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Antimicrobial Therapy in Respiratory Tract Diseases
ANTIMICROBIAL THERAPY IN RESPIR.<\.TORY TRACT DISEASES SAUL KRUGMAN, M.D.
I ndications for antimicrobial therapy in disease of the respiratory tract are rarely clear-cut. The pediatrician is constantly plagued by the decision "to treat or not to treat." An adimicrobial drug which may be lifesaving for an infant with severe bacterial pneumonia may be worthless or even harmful for a child with a viral infection. Two decades ago the choice of an antibacterial drug was a simple task. In 1940 only sulfonamides were available. Today more than 15 antimicrobial agents have been added to the formulary. The selection of the appropriate drug for the treatment of an infection requires both clinical acumen and a knowledge of the virtues, limitations and hazards of the various antimicrobial agents. FACTORS AFFECTING CHOICE OF ANTIBIOTICS
Figure 22 lists the various factors which may affect the selection of a particular antibiotic. Clinical Impression of Etiology
Information derived from a careful history and physical examination will enable a physician to classify a respiratory illness into one of the syndromes listed in Table 35. Each syndrome may be caused by a variety of etiologic agents, most commonly bacterial or viral. Rickettsial, parasitic and mycotic respiratory diseases are relatively uncommon. A knowledge of the most probable causative agent of each syndrome is helpful in assessing the clinical estimate of the etiology. For example, a clinical diagnosis of acute vesicular or ulcerative tonsillopharyngitis would suggest a viral etiology, most probably herpes simplex or Coxllqq
1200
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES CLINICAL IMPRESSION OF ETIOLOGY
IDENTIFICATION OF CAUSATIVE AGENT
2
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7 PHYSICIAN'S PREFERENCE
1-------------4
6 POTENTIAL TOXICITY
5 EPIDEMIOLOGIC FACTORS
Fig. 22. Factors affecting the choice of an antibiotic.
sackie A virus. These infections are not affected by antimicrobial therapy. On the other hand, a diagnosis of acute exudative tonsillopharyngitis suggests a streptococcal etiology. Identification of Causative Agent
The clinical estimate of the etiology may be confirmed or altered by the results of bacteriologic cultures. In acute exudative tonsillitis the identification of group A hemolytic streptococci on throat culture is confirmatory. Occasionally the results of the throat culture and failure to respond to penicillin therapy may suggest another etiology. For example, Hemophilus influenzae tonsillitis or viral tonsillitis will not be affected by penicillin therapy. Nature of the Infection
The kind of respiratory infection will affect the decision to withhold or initiate antimicrobial therapy. For example, most cases of acute nasopharyngitis and acute bronchiolitis have a viral etiology. In view of the benign nature of upper respiratory tract infections, initial therapy with antibiotics is rarely indicated. On the other hand, acute bronchiolitis carries a serious prognosis and often resembles severe bacterial bronchopneumonia. Consequently a physician would be justified in initiating antimicrobial therapy for this "nonbacterial" disease. Subsequently the treatment may be discontinued if the clinical course and bacteriologic reports rule out a bacterial etiology.
SAUL KRUGMAN TABLE
1201
35. Classification of Acute Respiratory Infections in Children by Clinical Syn· drome and Etiologic Agent* ETIOLOGY
CLINICAL SYNDROMES
Bacterial Common cold, febrile naso- Hemolytic streptococcus (in infants) pharyngitis, acute respiratory disease, acute catarrhal tonsillopharyngitis with or without conj unctivitis Acute tonsillopharyngitis (exudative or membranous)
Hemolytic streptococcus t Corynebacterium diphtheriae
Adenovirus Eaton-Liu (PAP) Parainfluenza 3 (HA-l) Respiratory syncytial (RS) ECHO 8, 20, 28 Coxsackie A Infectious mononucleosis t Adenovirus
Herpes simplex t Coxsackie At
Acute tonsillopharyngitis (vesicular or ulcerative) Acute epiglottitis (croup)
Viral
Hemophilus influenzae, type Bt
C. diphtheriae Acute laryngotracheitis with or without bron- H. influenzae chitis (croup)
Parainfluenza 1 (HA-2) t Adenovirus Parainfluenza 2 (CA) Influenza A Respiratory syncytial (RS) ECHO 11 Parainfluenza 3 (HA-l)
Acute bronchiolitis
H. influenzae ?
Adenovirus Parainfluenza 3 (HA-l) Eaton-Liu (PAP) Respiratory syncytial (RS) t
Acute pneumonitis
Pneumococcus t Staphylococcus Hemolytic streptococcus H. influenzae
Adenovirus Chickenpox Eaton-Liu (PAP) Influenza Measles Parainfluenza 3 (HA-l) Respiratory syncytial (RS) t Psittacosis
* Rickettsial,
parasitic and mycotic infections are not included in this table. t One of the most common etiologic agents. t Viral etiology not proved. PAP: primary atypical pneumonia. CA: croup-associated. HA: hemadsorption. Modified from S. Krugman and R. Ward: Infectious Diseases of Children. 2nd ed. St Louis, C. V. Mosby Company.
