarditis. However, penicillin and streptomycin in combination act synergistically in vitro and in vivo and currently are the favored treatment. The dosage of penicillin is determined by the in vitro sensitivity of the enterococcus. Twenty million units of potassium or sodium penicillill G in 1 or 2 liters of 5 per cent glucose in water or saline administered by constant intravenous infusion for six weeks is preferred by many. In addition, streptomycin is given at a dose of 1 gram intramuscularly twice daily for three weeks and then 0.5 gram twice a day for three weeks. Others prefer the use of intramuscular penicillin G given at a dose of one or two million units every two or three hours. Streptomycin is given as above. Constant intramuscular infusion of penicillin is also a useful technique that is often more acceptable to patients than the various methods mentioned. In all cases probenecid (Benemid) 0.5 gram every six hours is given. In the event of failure with either of these regimens larger doses of penicillin by continuous intravenous or intramuscular infusion may be used. If one is guided by the bactericidal potency of the treated patient'f' serum, the daily dose of penicillin may have to be increased to 50 or 100 million units. Such therapy is difficult and complicated and in these situations ristocetin and vancomycin have shown encouraging results. In isolated cases other regimens have been used successfully when penicillin and streptomycin have failed. However, results are inconsistent and their use should rarely be necessary with the advent of the newer antibiotics such as ristocetin and vancomycin. Staphylococci. Infection due to sensitive and relatively sensitive strains of staphylococcus are readily controlled by penicillin up to 12 million units a day plus probenecid 0.5 gm. every six hours for six weeks. The bactericidal effect may be enhanced by the concomitant use of streptomycin. The treatment of bacterial endocarditis due to penicillinresistant staphylococci will be discussed below. Miscellaneous Organisms. Pneumococci, Group A hemolytic streptococci and gonococci are usually readily susceptible to penicillin. Endocarditis due to these organisms should be treated with either aqueous penicillin G 500,000 units every six hours or aqueous procaine penicillin
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one million units every six to t\\clve hours for four to six weeks. Much larger doses of penicillin do not prove superior. The high mortality in pneumococcal endocarditis is not related to organism resistance and failure of bacteriologic cure but rather to the mechanical effects of valvular damage or associated disease. There is not a large accumulated experience in the management of endocarditis due to gram-negative organisms and other rare bacteria. In general, two or more agents are used in combination. Each antimicrobial should possess some antibacterial effect against the organism. In addition, each agent may delay or prevent the appearance of resistance to the other partners in the regimen. Meningococcic endocarditis is best treated with both penicillin and a sulfonamide in an attempt to eradicate both the valvular and meningeal foci.7 Four grams of sulfadiazine or a triple sulfonamide is given orally or intravenously followed by 1 gram orally every four hours plus one million units of penicillin G intramuscularly every two to three hours or 12 million units by continuous intravenous infusion. This combination is given for about five days after which one million units of procaine penicillin intramuscularly twice daily is substituted for penicillin G and therapy continued for two to four weeks. Bacterial endocarditis due to such gram-negative bacilli as E. coli, Aerobacter aerogenes and para colon bacilli is not only difficult to treat but the results in general are poor, perhaps because endocarditis due to these organisms develops in patients who are depleted and otherwise ill. At least two agents are used based on in vitro determinations. Even after the presumed proper therapy has been selected, the bactericidal activity of the patient's serum should be tested against the causative organism. Maximum tolerated doses are instituted. Chloramphenicol or tetracycline combined with streptomycin often proves to be the selected combination. Kanamycin also may demonstrate in vitro effectiveness. Therapy is continued for six weeks. Prolonged therapy with kanamycin must be continued with caution because of ototoxity and nephrotoxicity. Pseudomonas aeruginosa endocarditis is also seen on a backg:round of underlying significant disease. Polymyxin B or colistin methane sulfonate (Coly-mycin) plus tetracycline or streptomycin may be the chosen agents. Impairment of renal function and neurotoxicity may occur following treatment with polymycin or colistin sulfate. Endocarditis due to the proteus group of organisms is serious and also occurs in debilitated individuals. Many strains are relatively susceptible to penicillin but massive doses (up to 100 million units a day) may be required. Other proteus species can be treated with chloramphenicol or tetracycline plus streptomycin or kanamycin. Hemophilus influenzae endocarditis and brucella endocarditis are managed with tetracycline or chloramphenicol plus streptomycin as the agents of choice.
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Endocarditis with Negative Blood Cultures. At times a clinical diagnosis of bacterial endocarditis is seriously considered but bacteriologic confirmation is lacking. This unpleasant predicament occurs in 10 to 30 per cent of patients with bacterial endocarditis. Many factors 4 may be involved in the failure to obtain positive cultures. These includc components related to the organisms such as the manner in which they enter the blood stream from the lesion, their ability to multiply or their state of dormancy. The host may aggressively dispose of the circulating organisms through high levels of circulating antibodies and other methods. Antibiotics especially inadequate to eradicate the organisms may transiently control the bacteremia. Problems connected with bacteriologic technique may be responsible for false negative cultures. These include use of improper mediums, failure to retain the cultures under observation for sufficiently long periods, and failure to collect sufficient numbers of cultures at different periods. When routine cultures are negative mycotic endocarditis should he considered, especially in patients otherwise ill who have received prolonged antihiotics or corticosteroids. The history or clinical context of the case may suggest a specific organism and therefore the proper treatment regimen. Thus, when infection follows dental manipulation, Streptococcus viridans or fecalis should be considered. With urologic or intestinal infection or manipulation, Streptococcus fecalis and coliform organisms are suspected while with septic abortion coliform, staphylococci and anaerobic streptococci are under suspicion. In heroin addicts staphylococci and fungi may be responsible. If such events do not point the way toward a logical treatment schedule, therapy should be similar to that for a resistant streptococcus. Failure of response will demonstrate a need for larger doses or a change in the selection of antibiotics. SURGICAL THERAPY. Emergency surgical measures may be necessary in certain specific situations. Bacterial endarteritis refractory to therapy may require ligation of a patent ductus arteriosus, resection of an arteriovenous fistula, an area of coarctation or an accessible mycotic aneurysm. Embolectomy may be required and rupture of an infarcted and infected spleen or persistent splenic infection may require splenectomy. SERIOUS DRUG-RESISTANT STAPHYLOCOCCAL INFECTIONS
A perplexing problem of the antibiotic age has been the appearance of staphylococci resistant to antibiotics to which they initially were sensitive. Infections caused by these resistant staphylococci are increasing in hospitals. This phenomenon is related to the reservoir of antibioticresistant staphylococci in hospitals and the presence of susceptible hosts. These hosts represent the hospital patient population receptive
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Fig. 1. Bilateral extensive penicillinresistant staphylococcal pneumonia, hospital acquired, in an elderly debilitated diabetic hospitalized because of gangrene of the foot.