1202
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
Host Factors
A variety of host factors may influence the choice of a particular antimicrobial drug. A patient may be allergic to the drug of choice. In this event the second best drug would be selected. Other host factors such as age or the presence of another disease, e.g. rheumatic fever, would affect the selection of an antibiotic. Epidemiologic Factors
The estimate of the etiology of the respiratory syndrome will be influenced by the knowledge of an epidemic of a particular bacterial or viral infection in the community. A nonexudative tonsillopharyngitis usually has a viral etiology. In the presence of an epidemic of scarlet fever the likelihood of a streptococcal etiology would increase. Under these circumstances penicillin therapy would be indicated. Potential Toxicity
This factor is particularly important in situations which require the parenteral use of drugs such as bacitracin or neomycin. The virtues of these agents must be balanced against their nephrotoxic and ototoxic potentialities. Physician's Preference
Past personal experiences have a profound effect on a physician's choice of an antimicrobial agent. The unfortunate occurrence of a severe toxic reaction or a fatal anaphylactoid episode may prejudice a physician against a particular drug. Cost
The factor of cost may influence the choice of a sulfonamide in preference to a more expensive tetracycline preparation. ANTIMICROBIAL THERAPY OF SPECIFIC RESPIRATORY SYNDROMES Common Cold, Febrile Nasopharyngitis, Acute Respiratory Disease, and Acute Catarrhal Tonsillopharyngitis with or without Conjunctivitis
These four respiratory syndromes are most commonly identified as "upper respiratory tract infections." They are characterized by varying degrees of one or more of the following manifestions: nasal congestion and discharge, conjunctivitis, sore throat, cough, and tonsillopharyngeal
SAUL KRUGMAN
1203
reddening without exudate. As indicated in Table 35, these infections usually have a viral etiology. Adenovirus, parainfluenza, PAP, respiratory syncytial (RS), ECHO and Coxsackie viruses have been associated with these diseases. 1 , 2, 4, 6, 7, 11, 14 As newer respiratory viruses are identified, this list will increase. This clinical syndrome is rarely caused by bacteria. 5 Rarely the hemolytic streptococcus may be responsible for nasopharyngitis in infants. 12 ANTIMICROBIAL THERAPY. Antibiotics are not indicated for most upper respiratory tract infections of children; their use has neither therapeutic nor prophylactic efficacy. If a streptococcal etiology is suggested because of a known contact or a positive culture, penicillin therapy would be indicated. Acute Tonsillopharyngitis with Exudate or Membrane
The group A hemolytic streptococcus is the most common cause of this disease, which is characterized by fever, sore throat and an exudative or membranous tonsillopharyngitis. Diphtheria and infectious mononucleosis are less common causes. ANTIMICROBIAL THERAPY. The drug of choice is unquestionably penicillin. Optimum therapy may be achieved with anyone of the following schedules: 1. Aqueous procaine penicillin, 600,000 units intramuscularly, daily for 10 days. (This regimen is not recommended because of the large number of injections.) 2. Benzathine penicillin G, 600,000 units intramuscularly as a single injection. (The disadvantage of this regimen is the high incidence of severe local reactions.) 3. Oral penicillin G or V, 300,000 units 4 times daily for 10 days. (Penicillin G should be given on an empty stomach.) 4. Various combinations of 1 and 3, such as intramuscular therapy for 3 days and oral administration for 7 days. The regimen of penicillin therapy should be individualized. An effective, well tolerated and relatively inexpensive preparation is available as a mixture of 600,000 units of aqueous procaine penicillin and 600,000 units of benzathine penicillin G in a 2-ml. vial for intramuscular inoculation. S As indicated in Figure 23, a single injection provides an adequate antistreptococcal blood level for at least 10 days. Erythromycin is an effective substitute for the treatment of patients allergic to penicillin. The recommended dose is 20 mg. per pound of body weight per day (4 times daily) for a 10-day period. Sulfonamides are effective for prophylaxis but not treatment of streptococcal infections. 1'1
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RANGE OF PENICILLIN SENSITIVITY "IN VITRO" OF GROUP A STREPTOCOCCI
10
DAYS FOLLOWING INOCULATION AGE - 6 MOS. TO II YRS (4 YR)
NUMBER OF PATIENTS-36 AGE-7WKS TO 4YRS (I~YR)
WEIGHT- 20 TO 94 LBS (39 LBS)
WEIGHT - " TO 29 LBS (22 LBS)
NUMBER OF PATIENTS - 7 2
Fig, 23, Penicillin blood levels 7 and 10 days after a single injection of a mixture of aqueous procaine penicillin G (PPG) and benzathine penicillin G (BPG), Each black dot represents 1 blood level determination. (From S. Krugman and R. Ward: Infec· tious Diseases of Children, 2nd ed. C. V. Mosby Company.) Acute Tonsillopharyngitis-Vesicular or Ulcerative
The syndrome of fever, sore throat and vesicles or shallow 2- to 4-mm. ulcers is usually caused by Coxsackie A or herpes simplex virus. s. 13 Antimicrobial therapy has no effect on the natural course of these infections. Acute Epiglottitis
The syndrome of fever, barking cough, respiratory distress with inspiratory stridor, suprasternal retractions and a beefy, red, swollen epiglottis is most often caused by H. influenzae, type B. Other bacterial and viral agents are less common causes. ANTIMICROBIAL THERAPY. The drug of choice is either chloramphenicol or streptomycin. Our preference is chloramphenicol. In other clinics streptomycin may be preferred. It has been our practice to add a sulfonamide to the therapy. The following dosages are recommended: (a) chloramphenicol, 100 mg. per kilogram of body weight per day by mouth or intramuscularly; (b) sulfisoxazole or sulfadiazine, 150 mg. per kilogram of body weight per day by mouth. If streptomycin is used, the usual dose is 40 mg. per kilogram of body weight per day.