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Fig. 2. Widespread septic infarcts with abscess formation due to staphylococcal endocarditis of the tricuspid valve in a heroin addict.
to infection by virtue of debility, serious illness and depleted defense reactions from the use of corticosteroids, alkylating agents and folic acid antagonists.l1 In addition, portals of entry for infection are made available through surgical incisions, decubitus ulcers, tracheostomies, skin disease, indwelling venous catheters, etc. Staphylococcal cutaneous and generalized infections are noted in diabetics, newborn infants and nursing mothers. Staphylococcal pneumonia may be an aftermath of influenza while staphylococca lenterocolitis may complicate the use of broad-spectrum antibiotics. It is the rule to isolate in hospitals a high percentage of pathogenic staphylococci resistant to penicillin, streptomycin and the tetracyclines. As new antibacterial agents are introduced into the confined hospital environment additional resistant strains of staphylococci emerge. 8 So it is that staphylococci resistant to chloramphenicol, erythromycin and novobiocin appear as these antibiotics are used extensively. There is a significantly lower incidence of resistant staphylococcal infections acquired outside hospitals. Staphylococcal pneumonia occurs especially in the hospitalized patient seriously ill with an underlying disease such as malignancy, chronic pulmonary disease, congestive heart failure, blood dyscrasias, lymphoma, etc. (Fig. 1). Even with therapy mortality is high in these patients because of the background of serious underlying disease. Staphylococcal endocarditis seems to be increasing, comprising 5 to 20 per cent of all cases of bacterial endocarditis. Previously normal
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valves are present in about 50 per cent of cases. The mitral valve is most commonly involved while the aortic is the site next in frequency. There is a striking incidence of staphylococcal tricuspid valve endocarditis in heroin addicts who self-administer the narcotic intravenously (Fig. 2). An increase in staphylococcal endocarditis has been seen to follow intracardiac surgery. The mechanism that renders organisms resistant to penicillin is penicillinase production. It is this ability to produce penicillinase, the penicillin destroying enzyme, that permits many strains of Staphylococcus aureus and even some strains of Staphylococcus albus to remain untouched and actively capable of multiplication in the presence of penicillin. The penicillinase splits the penicillin ring, thereby removing its antibacterial properties. Penicillinase production may actually increase in response to penicillin therapy so that it would appear illogical to use massive doses of penicillin in infections due to resistant staphylococci. Treatment
Until fairly recently, treatment of severe penicillin-resistant staphylococcal infections was unsatisfactory. Bactericidal therapy is desirable but no truly bactericidal effective, nontoxic drugs were available. Hence, the practice was to use different regimens combining two or more drugs demonstrating in vitro activity to obtain summation or enhancing effect or prevent emergence of resistance. This usually meant chloramphenicol and erythromycin or novobiocin in full doses. Other eombinations of bacitracin, neomycin, tetracyclines, oleandomycin and streptomycin were used with irregular, unpredictable, toxic and too often inadequate effects. Another regimen used in the treatment of penicillin-resistant staphylococcal infections was large doses of aqueous penicillin G (10 to 100 million units) with an accompanying antimicrobial with demonstrated in vitro activity. With the advent of kanamycin, vancomycin, ristocetin and dimethoxyphenyl penicillin there was a "new look" in thp. management of serious resistant staphylococcal infections. Kanamycin, though bactericidal and effective against Staphylococcus aureus, had a transient fling because of serious irreversible ototoxicity and occasional significant nephrotoxicity. However, its efficacy cannot be denied. Vancomycin is bactericida.l and active against gram-positive organisms including almost all strains of Staphylococcus aureus. Native resistant staphylococci are rare and acquired resistance is insignificant. Vancomycin is given intravenously 0.5 gram every six hours or 1 gram every 12 hours dissolved in 100 to 200 cc. of 5 per cent glucose in water. Later in the course of therapy the dose may be reduced to 1 gram a day.
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Thrombophlebitis is frequently noted even though its incidence is reduced by using dilute solutions and varying the sites of injections. Drug fever and rash are also seen. The drug accumulates and in the presence of renal impairment blood levels may be excessive, resulting in deafness. In patients with staphylococcal endocarditis, treatment is continued two to four weeks. Ristocetin is also bactericidal and active against gram-positive organisms including staphylococci. Significant resistance does not emerge in vitro or in vivo although there is not total agreement regarding its therapeutic efficacy in the treatment of serious staphylococcal infections. Ristocetin is administered intravenously, 25 mg.jkg. per day in two divided doses in 50 to 100 cc. of 5 per cent glucose or saline in about 15 minutes. Although toxic reactions including thrombophlebitis, neutropenia, thrombocytopenia, fever and rash are observed with large doses especially, serious complications are considerably less frequent when the daily dose is kept under 2 grams. In staphylococcal endocarditis therapy is continued two to four weeks. A most important breakthrough came with the development of dimethoxyphenyl penicillin (methicillin; Staphcillin) a semisynthetic penicillin very resistant to penicillinase and strongly effective against penicillin-resistant staphylococci. Resistance of primary isolates of staphylococci are extremely rare. Methicillin is rapidly absorbed when given intramusrularly and is systemically ineffective when administered by mouth. It may also be injected intravenously. The dose is 1 to 1..5 grams every four to six hours. This antibiotic can also be given intrathecally. Patients with a history of previous sensitivity reactions to other penicillins are more likely to react adversely to this penicillin. Because of its efficacy and low toxicity methicillin is the preferred drug for serious penicillin G resistant staphylococcal infections. It is likely tu be effective in 60 to 70 per cent of these infections. SURGICAL THERAPY. Drainage of accumulations of pus is all important facet in the eradication of staphylococcal infections. An important exception to this concept is staphylococcal lung abscess which of tell resolves without surgery. GRAM-NEGATIVE BACTEREMIA
Fulminating bacteremia due to gram-negative enteric flora such as Escherichia coli, Aerobacter aerogenes, "paracolon" bacilli and related Proteus species and Pseudomonas aeruginosa is even more difficult to control than serious staphylococcal infections. These organisms include mixtures of sensitive and resistant strains and most of the antibiotics that demonstrate aetivity agaim;t these organisms are bacteriostatie. Not infrequently, even in the presence of infection due to the sensitive species, appropriate antimicrobial therapy is ineffective.