SAUL KRUGMAN
1205
Acute Laryngotracheitis with or without Bronchitis
The clinical manifestations of this syndrome closely resemble those of acute epiglottitis. The obstruction, however, is more apt to be subglottic than supraglottic. As indicated in Table 35, acute laryngotracheitis is usually caused by one of many viral agents, most commonly Myxovirus parainfluenzae, type 1. ANTIMICROBIAL THERAPY. It is difficult to make a clinical differentiation between bacterial and viral causes of laryngotracheobronchitis. In view of the poor prognosis associated with this disease and the importance of early, optimum therapy, it has been our practice to treat with antimicrobials until we can be certain that we are not dealing with a bacterial infection. Our regimen of therapy has included both penicilin and chloramphenicol. Acute Bronchiolitis
This syndrome is seen most often in infants below the age of 18 months. The illness usually begins with an upper respiratory tract infection which progresses rapidly to severe cough, respiratory distress, retraction of the intercostal spaces, cyanosis and prostration. The respirations are rapid (about 60 per minute), shallow, labored and accompanied by wheezing. The physical findings and roentgenogram are compatible with the picture of obstructive emphysema; e.g. hyperresonant percussion note, prolonged expiration, and abnormally transparent lung field with depressed diaphragms. As indicated in Table 35, several infectious agents may cause acute bronchiolitis. It seems, however, that most cases have a viral etiology. Recent studies have incriminated the respiratory syncytial (RS) virus as a relatively common cause. 2 ANTIMICROBIAL THERAPY. The efficacy of antimicrobials for the treatment of acute bronchiolitis is questionable. The dramatic response observed with therapy of pneumococcal pneumonia has not been observed with most cases of acute bronchiolitis. Nevertheless it seems rational to recommend antimicrobial therapy for the following reasons: 1. A clinical differentiation between acute bronchiolitis and acute bacterial bronchopneumonia of infants is difficult and often impossible. Accordingly, it would be wise to initiate therapy with antimicrobial drugs. 2. Recent studies have indicated that corticosteroid therapy may provide symptomatic relief. 10 Patients receiving this therapy should also be given antibiotics, especially if the causative agent of the bronchiolitis is unknown. In the absence of a known causative agent it would be wise to provide broad-spectrum coverage. Aqueous procaine penicillin, 600,000
1206
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
(See Legend on facing page.)
SAUL KRUGMAN
1207
Fig. 24. Roentgenograms of E. R., a 3-month·old infant with acute staphylococcal pneumonia, showing typical progression from consolidation to pneumatocele formation and pyopneumothorax to final resolution. A, Roentgenogram taken on admission, Feb. 6, 1958 (third day of iIlness), showing an area of consolidation in the left midlung field. B, Roentgenogram taken Feb. 10, 1958 (seventh day of iIlness), showing pneumatocele formation and pyopneumothorax. The heart and mediastinum are dis· placed to the opposite side. C, Roentgenogram taken Feb. 28, 1958 (twenty·fifth day of iIlness), showing pneumatocele5, pyopneumothorax and shift of mediastinum still present. D, Roentgenogram taken March 28, 1958 (fifty-third day of iIlness), showing considerable clearing. (From S. Krugman and R. Ward: Infectious Diseases of Children. 2nd ed. C. V. Mosby Company.)
] 208
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
units intramuscularly once daily, plus either chloramphenicol or tetracycline is recommended. Acute Pneumonitis
The diagnosis of pneumonia is suggested by the occurrence of fever, cough, respiratory distress and localized pulmonary signs. The etiology is most commonly bacterial or viral. The various etiologic agents respon· sible for pneumonia are listed in Table 35. The roentgenogram and blood cell count may provide an early clue to the type of pneumonia. A polymorphonuclear leukocytosis plus lobar consolidation suggests a pneumococcal etiology. The presence of pneumatoceles, empyema or pyopneumothorax implicates the staphylococcus (Fig. 24). A positive blood culture is a helpful diagnostic aid. In general, however, it is difficult to differentiate bacterial from viral pneumonitis during the early stage of the disease. ANTIMICROBIAL THERAPY. Early specific antimicrobial therapy of bacterial pneumonia in infants and children will prevent unnecessary complications and improve the prognosis. Consequently, antimicrobial therapy should be started as soon as a diagnosis of pneumonia is suspected. The treatment should be aimed at the most probable bacterial cause. Pneumococcal Pneumonia. Adequate therapy can be instituted with anyone of the following antimicrobial drugs: penicillin, tetracycline, erythromycin, chloramphenicol or sulfonamides. Penicillin is undoubtedly the most effective drug. A dramatic response to therapy is usually observed within one to two days. Treatment should be continued for at least five days after the temperature has become normal. The following dosage schedules are suggested: PENICILLIN:
TETRACYCLINE: ERYTHROMYCIN:
(a) aqueous procaine penicillin, 600,000 units intramuscularly once daily, or (b) penicillin by mouth, 300,000 to 500,000 units 4 times daily, or (c) a single intramuscular inoculation of aqueous procaine penicillin, 600,000 units, combined with benzathine penicillin G, 600,000 units. This preparation is available in a 2-ml. vial. It is well tolerated,S and it provides a blood level bactericidal for pneumococci for at least 10 days after a single injection (Fig. 23). 25 mg. per kilogram of body weight daily in 4 doses by mouth 50 mg. per kilogram of body weight daily in 4 doses by mouth
SAUL KRUGMAN CHLORAMPHENICOL: SULFADIAZINE
9
120
same dose as erythromycin
)
SULFISOXAZOLE TRIPLE SULFON-
J
200 mg. per kilogram of body weight daily in 4 doses
AMIDES
Many cases of pneumococcal pneumonia can be treated effectively with a single injection of a mixture of aqueous procaine penicillin, 600,000 units, and benzathine penicillin G, 600,000 units. The dramatic response to this therapy in a nine-year-old boy with pneumococcal tonsillitis and pneumonia is described in the following case report and illustrated in Figure 25. CASE REPORT. T.A., a 9-year-old boy, was seen on his first day of illness (9/20/1960) after sudden onset of fever, sore throat, anorexia and vomiting. Physical examination revealed fever (104.5 F.), follicular tonsillitis and a polynucleosis ( 30,000 white blood cells with 93 per cent polymorphonuclear leukocytes). The initial clinical impression was streptococcal tonsillitis. Accordingly, the patient was inoculated with a single intramuscular dose of a 2-m!. mixture containing aqueous procaine 0
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PENICILLIN
Fig. 25. Treatment of type 1 pneumococcal tonsillitis and pneumonia with a single injection of a penicillin preparation containing 600,000 units of aqueous procaine penicillin and 600,000 units of benzathine penicillin C. Note the dramatic subsidence of fever, the clearing of the exudative tonsillitis and pulmonary consolidation, and the rapid elimination of the type 1 pneumococci from the throat and blood. The penicillin blood level at 11 days (0.04 unit per mI.) still exceeded the sensitivity of the patient's type 1 pneumococcus «0.025 unit of penicillin per mI.).