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The incidence of serious infection due to these gram-negative organisms is increasing. This is in part related to the use of broad-spectrum antibiotics which by eradication of sensitive organisms permits resistant varieties to grow luxuriantly. Many of the gram-negative organisms listed are among those which survive, grow and infect. Not infrequently prior to the bacteremia patients have received antibiotics prophylactically or for the treatment of another infection. 2 In addition, the "soil" on which these organisms can implant and thrive resides in those with depleted resistance including patients with carcinoma, blood dyscrasias, cirrhosis, diabetes, tuberculosis and chronic lung disease. Premature infants, children with congenital disorders and those with severe acquired diseases are also susceptible. Other factors contributing to an altered immune state include the use of anticancer therapy and adrenocorticosteroids. This variety of bacteremia affects men more often than women, especially over the age of 50. The genitourinary tract is the most frequent portal of entry followed next by the gastrointestinal system including the biliary system. The skin is sometimes incriminated while in others no site of entry can be detected. Many cases are preceded by operative or manipulative procedure on the genitourinary, gastrointestinal or biliary tracts. IS Severe circulatory collapse, perhaps related to release of endotoxin, is a common manifestation of gram-negative bacteremia l4-certainly much more so than in gram-positive bacteremia. Fever, chills, prostration and stupor are often noted. The prognosis is often grave, especially in patients with serious accompanying disorders which by themselves are incurable and accountable for the outcome. Treatment
Treatment is directed toward restoration of blood volume and the use of pressor agents to maintain blood pressure. There is considerable controversy regarding the therapeutic role of adrenal corticosteroids in peripheral vascular failure due to infection. 10, 12 However, since the mortality of patients with bacteremia and shock is so high, corticosteroid therapy would appear justifiable while the controversy rages and supporting or opposing evidence is being gathered. Experimental and clinical data suggest that, to be useful, large doses of corticosteroids are needed early in the course of the circulatory collapse. Cortisol (hydrocortisone) 300 mg. to 500 mg. or the equivalent of its analogues is administered intravenously every 6 to 12 hours. In general, such therapy will produce its effect in two or three days or not at all. Thus, there is no justification for prolonged use of corticosteroids in this condition. Currently, there is no evidence of harmful effects from this regimen. Vigorous antibacterial therapy should be started promptly. Chloram-
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phenicol or tetracycline, 500 mg. intravenously every six hours should be used while awaiting the results of in vitro sensitivity tests since none of the available antibiotics is consistently effective against all gramnegative enteric bacilli. This therapy may be combined with 2 gm. of streptomycin intramuscularly daily. If there is initi.al control, 250 mg. of chloramphenicol or tetracycline orally every four to six hours can be given. Kanamycin though ototoxic is often effective in vitro against Proteus species, aerobacteria and E. coli. Colistin methane sulfonate (Coly-Mycin) is commonly useful for infections due to E. coli, aerobacter and especially Pseudomonas aeroginosa. It is administered intramuscularly at a maximum dose of 5 mg./kg. per day. Polymyxin B, 2.5 mg./kg. in divided doses, is usually active against pseudomonas. KLEBSIELLA (FRIEDLANDER'S) PNEUMONIA
Although representing only about 1 per cent of all pneumonias, Friedlander's pneumonia is important because of its seriousness, high mortality, tendency to cause pulmonary destruction resulting in chronic lung disease and failure of response to penicillin therapy. It is caused by Klebsiella pneumoniae (related to Aerobacter aerogenes by bacteriologic criteria), a short gram-negative bacillus having a thick capsule. The disease occurs most commonly in males after the age of 40 and is often seen in association with alcoholism and debilitated states. Acute Friedlander's pneumonia is characterized by profound toxicity and at times collapse. The sputum is usually bloody or at least brick-red, and although often described in the literature as "sticky, mucinous and stringy," the latter characteristics are often lacking. The gross appearance of the lung readily explains the roentgenographic findings. In the early phase, there is an extensive bronchopneumonia which soon becomes confluent, resulting in massive lobar or pseudolobar consolidation in one or both lungs. Areas of suppuration are present, containing a heavy gelatinous exudate that may cause bronchial obstruction, thereby predisposing to more inflammation and bulging of the involved lobe. The zones of necrosis may coalesce, giving rise to larger cavities. In contrast to most other acute pneumonias, Klebsiella pneumonia may become chronic, resulting in lung abscess, bronchiectasis and fibrosis. The x-ray (Fig. 3) reveals a patchy, lobular consolidation in the very early phase which progresses to a dense consolidation that may resemble tumor. Small areas of rarefaction representing the presence of necrosis are seen scattered in the consolidated lung. Further destruction of the lung results in abscess formation. In the chronic phase the lobe is shrunken and fibrotic and contains multiple abscesses, although at times there may be a single thick-walled cavity. The close resemblance to tuberculosis, bronchiectasis, neoplasm, fungous infection and lung
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Fig. 3. A, Consolidation of upper half of right lung due to Klebsiella pneumoniae. "Highlights" within the opacification represent areas of suppuration. B, Slowly resolving pneumonia due to K. pneumoniae. There was very little resolution after 1 month. C, Lobar pneumonia and empyema due to K. pneumoniae.