1210
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
Fig. 26. A, Roentgenogram of chest (patient T.A., Figure 25) taken on third day of illness, showing consolidation of the posterior segment of the right upper lobe. B, Roentgenogram taken on eleventh day of illness, showing clearing of the consolidation. penicillin, 600,000 units, and benzathine penicillin G, 600,000 units. The following day (9/21/1960) the admission throat culture and blood culture were reported positive for pneumococci, type l. No additional therapy was given. Blood cultures obtained on September 21 and 22 were negative. A roentgenogram of the chest taken on September 22 (third day of illness) revealed a consolidation of the posterior segment of the right upper lobe (Fig. 26, A).
SAUL KRUGMAN
1211
Fever subsided within 24 hours after initiation of penicillin therapy. The exudate disappeared from the tonsils by the fifth day. In spite of roentgen evidence of pneumonia, no cough was present. Pulmonary consolidation showed considerable clearing by the eighth day and was gone by the eleventh day (9/30/1960), as indicated in Figure 26, B. Blood levels were determined 3, 8 and 11 days after the single injection of penicillin. As indicated in Figure 25, the levels of 0.155,0.056 and 0.04 unit per milliliter exceeded the penicillin sensitivity of the patient"s type 1 pneumococcus.
Staphylococcal Pneumonia. In infants this illness usually begins as an upper respiratory tract infection. The symptoms progress rapidly with increasing cough, tachypnea, dyspnea, subcostal retractions, and fever. Subsequently there may be abdominal distention, pallor, cyanosis, prostration and possibly death. The physical findings vary with the pulmonary involvement, e.g. consolidation, abscess formation, pneumatoceles, empyema, pneumothorax or pyopneumothorax. The typical roentgen findings of rapidly changing infiltration, pneumatoceles, pneumothorax and empyema are illustrated in Figure 24. Staphylococcal pneumonia in an infant is an acute medical emergency. The chances for survival will be significantly improved by early, optimum and intensive antimicrobial therapy. Delay in therapy may be followed by an irreversible chronic suppurative process. The various antistaphylococcal drugs recommended for the treatment of severe infections are listed in Table 36. As a general principle it may be wise to use one of the bactericidal drugs (penicillin, bacitracin, vancomycin or kanamycin) plus one of the bacteriostatic drugs (chloramphenicol, erythromycin, novobiocin or ristocetin). Streptomycin and tetracyclines have been less effective in recent years. Sodium dimethoxyphenyl penicillin, a new penicillin which is not inactivated by staphylococcal penicillinase, has minimized the need for combination therapy.3 The patient's clinical response and the results of sensitivity tests will influence subsequent changes in therapy. The duration of antimicrobial therapy must be individualized. It may range between two weeks and two months, dependent upon the extent of pulmonary involvement and the presence or absence of complications. Hemophilus Influenzae Pneumonia. The clinical manifestations are similar to those of pneumococcal pneumonia. Failure to respond to penicillin therapy· may provide the first clue to the correct diagnosis, which is confirmed by a positive nasopharyngeal or blood culture. Chloramphenicol or streptomycin therapy is indicated. Viral Pneumonia. Most viral pneumonias are self-limited infections which are not affected by antimicrobial therapy. Psittacosis, one of the larger viruses, will respond to tetracycline therapy. A recent study has indicated that demethylchlortetracycline is an effective therapeutic
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TABLE
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36. Antimicrobial Drugs for Therapy of Severe Staphylococcal Infections* Oral
Penicillin: Aqueous crystalline Sodium dimethoxyphenyl
Bacitracin
Intramuscular
Chloramphenicol (Chloromycetin)
2000 units/kg. of body 600-1000 units/kg. of body weight/day in weight/day in 4 doses 3 doses Maximum: 50,000 units/day
g ~
Rare in children Poor gastrointestinal absorption Poor gastrointestinal absorption
~ ~ >< Z [;l
en >0
100 mg./kg. of body 25-50 mg./kg. of body weight/day in 4 doses weight/day in 3 doses Maximum: 2 gm./day 100 mg./kg. of body weight/day in 3 doses Maximum: 2 gm./day