abscess is often striking. It must be emphasized that the x-ray findings may merely show ordinary lobar consolidation indistinguishable from that seen in pneumococcal lobar pneumonia. In some patients, the disease is insidious and the x-ray manifestations resemble those of the chronic form from the onset. Because there is nothing absolutely diagnostic about the clinical course or roentgenographic pattern, diagnosis depends on the isolation of Friedlander's bacilli from the sputum or blood. A stained sputum smear demonstrating short gram-negative rods should be accepted as a
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presumptive diagnosis requiring immediate therapy. Empyema, meningitis and pericarditis are frequent complications. Treatment
Chloramphenicol or tetracycline 0.5 gm. every four hours plus streptomycin 1 gm. every 12 hours gives the best results when these agents are used early. After an initial response the broad-spectrum antibiotic may be given at intervals of six hours. Streptomycin is reduced to 1 gm. daily after about a week. In the state of chronicity, surgical resection for the destroyed segment or lobe may be necessary. Obviously many other infectious disorders of an emergency nature could be included in this discussion. However, the four described often represent severe, life-threatening situations and are seen frequently enough to warrant thorough familiarity with their management. In addition, the treatment of these conditions provides a broad base for the principles involved in antibiotic therapy in general. REFERENCES 1. Bennett, I. L. and Hook, E. W.: Disease of Month, Nov., 1957. 2. Curtin"J. A., Petersdorf, R. G. and Bennett, L L.: Pseudomonas Bacteremia. Ann. Int. Med. 54: 1077, 1961. 3. Finland, M.: Current Status of Therapy in Bacterial Endocarditis. J.A.M.A. 166.: 364,1958. 4. Finland, M.: Treatment of Bacterial Endocarditis. New England J. Med. 250: 419, 1954. 5. Friedberg, C. K.: Diseases of the Heart. 2nd Ed., Philadelphia, W. B. Saunders Co., 1958. 6. Griffith, G. C. and Levinson, D. C.: Subacute Bacterial Endoearditis. California Med., 71: 403, 1949. 7. Kellow, W. F. and Dowling, H. F.: Current Concepts in Management of Bacterial Endocarditis. A.M.A. Arch. Int. Med. 100: 322, 1957. 8. Lepper, M. H., Moulton, B., Dowling, H. F., Jackson, G. G. and Kofman, S.: Epidemiology of Erythromycin-Resistant Staphylococci in a Hospital Population. Antibiotics Annals, New York, N. Y., Medical Encyclopedia, Inc., 1953. 9. Lowbury, E. J. L.: Clinical Problems of Drug Resistant Pathogens. Brit. M. Bull. 16: 73, 1960. 10. Melby, J. C.: Adrenocorticosteroids in Medical Emergencies. M. CLIN. NORTH AMERICA 45: 875, 1961. 11. Rogers, D. E.: Staphylococcal Infeetions. Disease of Month, April, 1958. 12. Spink, W. W.: Adrenocortical Steroids in the Management of Selected Patients with Infectious Diseases. Ann. Int. Med. 53: 1, 1960. 13. Spittel, J. A., Martin, W. J. and Nichols, D. R.: Bacteremia Owing to GramNegative Bacilli. Ann. Int. Med. 44: 302, 1956. 14. Weil, M. H. and Spink, W. W.: Shock Syndrome Associated with Bacteremia Due to Gram-Negative Bacilli. A.M.A. Arch. Int. Med. 101: ]84, 1958.
THERE ARE many infectious diseases whose usual course is calm and uncomplicated yet in which occasionally imperative complications occur. Other rare contagious diseases are seen that present pressing clinical problems. There are also common infectious diseases that are therapeutically troublesome and demand exacting attention. They require careful appraisal because specific agents for their management are available. This essay will be concerned only with several entities in the last category. BACTERIAL ENDOCARDITIS
Under most circumstances the treatment of bacterial endocarditis is urgent but not emergent. That is, the importance of establishing the precise etiologic identification of the causative agent is so great that therapy in most situations can be withheld until adequate blood cultures have been obtained. This becomes apparent when it is appreciated that the major attack in this disease is the proper application of antibiotics. This means isolation of the responsible organism and the determination of its sensitivity to a variety of antimicrobial substances. Only in this way can one make an intelligent selection of the appropriate agent or combination of agents including dosage and duration of treatment. Diagnosis The best results in the management of bacterial endocarditis are obtained when the diagnosis is made early and treatment instituted promptly. This means that unnecessary delay in diagnosis while awaiting the classical clinical syndrome to develop cannot be condoned, nor can the diagnosis be eliminated because blood cultures are negative. Rather, the most sensible approach should be based on the acceptance of minimal clinical diagnostic criteria, proper performance of blood cultures and establishment of treatment before the valvular infection becomes firmly established or serious complications ensue. This means that bacterial
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endocarditis is the primary consideration in the patient with an organic heart murmur and unexplained fever whether or not embolic phenomena, enlarged spleen, anemia, microscopic hematuria, clubbing, etc., are present. Similarly the diagnosis is paramount in a patient with known rheumatic heart disease or a congenital cardiac lesion with unexplained fever especially with a history of recent dental manipulation, urologic procedures or intestinal surgery. Blood cultures made under these circumstances will be rewarding, for the commonest reason for delay in the diagnosis of bacterial endocarditis is failure to obtain blood cultures early in the course of the disease when the clinical manifestations are subtle. 5 In most cases positive blood cultures are either obtained on the first few attempts or not at all. 6 At least four cultures daily at different times of the day for two to five days will provide a higher yield than many cultures throughout a single day. In patients who are very seriously ill because of marked toxicity, congestive heart failure, or widespread embolization especially to the central nervous system therapy even though it is vital, can usually await several blood cultures obtained during a period of several hours. Attempts to increase the blood culture yield by either an increase in the number of daily cultures or extending the collection beyond several days is unsound and do not justify a delay in the decision regarding therapy. About an hour elapses between the sudden entrance of bacteria into the blood stream and the onset of a chill or temperature spike. Thus, in patients with intermittent chills or peaks in temperature, blood cultures should be obtained about an hour before thc anticipated rigor or tempcrature rise whenever possible.! Blood for cultures should be adequate in amount (20 to 30 cc.) and inoculated into aerobic and anaerobic media. It is desirable to incubate a few cultures under increased carbon dioxide tension. Most positive cultures are obtained with routine enriched laboratory mediums. However, special mediums and growth requirements may be necessary when infections due to "finicky" organisms are suspected. Although growth usually occurs in a few days, cultures should not be discarded before three weeks because growth may be delayed when the number of organisms is small, the bacteria slow-growing or in the presence of suppressive substances in the blood. Arterial blood offers no superiority for culture over venous blood, for insignificant numbers of organisms are sequestered in an extremity. Bone marrow culture may be advantageous, however, for granulomatous infections. At times in patients recently receiving antibiotics, bone marrow cultures may be positive when routine blood cultures are negative. 4 False-negative blood cultures occur not infrequently in patients receiving or recently treated with antibiotics. Whenever possible such antimicrobial therapy should be suspended for several days to
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permit its elimination before blood cultures are procured. In the presence of antimicrobial agents in the blood, inhibitory substances may be added to the culture mediums in an attempt to increase the culture yield. Thus, para-aminobenzoic acid may be used to inactivate sulfonamides, penicillinase to oppose penicillin and magnesium sulfate to eounteract the tetracyclines. These culture methods, although of some usefulness, are not preferred over the technique of interrupting antibacterial therapy before obtaining blood cultures. 3 In many situations, following the identification of the responsible organism its susceptibility to antibacterial agents should be determined. This technique need not be a routine procedure, for eertain organisms such as pneumococci and group A hemolytic streptoeocci are never resistant to penicillin. Tube dilution sensitivity determinations are most useful in testing organisms that vary in their degree of sensitivity to penicillin such as streptocoeci of the viridans group, enterocoeei and micrococei pyogenes var. aureus (Staphylococcus aureus), sinee the selected dose of penieillin will be appreciably influenced by the degree of susceptibility of these organisms. Sensitivity studies are also necessary for organisms that vary in their sensitivity to various antibiotics, for the choice of the proper antibiotic is thus determined. Treatment
In the selection of therapeutic agents bacterieidal antibiotics (penicillin, streptomycin, vancomycin, ristocetin, dimethoxyphenyl penicillin (methecillin) are always given preference over bacteriostatic drugs (tetracyclines and chloramphenicol). Streptomycin should never be used alone but it is an important adjunctive antibiotic to be used concomitantly with other agents. Proper diagnostic measures having been instituted, therapy should be begun before the results of blood cultures are known, for early treatment bears the best results. Since the great majority of organisms causing bacterial endocarditis are penicillin-susceptible to a greater or lesser degree, this agent becomes the logical choice during this temporary period in which one is "flying blind" while anxiously awaiting the laboratory results. Large doses of penicillin are more rational during this temporary trial in order that infections due to relatively penicillinresistant organisms such as enterococci will be adequately managed. For this purpose 20 million units of potassium or sodium penicillin G in 1 or 2 liters of 5 per cent glucose in water or saline is administered daily by continuous slow intravenous infusion. Instead of the continuous intravenous route, one to two million units of penicillin G may be given intramuscularly every two or three hours for a total minimum daily dose of 12 million units. With either regimen 1 gram of streptomycin every 12 hours is given intramuscularly. Probenecid, 0.5 gm. orally every six hours, is a useful adjuvant in intermittent intramuscular treat~
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ment since it permits the use of smaller and therefore better tolerated doses, provides about a twofold increase in penicillin blood levels, and allows a longer interval between injections. With the concomitant use of probenecid, many prefer the intermittent intramuscular route for penicillin administration except when extremely massive doses are required. Because of the statistical likelihood of bacterial endocarditis being due to streptococci of the viridans group and therefore penicillin sensitive, the use of one million units of aqueous procaine penicillin and 1 gram of streptomycin intramuscularly twice daily is recommended by some in this phase before cultures are reported. When the blood culture is reported and sensitivities are determined, the choice and dosage of antibiotics may be altered as indicated. If the blood cultures are negative the regimen is continued if there is a favorable response, or it is altered by increasing the amount of penicillin or changing antibiotics if the response is inadequate. TREATMENT REGIMENS FOR SPECIFIC VARIETIES OF BACTERIAL ENDOCARDITIS. Streptococcus viridans. Endocarditis due to streptococci of the viridans group is the most common variety, occurring in 75 to 85 per cent of all cases. The organisms of this group are quite sensitive to penicillin at an in vitro level readily attained. However, elimination of bacteria from vegetations requires larger amounts of an effective antibiotic than is indicated bythe in vitro bactericidal level. For this reason, larger doses of penicillin are used than are required to reach this bactericidallevel. Most streptococci of the viridans group are sensitive to 0.1 mcg. of penicillin or less per cubic centimeter. Bacterial endocarditis of this variety is usually effectively treated by one million units of aqueous procaine penicillin and 1 gram of streptomycin intramuscularly twice a day for two weeks. Because higher peak levels are attained with sodium penicillin G, some clinicians prefer this variety administered at a dose of 500,000 to one million units intramuscularly every six hours plus 1 gram of streptomycin twice daily. Less sensitive strains of streptococcus viridans are inhibited by 0.2 mcg. of penicillin of more per cubic centimeter. These infections are treated with the same regimen used for enterococcal endocarditis (see below). Oral penicillin may be substituted in the management of highly susceptible strains of streptococci provided facilities are available for penicillin level estimations. As an alternative one may determine by serial dilution the bactericidal effect of the patient's serum on the causative organism. The serum should be bactericidal when diluted to 1:4 or greater. Enterococci. Enterococci are nonhemolytic streptococci commonly found in the intestinal tract and hence the group is often called Strep-
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tococcus fecalis. Enterococcal endoearditis now comprises 5 to 20 per cent of all cases of endocarditis. This variety is important not only because its incidence is increasing but also because enterococci possess a relative or absolute resistance to penicillin. Enterococcal endocarditis occurs most often after disease or instrumentation of the genitourinary tract. Although most enterococci are inhibited by 1 to 10 units of penicillin per cubic centimeter (levels attainable with high penieillin dosage), clinical experience attests to the inadequacy of penicillin alone in the management of enterococcal endocarditis. Similarly, streptomycin alone is deficient therapy in this form of endocarditis. However, penicillin and streptomycin in combination act synergistically in vitro and in vivo and currently are the favored treatment. The dosage of penicillin is determined by the in vitro sensitivity of the enterococcus. Twenty million units of potassium or sodium penicillill G in 1 or 2 liters of 5 per cent glucose in water or saline administered by constant intravenous infusion for six weeks is preferred by many. In addition, streptomycin is given at a dose of 1 gram intramuscularly twice daily for three weeks and then 0.5 gram twice a day for three weeks. Others prefer the use of intramuscular penicillin G given at a dose of one or two million units every two or three hours. Streptomycin is given as above. Constant intramuscular infusion of penicillin is also a useful technique that is often more acceptable to patients than the various