~
::0
Nephrotoxic
40-50 mg./kg. of body weight/day in 2 doses Maximum: 2 gm./day
100 mg./kg. of body weight/day in 4 doses Maximum: 2 gm./day
REMARKS
Intravenous
8-12 million units/day 8-12 million units/day in 4 doses in 6 doses 100 mg./kg. of body 100 mg./kg. of body weight/day in 4 doses weight
Vancomycin (Vancocin)
Kanamycin (Kantrex)
TOXICITY
DOSEt
DRUG
Pain at site of injection Phlebitis
Poor gastroin testinal absorption
Nephrotoxic Deafness
Poor gastrointestinal absorption
i "J
~
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sa
en t"l
100 mg./kg. of body weight/day in 3 doses Maximum: 2 gm./day
Aplastic anemia (very rare)
Excellent gastrointestinal absorption
~
t"l
en
Erythromycin (Erythrocin; Ilotycin)
50 mg./kg. of body weight/day in 4 doses Maximum: 2 gm./day
Novobiocin (Albamycin; Cathomycin)
25-40 mg./kg. of body weight/day in 4 doses Maximum: 1-2 gm./ day
Ristocetin (Spontin)
25 mg./kg. of body weight/day in 2 doses Maximum: 1 gm./day
30 mg./kg. of body Nausea weight/day in 3 doses Vomiting Maximum; 1 gm./day Superinfection (not common)
Good gastroin testinal absorption
25 mg./kg. of body weight/day in 2 doses Maximum: 1 gm./day
Rash Drug fever Diarrhea Granulopenia
Good gastroin testinal absorption
25
Rash Thrombophlebitis Drug fever Neutropenia
Poor gastrointestinal absorption
mg./kg. of body weight/day in 2 or 3 doses Maximum: 2 gm./day
* Staphylococcal pneumonia, osteomyelitis, septicemia, endocarditis or meningitis. t
For premature and newborn infants one fourth of the dose is recommended.
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1214
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
agent for the treatment of cold-agglutinin-positive primary atypical pneumonia caused by the Eaton (PAP) virus. 7 A diagnosis of viral pneumonia is usually made by exclusion. Consequently, antimicrobial therapy would be indicated until a bacterial etiology can be definitely excluded. Tetracycline therapy would be in· dicated for cold-agglutinin-positive primary atypical pneumonia. Pneumonia of Unknown Etiology. Antimicrobial therapy should be aimed at the most probable bacterial causes of the infection. In infants the suspects would be pneumococci, Hemophilus influenzae and staphylococci. Therefore a possible initial choice of drugs would be a combination of penicillin plus chloramphenicol or streptomycin. In older children the most common bacterial causes would be pneumococci, streptococci or cold-agglutinin-positive primary atypical pneumonia. Therefore it may be wise to initiate therapy with penicillin. In the absence of a clinical response, tetracycline may be added. Otitis Media
A discussion of antimicrobial therapy for diseases of the respiratory tract would be incomplete without a brief consideration of otitis media. Acute purulent otitis media requires early, optimum therapy. In infants most cases are due to pneumococci and Hemophilus influenzae. In older children pneumococci and hemolytic streptococci are the most common causes. Consequently a useful and effective combination includes penicillin and a sulfonamide. If the clinical response is not satisfactory, the sulfonamide may be replaced with chloramphenicol or tetracycline. REFERENCES
1. Andrews, C. H., Bang, F. B., Chanock, R. M., and Zdanov, V. M.: Parainfluenza
2. 3. 4. 5. 6. 7. 8.
Viruses 1, 2 and 3. Suggested Names for Recently Described Myxoviruses. Virology, 8:129, 1959. Beem, M., Wright, F. H., Hamre, D., Egerer, R., and Oehme, D.: Association of the Chimpanzee Coryza Agent with Acute Respiratory Disease in Children. New England J. Med., 263:523, 1960. Bunn, P. A., Knight, R., and Amberg, J.: Some Notes about a New Synthetic Penicillin for Staphylococcal Disease. New York State J. Med., 60:3074, 1960. Chanock, R. M., and others: Newly Recognized Myxoviruses from Children with Respiratory Disease. New England J. Med., 258:207, 1958. Dingle, J. H., and others: Study of Illness in Group of Cleveland Families. Am. J. Hyg., 58:16, 1953. Huebner, R. J., Cole, R. M., Beeman, E. A., Bell, J. A., and Peers, J. H.: Her· pangina: Etiologic Studies of a Specific Infectious Disease. l.A.M.A., 145:628, 1951. Kingston, J. R., and others: Eaton Agent Pneumonia. l.A.M.A., 176:118, 1960. Krugman, S., and Ebin, E. V.: Improved Local Tolerance to Penicillin. Pediatrics, 21:243, 1958.
SAUL KRUGMAN
1215
9. Mortimer, E. A., Jr., and Watterson, R. L.: Bacteriologic Investigation of Otitis Media in Infancy. Pediatrics, 17:359, 1956. 10. Osaki, F. A., Salitsky, S., and Barness, L. A.: Steroid Therapy in Bronchiolitis: A Double Blind Study. Abstract. American Pediatric Society Meeting, Atlantic City, May 2, 1961. 11. Parrott, R. H.: Newly Isolated Viruses in Respiratory Disease. Pediatrics, 20: 1060,1957. 12. Powers, G. F., and Boisvert, P. L.: Age as a Factor in Streptococcus. J. Pediat., 25:481, 1944. 13. Scott, T. F. M., Steigman, A. J., and Convey, J. H.: Acute Infectious Gingivosto· matitis; Etiology, Epidemiology and Clinical Picture of a Common Disorder Caused by the Virus of Herpes Simplex. J.A.M.A., 117:999, 1941. 14. Vargosko, A. J., and others: Association of Type 2 Hemadsorption (Parainfluenza 1) Virus and Asian Influenza A Virus with Infectious Croup. New England f. Med., 261:1,1959. 550 - 1st Ave. New York 16, N.Y.
i
: i
I ndications for antimicrobial therapy in disease of the respiratory tract are rarely clear-cut. The pediatrician is constantly plagued by the decision "to treat or not to treat." An adimicrobial drug which may be lifesaving for an infant with severe bacterial pneumonia may be worthless or even harmful for a child with a viral infection. Two decades ago the choice of an antibacterial drug was a simple task. In 1940 only sulfonamides were available. Today more than 15 antimicrobial agents have been added to the formulary. The selection of the appropriate drug for the treatment of an infection requires both clinical acumen and a knowledge of the virtues, limitations and hazards of the various antimicrobial agents. FACTORS AFFECTING CHOICE OF ANTIBIOTICS
Figure 22 lists the various factors which may affect the selection of a particular antibiotic. Clinical Impression of Etiology
Information derived from a careful history and physical examination will enable a physician to classify a respiratory illness into one of the syndromes listed in Table 35. Each syndrome may be caused by a variety of etiologic agents, most commonly bacterial or viral. Rickettsial, parasitic and mycotic respiratory diseases are relatively uncommon. A knowledge of the most probable causative agent of each syndrome is helpful in assessing the clinical estimate of the etiology. For example, a clinical diagnosis of acute vesicular or ulcerative tonsillopharyngitis would suggest a viral etiology, most probably herpes simplex or Coxllqq
1200
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES CLINICAL IMPRESSION OF ETIOLOGY
IDENTIFICATION OF CAUSATIVE AGENT
2
~8------------~
7 PHYSICIAN'S PREFERENCE
1-------------4
6 POTENTIAL TOXICITY
5 EPIDEMIOLOGIC FACTORS
Fig. 22. Factors affecting the choice of an antibiotic.
sackie A virus. These infections are not affected by antimicrobial therapy. On the other hand, a diagnosis of acute exudative tonsillopharyngitis suggests a streptococcal etiology. Identification of Causative Agent
The clinical estimate of the etiology may be confirmed or altered by the results of bacteriologic cultures. In acute exudative tonsillitis the identification of group A hemolytic streptococci on throat culture is confirmatory. Occasionally the results of the throat culture and failure to respond to penicillin therapy may suggest another etiology. For example, Hemophilus influenzae tonsillitis or viral tonsillitis will not be affected by penicillin therapy. Nature of the Infection
The kind of respiratory infection will affect the decision to withhold or initiate antimicrobial therapy. For example, most cases of acute nasopharyngitis and acute bronchiolitis have a viral etiology. In view of the benign nature of upper respiratory tract infections, initial therapy with antibiotics is rarely indicated. On the other hand, acute bronchiolitis carries a serious prognosis and often resembles severe bacterial bronchopneumonia. Consequently a physician would be justified in initiating antimicrobial therapy for this "nonbacterial" disease. Subsequently the treatment may be discontinued if the clinical course and bacteriologic reports rule out a bacterial etiology.
SAUL KRUGMAN TABLE
1201
35. Classification of Acute Respiratory Infections in Children by Clinical Syn· drome and Etiologic Agent* ETIOLOGY
CLINICAL SYNDROMES
Bacterial Common cold, febrile naso- Hemolytic streptococcus (in infants) pharyngitis, acute respiratory disease, acute catarrhal tonsillopharyngitis with or without conj unctivitis Acute tonsillopharyngitis (exudative or membranous)
Hemolytic streptococcus t Corynebacterium diphtheriae
Adenovirus Eaton-Liu (PAP) Parainfluenza 3 (HA-l) Respiratory syncytial (RS) ECHO 8, 20, 28 Coxsackie A Infectious mononucleosis t Adenovirus
Herpes simplex t Coxsackie At
Acute tonsillopharyngitis (vesicular or ulcerative) Acute epiglottitis (croup)
Viral
Hemophilus influenzae, type Bt
C. diphtheriae Acute laryngotracheitis with or without bron- H. influenzae chitis (croup)
Parainfluenza 1 (HA-2) t Adenovirus Parainfluenza 2 (CA) Influenza A Respiratory syncytial (RS) ECHO 11 Parainfluenza 3 (HA-l)
Acute bronchiolitis
H. influenzae ?
Adenovirus Parainfluenza 3 (HA-l) Eaton-Liu (PAP) Respiratory syncytial (RS) t
Acute pneumonitis
Pneumococcus t Staphylococcus Hemolytic streptococcus H. influenzae
Adenovirus Chickenpox Eaton-Liu (PAP) Influenza Measles Parainfluenza 3 (HA-l) Respiratory syncytial (RS) t Psittacosis
* Rickettsial,
parasitic and mycotic infections are not included in this table. t One of the most common etiologic agents. t Viral etiology not proved. PAP: primary atypical pneumonia. CA: croup-associated. HA: hemadsorption. Modified from S. Krugman and R. Ward: Infectious Diseases of Children. 2nd ed. St Louis, C. V. Mosby Company.