methods mentioned. In all cases probenecid (Benemid) 0.5 gram every six hours is given. In the event of failure with either of these regimens larger doses of penicillin by continuous intravenous or intramuscular infusion may be used. If one is guided by the bactericidal potency of the treated patient'f' serum, the daily dose of penicillin may have to be increased to 50 or 100 million units. Such therapy is difficult and complicated and in these situations ristocetin and vancomycin have shown encouraging results. In isolated cases other regimens have been used successfully when penicillin and streptomycin have failed. However, results are inconsistent and their use should rarely be necessary with the advent of the newer antibiotics such as ristocetin and vancomycin. Staphylococci. Infection due to sensitive and relatively sensitive strains of staphylococcus are readily controlled by penicillin up to 12 million units a day plus probenecid 0.5 gm. every six hours for six weeks. The bactericidal effect may be enhanced by the concomitant use of streptomycin. The treatment of bacterial endocarditis due to penicillinresistant staphylococci will be discussed below. Miscellaneous Organisms. Pneumococci, Group A hemolytic streptococci and gonococci are usually readily susceptible to penicillin. Endocarditis due to these organisms should be treated with either aqueous penicillin G 500,000 units every six hours or aqueous procaine penicillin
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one million units every six to t\\clve hours for four to six weeks. Much larger doses of penicillin do not prove superior. The high mortality in pneumococcal endocarditis is not related to organism resistance and failure of bacteriologic cure but rather to the mechanical effects of valvular damage or associated disease. There is not a large accumulated experience in the management of endocarditis due to gram-negative organisms and other rare bacteria. In general, two or more agents are used in combination. Each antimicrobial should possess some antibacterial effect against the organism. In addition, each agent may delay or prevent the appearance of resistance to the other partners in the regimen. Meningococcic endocarditis is best treated with both penicillin and a sulfonamide in an attempt to eradicate both the valvular and meningeal foci.7 Four grams of sulfadiazine or a triple sulfonamide is given orally or intravenously followed by 1 gram orally every four hours plus one million units of penicillin G intramuscularly every two to three hours or 12 million units by continuous intravenous infusion. This combination is given for about five days after which one million units of procaine penicillin intramuscularly twice daily is substituted for penicillin G and therapy continued for two to four weeks. Bacterial endocarditis due to such gram-negative bacilli as E. coli, Aerobacter aerogenes and para colon bacilli is not only difficult to treat but the results in general are poor, perhaps because endocarditis due to these organisms develops in patients who are depleted and otherwise ill. At least two agents are used based on in vitro determinations. Even after the presumed proper therapy has been selected, the bactericidal activity of the patient's serum should be tested against the causative organism. Maximum tolerated doses are instituted. Chloramphenicol or tetracycline combined with streptomycin often proves to be the selected combination. Kanamycin also may demonstrate in vitro effectiveness. Therapy is continued for six weeks. Prolonged therapy with kanamycin must be continued with caution because of ototoxity and nephrotoxicity. Pseudomonas aeruginosa endocarditis is also seen on a backg:round of underlying significant disease. Polymyxin B or colistin methane sulfonate (Coly-mycin) plus tetracycline or streptomycin may be the chosen agents. Impairment of renal function and neurotoxicity may occur following treatment with polymycin or colistin sulfate. Endocarditis due to the proteus group of organisms is serious and also occurs in debilitated individuals. Many strains are relatively susceptible to penicillin but massive doses (up to 100 million units a day) may be required. Other proteus species can be treated with chloramphenicol or tetracycline plus streptomycin or kanamycin. Hemophilus influenzae endocarditis and brucella endocarditis are managed with tetracycline or chloramphenicol plus streptomycin as the agents of choice.
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Endocarditis with Negative Blood Cultures. At times a clinical diagnosis of bacterial endocarditis is seriously considered but bacteriologic confirmation is lacking. This unpleasant predicament occurs in 10 to 30 per cent of patients with bacterial endocarditis. Many factors 4 may be involved in the failure to obtain positive cultures. These includc components related to the organisms such as the manner in which they enter the blood stream from the lesion, their ability to multiply or their state of dormancy. The host may aggressively dispose of the circulating organisms through high levels of circulating antibodies and other methods. Antibiotics especially inadequate to eradicate the organisms may transiently control the bacteremia. Problems connected with bacteriologic technique may be responsible for false negative cultures. These include use of improper mediums, failure to retain the cultures under observation for sufficiently long periods, and failure to collect sufficient numbers of cultures at different periods. When routine cultures are negative mycotic endocarditis should he considered, especially in patients otherwise ill who have received prolonged antihiotics or corticosteroids. The history or clinical context of the case may suggest a specific organism and therefore the proper treatment regimen. Thus, when infection follows dental manipulation, Streptococcus viridans or fecalis should be considered. With urologic or intestinal infection or manipulation, Streptococcus fecalis and coliform organisms are suspected while with septic abortion coliform, staphylococci and anaerobic streptococci are under suspicion. In heroin addicts staphylococci and fungi may be responsible. If such events do not point the way toward a logical treatment schedule, therapy should be similar to that for a resistant streptococcus. Failure of response will demonstrate a need for larger doses or a change in the selection of antibiotics. SURGICAL THERAPY. Emergency surgical measures may be necessary in certain specific situations. Bacterial endarteritis refractory to therapy may require ligation of a patent ductus arteriosus, resection of an arteriovenous fistula, an area of coarctation or an accessible mycotic aneurysm. Embolectomy may be required and rupture of an infarcted and infected spleen or persistent splenic infection may require splenectomy. SERIOUS DRUG-RESISTANT STAPHYLOCOCCAL INFECTIONS
A perplexing problem of the antibiotic age has been the appearance of staphylococci resistant to antibiotics to which they initially were sensitive. Infections caused by these resistant staphylococci are increasing in hospitals. This phenomenon is related to the reservoir of antibioticresistant staphylococci in hospitals and the presence of susceptible hosts. These hosts represent the hospital patient population receptive
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Fig. 1. Bilateral extensive penicillinresistant staphylococcal pneumonia, hospital acquired, in an elderly debilitated diabetic hospitalized because of gangrene of the foot.
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Fig. 2. Widespread septic infarcts with abscess formation due to staphylococcal endocarditis of the tricuspid valve in a heroin addict.