1202
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
Host Factors
A variety of host factors may influence the choice of a particular antimicrobial drug. A patient may be allergic to the drug of choice. In this event the second best drug would be selected. Other host factors such as age or the presence of another disease, e.g. rheumatic fever, would affect the selection of an antibiotic. Epidemiologic Factors
The estimate of the etiology of the respiratory syndrome will be influenced by the knowledge of an epidemic of a particular bacterial or viral infection in the community. A nonexudative tonsillopharyngitis usually has a viral etiology. In the presence of an epidemic of scarlet fever the likelihood of a streptococcal etiology would increase. Under these circumstances penicillin therapy would be indicated. Potential Toxicity
This factor is particularly important in situations which require the parenteral use of drugs such as bacitracin or neomycin. The virtues of these agents must be balanced against their nephrotoxic and ototoxic potentialities. Physician's Preference
Past personal experiences have a profound effect on a physician's choice of an antimicrobial agent. The unfortunate occurrence of a severe toxic reaction or a fatal anaphylactoid episode may prejudice a physician against a particular drug. Cost
The factor of cost may influence the choice of a sulfonamide in preference to a more expensive tetracycline preparation. ANTIMICROBIAL THERAPY OF SPECIFIC RESPIRATORY SYNDROMES Common Cold, Febrile Nasopharyngitis, Acute Respiratory Disease, and Acute Catarrhal Tonsillopharyngitis with or without Conjunctivitis
These four respiratory syndromes are most commonly identified as "upper respiratory tract infections." They are characterized by varying degrees of one or more of the following manifestions: nasal congestion and discharge, conjunctivitis, sore throat, cough, and tonsillopharyngeal
SAUL KRUGMAN
1203
reddening without exudate. As indicated in Table 35, these infections usually have a viral etiology. Adenovirus, parainfluenza, PAP, respiratory syncytial (RS), ECHO and Coxsackie viruses have been associated with these diseases. 1 , 2, 4, 6, 7, 11, 14 As newer respiratory viruses are identified, this list will increase. This clinical syndrome is rarely caused by bacteria. 5 Rarely the hemolytic streptococcus may be responsible for nasopharyngitis in infants. 12 ANTIMICROBIAL THERAPY. Antibiotics are not indicated for most upper respiratory tract infections of children; their use has neither therapeutic nor prophylactic efficacy. If a streptococcal etiology is suggested because of a known contact or a positive culture, penicillin therapy would be indicated. Acute Tonsillopharyngitis with Exudate or Membrane
The group A hemolytic streptococcus is the most common cause of this disease, which is characterized by fever, sore throat and an exudative or membranous tonsillopharyngitis. Diphtheria and infectious mononucleosis are less common causes. ANTIMICROBIAL THERAPY. The drug of choice is unquestionably penicillin. Optimum therapy may be achieved with anyone of the following schedules: 1. Aqueous procaine penicillin, 600,000 units intramuscularly, daily for 10 days. (This regimen is not recommended because of the large number of injections.) 2. Benzathine penicillin G, 600,000 units intramuscularly as a single injection. (The disadvantage of this regimen is the high incidence of severe local reactions.) 3. Oral penicillin G or V, 300,000 units 4 times daily for 10 days. (Penicillin G should be given on an empty stomach.) 4. Various combinations of 1 and 3, such as intramuscular therapy for 3 days and oral administration for 7 days. The regimen of penicillin therapy should be individualized. An effective, well tolerated and relatively inexpensive preparation is available as a mixture of 600,000 units of aqueous procaine penicillin and 600,000 units of benzathine penicillin G in a 2-ml. vial for intramuscular inoculation. S As indicated in Figure 23, a single injection provides an adequate antistreptococcal blood level for at least 10 days. Erythromycin is an effective substitute for the treatment of patients allergic to penicillin. The recommended dose is 20 mg. per pound of body weight per day (4 times daily) for a 10-day period. Sulfonamides are effective for prophylaxis but not treatment of streptococcal infections. 1'1
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1204
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES DOSE (2 MU ] [ PPG-600,000 U BPG-600,000U
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RANGE OF PENICILLIN SENSITIVITY "IN VITRO" OF GROUP A STREPTOCOCCI
10
DAYS FOLLOWING INOCULATION AGE - 6 MOS. TO II YRS (4 YR)
NUMBER OF PATIENTS-36 AGE-7WKS TO 4YRS (I~YR)
WEIGHT- 20 TO 94 LBS (39 LBS)
WEIGHT - " TO 29 LBS (22 LBS)
NUMBER OF PATIENTS - 7 2
Fig, 23, Penicillin blood levels 7 and 10 days after a single injection of a mixture of aqueous procaine penicillin G (PPG) and benzathine penicillin G (BPG), Each black dot represents 1 blood level determination. (From S. Krugman and R. Ward: Infec· tious Diseases of Children, 2nd ed. C. V. Mosby Company.) Acute Tonsillopharyngitis-Vesicular or Ulcerative
The syndrome of fever, sore throat and vesicles or shallow 2- to 4-mm. ulcers is usually caused by Coxsackie A or herpes simplex virus. s. 13 Antimicrobial therapy has no effect on the natural course of these infections. Acute Epiglottitis
The syndrome of fever, barking cough, respiratory distress with inspiratory stridor, suprasternal retractions and a beefy, red, swollen epiglottis is most often caused by H. influenzae, type B. Other bacterial and viral agents are less common causes. ANTIMICROBIAL THERAPY. The drug of choice is either chloramphenicol or streptomycin. Our preference is chloramphenicol. In other clinics streptomycin may be preferred. It has been our practice to add a sulfonamide to the therapy. The following dosages are recommended: (a) chloramphenicol, 100 mg. per kilogram of body weight per day by mouth or intramuscularly; (b) sulfisoxazole or sulfadiazine, 150 mg. per kilogram of body weight per day by mouth. If streptomycin is used, the usual dose is 40 mg. per kilogram of body weight per day.