to infection by virtue of debility, serious illness and depleted defense reactions from the use of corticosteroids, alkylating agents and folic acid antagonists.l1 In addition, portals of entry for infection are made available through surgical incisions, decubitus ulcers, tracheostomies, skin disease, indwelling venous catheters, etc. Staphylococcal cutaneous and generalized infections are noted in diabetics, newborn infants and nursing mothers. Staphylococcal pneumonia may be an aftermath of influenza while staphylococca lenterocolitis may complicate the use of broad-spectrum antibiotics. It is the rule to isolate in hospitals a high percentage of pathogenic staphylococci resistant to penicillin, streptomycin and the tetracyclines. As new antibacterial agents are introduced into the confined hospital environment additional resistant strains of staphylococci emerge. 8 So it is that staphylococci resistant to chloramphenicol, erythromycin and novobiocin appear as these antibiotics are used extensively. There is a significantly lower incidence of resistant staphylococcal infections acquired outside hospitals. Staphylococcal pneumonia occurs especially in the hospitalized patient seriously ill with an underlying disease such as malignancy, chronic pulmonary disease, congestive heart failure, blood dyscrasias, lymphoma, etc. (Fig. 1). Even with therapy mortality is high in these patients because of the background of serious underlying disease. Staphylococcal endocarditis seems to be increasing, comprising 5 to 20 per cent of all cases of bacterial endocarditis. Previously normal
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valves are present in about 50 per cent of cases. The mitral valve is most commonly involved while the aortic is the site next in frequency. There is a striking incidence of staphylococcal tricuspid valve endocarditis in heroin addicts who self-administer the narcotic intravenously (Fig. 2). An increase in staphylococcal endocarditis has been seen to follow intracardiac surgery. The mechanism that renders organisms resistant to penicillin is penicillinase production. It is this ability to produce penicillinase, the penicillin destroying enzyme, that permits many strains of Staphylococcus aureus and even some strains of Staphylococcus albus to remain untouched and actively capable of multiplication in the presence of penicillin. The penicillinase splits the penicillin ring, thereby removing its antibacterial properties. Penicillinase production may actually increase in response to penicillin therapy so that it would appear illogical to use massive doses of penicillin in infections due to resistant staphylococci. Treatment
Until fairly recently, treatment of severe penicillin-resistant staphylococcal infections was unsatisfactory. Bactericidal therapy is desirable but no truly bactericidal effective, nontoxic drugs were available. Hence, the practice was to use different regimens combining two or more drugs demonstrating in vitro activity to obtain summation or enhancing effect or prevent emergence of resistance. This usually meant chloramphenicol and erythromycin or novobiocin in full doses. Other eombinations of bacitracin, neomycin, tetracyclines, oleandomycin and streptomycin were used with irregular, unpredictable, toxic and too often inadequate effects. Another regimen used in the treatment of penicillin-resistant staphylococcal infections was large doses of aqueous penicillin G (10 to 100 million units) with an accompanying antimicrobial with demonstrated in vitro activity. With the advent of kanamycin, vancomycin, ristocetin and dimethoxyphenyl penicillin there was a "new look" in thp. management of serious resistant staphylococcal infections. Kanamycin, though bactericidal and effective against Staphylococcus aureus, had a transient fling because of serious irreversible ototoxicity and occasional significant nephrotoxicity. However, its efficacy cannot be denied. Vancomycin is bactericida.l and active against gram-positive organisms including almost all strains of Staphylococcus aureus. Native resistant staphylococci are rare and acquired resistance is insignificant. Vancomycin is given intravenously 0.5 gram every six hours or 1 gram every 12 hours dissolved in 100 to 200 cc. of 5 per cent glucose in water. Later in the course of therapy the dose may be reduced to 1 gram a day.
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Thrombophlebitis is frequently noted even though its incidence is reduced by using dilute solutions and varying the sites of injections. Drug fever and rash are also seen. The drug accumulates and in the presence of renal impairment blood levels may be excessive, resulting in deafness. In patients with staphylococcal endocarditis, treatment is continued two to four weeks. Ristocetin is also bactericidal and active against gram-positive organisms including staphylococci. Significant resistance does not emerge in vitro or in vivo although there is not total agreement regarding its therapeutic efficacy in the treatment of serious staphylococcal infections. Ristocetin is administered intravenously, 25 mg.jkg. per day in two divided doses in 50 to 100 cc. of 5 per cent glucose or saline in about 15 minutes. Although toxic reactions including thrombophlebitis, neutropenia, thrombocytopenia, fever and rash are observed with large doses especially, serious complications are considerably less frequent when the daily dose is kept under 2 grams. In staphylococcal endocarditis therapy is continued two to four weeks. A most important breakthrough came with the development of dimethoxyphenyl penicillin (methicillin; Staphcillin) a semisynthetic penicillin very resistant to penicillinase and strongly effective against penicillin-resistant staphylococci. Resistance of primary isolates of staphylococci are extremely rare. Methicillin is rapidly absorbed when given intramusrularly and is systemically ineffective when administered by mouth. It may also be injected intravenously. The dose is 1 to 1..5 grams every four to six hours. This antibiotic can also be given intrathecally. Patients with a history of previous sensitivity reactions to other penicillins are more likely to react adversely to this penicillin. Because of its efficacy and low toxicity methicillin is the preferred drug for serious penicillin G resistant staphylococcal infections. It is likely tu be effective in 60 to 70 per cent of these infections. SURGICAL THERAPY. Drainage of accumulations of pus is all important facet in the eradication of staphylococcal infections. An important exception to this concept is staphylococcal lung abscess which of tell resolves without surgery. GRAM-NEGATIVE BACTEREMIA
Fulminating bacteremia due to gram-negative enteric flora such as Escherichia coli, Aerobacter aerogenes, "paracolon" bacilli and related Proteus species and Pseudomonas aeruginosa is even more difficult to control than serious staphylococcal infections. These organisms include mixtures of sensitive and resistant strains and most of the antibiotics that demonstrate aetivity agaim;t these organisms are bacteriostatie. Not infrequently, even in the presence of infection due to the sensitive species, appropriate antimicrobial therapy is ineffective.
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The incidence of serious infection due to these gram-negative organisms is increasing. This is in part related to the use of broad-spectrum antibiotics which by eradication of sensitive organisms permits resistant varieties to grow luxuriantly. Many of the gram-negative organisms listed are among those which survive, grow and infect. Not infrequently prior to the bacteremia patients have received antibiotics prophylactically or for the treatment of another infection. 2 In addition, the "soil" on which these organisms can implant and thrive resides in those with depleted resistance including patients with carcinoma, blood dyscrasias, cirrhosis, diabetes, tuberculosis and chronic lung disease. Premature infants, children with congenital disorders and those with severe acquired diseases are also susceptible. Other factors contributing to an altered immune state include the use of anticancer therapy and adrenocorticosteroids. This variety of bacteremia affects men more often than women, especially over the age of 50. The genitourinary tract is the most frequent portal of entry followed next by the gastrointestinal system including the biliary system. The skin is sometimes incriminated while in others no site of entry can be detected. Many cases are preceded by operative or manipulative procedure on the genitourinary, gastrointestinal or biliary tracts. IS Severe circulatory collapse, perhaps related to release of endotoxin, is a common manifestation of gram-negative bacteremia l4-certainly much more so than in gram-positive bacteremia. Fever, chills, prostration and stupor are often noted. The prognosis is often grave, especially in patients with serious accompanying disorders which by themselves are incurable and accountable for the outcome. Treatment
Treatment is directed toward restoration of blood volume and the use of pressor agents to maintain blood pressure. There is considerable controversy regarding the therapeutic role of adrenal corticosteroids in peripheral vascular failure due to infection. 10, 12 However, since the mortality of patients with bacteremia and shock is so high, corticosteroid therapy would appear justifiable while the controversy rages and supporting or opposing evidence is being gathered. Experimental and clinical data suggest that, to be useful, large doses of corticosteroids are needed early in the course of the circulatory collapse. Cortisol (hydrocortisone) 300 mg. to 500 mg. or the equivalent of its analogues is administered intravenously every 6 to 12 hours. In general, such therapy will produce its effect in two or three days or not at all. Thus, there is no justification for prolonged use of corticosteroids in this condition. Currently, there is no evidence of harmful effects from this regimen. Vigorous antibacterial therapy should be started promptly. Chloram-
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phenicol or tetracycline, 500 mg. intravenously every six hours should be used while awaiting the results of in vitro sensitivity tests since none of the available antibiotics is consistently effective against all gramnegative enteric bacilli. This therapy may be combined with 2 gm. of streptomycin intramuscularly daily. If there is initi.al control, 250 mg. of chloramphenicol or tetracycline orally every four to six hours can be given. Kanamycin though ototoxic is often effective in vitro against Proteus species, aerobacteria and E. coli. Colistin methane sulfonate (Coly-Mycin) is commonly useful for infections due to E. coli, aerobacter and especially Pseudomonas aeroginosa. It is administered intramuscularly at a maximum dose of 5 mg./kg. per day. Polymyxin B, 2.5 mg./kg. in divided doses, is usually active against pseudomonas. KLEBSIELLA (FRIEDLANDER'S) PNEUMONIA
Although representing only about 1 per cent of all pneumonias, Friedlander's pneumonia is important because of its seriousness, high mortality, tendency to cause pulmonary destruction resulting in chronic lung disease and failure of response to penicillin therapy. It is caused by Klebsiella pneumoniae (related to Aerobacter aerogenes by bacteriologic criteria), a short gram-negative bacillus having a thick capsule. The disease occurs most commonly in males after the age of 40 and is often seen in association with alcoholism and debilitated states. Acute Friedlander's pneumonia is characterized by profound toxicity and at times collapse. The sputum is usually bloody or at least brick-red, and although often described in the literature as "sticky, mucinous and stringy," the latter characteristics are often lacking. The gross appearance of the lung readily explains the roentgenographic findings. In the early phase, there is an extensive bronchopneumonia which soon becomes confluent, resulting in massive lobar or pseudolobar consolidation in one or both lungs. Areas of suppuration are present, containing a heavy gelatinous exudate that may cause bronchial obstruction, thereby predisposing to more inflammation and bulging of the involved lobe. The zones of necrosis may coalesce, giving rise to larger cavities. In contrast to most other acute pneumonias, Klebsiella pneumonia may become chronic, resulting in lung abscess, bronchiectasis and fibrosis. The x-ray (Fig. 3) reveals a patchy, lobular consolidation in the very early phase which progresses to a dense consolidation that may resemble tumor. Small areas of rarefaction representing the presence of necrosis are seen scattered in the consolidated lung. Further destruction of the lung results in abscess formation. In the chronic phase the lobe is shrunken and fibrotic and contains multiple abscesses, although at times there may be a single thick-walled cavity. The close resemblance to tuberculosis, bronchiectasis, neoplasm, fungous infection and lung
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Fig. 3. A, Consolidation of upper half of right lung due to Klebsiella pneumoniae. "Highlights" within the opacification represent areas of suppuration. B, Slowly resolving pneumonia due to K. pneumoniae. There was very little resolution after 1 month. C, Lobar pneumonia and empyema due to K. pneumoniae.
abscess is often striking. It must be emphasized that the x-ray findings may merely show ordinary lobar consolidation indistinguishable from that seen in pneumococcal lobar pneumonia. In some patients, the disease is insidious and the x-ray manifestations resemble those of the chronic form from the onset. Because there is nothing absolutely diagnostic about the clinical course or roentgenographic pattern, diagnosis depends on the isolation of Friedlander's bacilli from the sputum or blood. A stained sputum smear demonstrating short gram-negative rods should be accepted as a
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presumptive diagnosis requiring immediate therapy. Empyema, meningitis and pericarditis are frequent complications. Treatment
Chloramphenicol or tetracycline 0.5 gm. every four hours plus streptomycin 1 gm. every 12 hours gives the best results when these agents are used early. After an initial response the broad-spectrum antibiotic may be given at intervals of six hours. Streptomycin is reduced to 1 gm. daily after about a week. In the state of chronicity, surgical resection for the destroyed segment or lobe may be necessary. Obviously many other infectious disorders of an emergency nature could be included in this discussion. However, the four described often represent severe, life-threatening situations and are seen frequently enough to warrant thorough familiarity with their management. In addition, the treatment of these conditions provides a broad base for the principles involved in antibiotic therapy in general. REFERENCES 1. Bennett, I. L. and Hook, E. W.: Disease of Month, Nov., 1957. 2. Curtin"J. A., Petersdorf, R. G. and Bennett, L L.: Pseudomonas Bacteremia. Ann. Int. Med. 54: 1077, 1961. 3. Finland, M.: Current Status of Therapy in Bacterial Endocarditis. J.A.M.A. 166.: 364,1958. 4. Finland, M.: Treatment of Bacterial Endocarditis. New England J. Med. 250: 419, 1954. 5. Friedberg, C. K.: Diseases of the Heart. 2nd Ed., Philadelphia, W. B. Saunders Co., 1958. 6. Griffith, G. C. and Levinson, D. C.: Subacute Bacterial Endoearditis. California Med., 71: 403, 1949. 7. Kellow, W. F. and Dowling, H. F.: Current Concepts in Management of Bacterial Endocarditis. A.M.A. Arch. Int. Med. 100: 322, 1957. 8. Lepper, M. H., Moulton, B., Dowling, H. F., Jackson, G. G. and Kofman, S.: Epidemiology of Erythromycin-Resistant Staphylococci in a Hospital Population. Antibiotics Annals, New York, N. Y., Medical Encyclopedia, Inc., 1953. 9. Lowbury, E. J. L.: Clinical Problems of Drug Resistant Pathogens. Brit. M. Bull. 16: 73, 1960. 10. Melby, J. C.: Adrenocorticosteroids in Medical Emergencies. M. CLIN. NORTH AMERICA 45: 875, 1961. 11. Rogers, D. E.: Staphylococcal Infeetions. Disease of Month, April, 1958. 12. Spink, W. W.: Adrenocortical Steroids in the Management of Selected Patients with Infectious Diseases. Ann. Int. Med. 53: 1, 1960. 13. Spittel, J. A., Martin, W. J. and Nichols, D. R.: Bacteremia Owing to GramNegative Bacilli. Ann. Int. Med. 44: 302, 1956. 14. Weil, M. H. and Spink, W. W.: Shock Syndrome Associated with Bacteremia Due to Gram-Negative Bacilli. A.M.A. Arch. Int. Med. 101: ]84, 1958.