SAUL KRUGMAN
1205
Acute Laryngotracheitis with or without Bronchitis
The clinical manifestations of this syndrome closely resemble those of acute epiglottitis. The obstruction, however, is more apt to be subglottic than supraglottic. As indicated in Table 35, acute laryngotracheitis is usually caused by one of many viral agents, most commonly Myxovirus parainfluenzae, type 1. ANTIMICROBIAL THERAPY. It is difficult to make a clinical differentiation between bacterial and viral causes of laryngotracheobronchitis. In view of the poor prognosis associated with this disease and the importance of early, optimum therapy, it has been our practice to treat with antimicrobials until we can be certain that we are not dealing with a bacterial infection. Our regimen of therapy has included both penicilin and chloramphenicol. Acute Bronchiolitis
This syndrome is seen most often in infants below the age of 18 months. The illness usually begins with an upper respiratory tract infection which progresses rapidly to severe cough, respiratory distress, retraction of the intercostal spaces, cyanosis and prostration. The respirations are rapid (about 60 per minute), shallow, labored and accompanied by wheezing. The physical findings and roentgenogram are compatible with the picture of obstructive emphysema; e.g. hyperresonant percussion note, prolonged expiration, and abnormally transparent lung field with depressed diaphragms. As indicated in Table 35, several infectious agents may cause acute bronchiolitis. It seems, however, that most cases have a viral etiology. Recent studies have incriminated the respiratory syncytial (RS) virus as a relatively common cause. 2 ANTIMICROBIAL THERAPY. The efficacy of antimicrobials for the treatment of acute bronchiolitis is questionable. The dramatic response observed with therapy of pneumococcal pneumonia has not been observed with most cases of acute bronchiolitis. Nevertheless it seems rational to recommend antimicrobial therapy for the following reasons: 1. A clinical differentiation between acute bronchiolitis and acute bacterial bronchopneumonia of infants is difficult and often impossible. Accordingly, it would be wise to initiate therapy with antimicrobial drugs. 2. Recent studies have indicated that corticosteroid therapy may provide symptomatic relief. 10 Patients receiving this therapy should also be given antibiotics, especially if the causative agent of the bronchiolitis is unknown. In the absence of a known causative agent it would be wise to provide broad-spectrum coverage. Aqueous procaine penicillin, 600,000
1206
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
(See Legend on facing page.)
SAUL KRUGMAN
1207
Fig. 24. Roentgenograms of E. R., a 3-month·old infant with acute staphylococcal pneumonia, showing typical progression from consolidation to pneumatocele formation and pyopneumothorax to final resolution. A, Roentgenogram taken on admission, Feb. 6, 1958 (third day of iIlness), showing an area of consolidation in the left midlung field. B, Roentgenogram taken Feb. 10, 1958 (seventh day of iIlness), showing pneumatocele formation and pyopneumothorax. The heart and mediastinum are dis· placed to the opposite side. C, Roentgenogram taken Feb. 28, 1958 (twenty·fifth day of iIlness), showing pneumatocele5, pyopneumothorax and shift of mediastinum still present. D, Roentgenogram taken March 28, 1958 (fifty-third day of iIlness), showing considerable clearing. (From S. Krugman and R. Ward: Infectious Diseases of Children. 2nd ed. C. V. Mosby Company.)
] 208
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
units intramuscularly once daily, plus either chloramphenicol or tetracycline is recommended. Acute Pneumonitis
The diagnosis of pneumonia is suggested by the occurrence of fever, cough, respiratory distress and localized pulmonary signs. The etiology is most commonly bacterial or viral. The various etiologic agents respon· sible for pneumonia are listed in Table 35. The roentgenogram and blood cell count may provide an early clue to the type of pneumonia. A polymorphonuclear leukocytosis plus lobar consolidation suggests a pneumococcal etiology. The presence of pneumatoceles, empyema or pyopneumothorax implicates the staphylococcus (Fig. 24). A positive blood culture is a helpful diagnostic aid. In general, however, it is difficult to differentiate bacterial from viral pneumonitis during the early stage of the disease. ANTIMICROBIAL THERAPY. Early specific antimicrobial therapy of bacterial pneumonia in infants and children will prevent unnecessary complications and improve the prognosis. Consequently, antimicrobial therapy should be started as soon as a diagnosis of pneumonia is suspected. The treatment should be aimed at the most probable bacterial cause. Pneumococcal Pneumonia. Adequate therapy can be instituted with anyone of the following antimicrobial drugs: penicillin, tetracycline, erythromycin, chloramphenicol or sulfonamides. Penicillin is undoubtedly the most effective drug. A dramatic response to therapy is usually observed within one to two days. Treatment should be continued for at least five days after the temperature has become normal. The following dosage schedules are suggested: PENICILLIN:
TETRACYCLINE: ERYTHROMYCIN:
(a) aqueous procaine penicillin, 600,000 units intramuscularly once daily, or (b) penicillin by mouth, 300,000 to 500,000 units 4 times daily, or (c) a single intramuscular inoculation of aqueous procaine penicillin, 600,000 units, combined with benzathine penicillin G, 600,000 units. This preparation is available in a 2-ml. vial. It is well tolerated,S and it provides a blood level bactericidal for pneumococci for at least 10 days after a single injection (Fig. 23). 25 mg. per kilogram of body weight daily in 4 doses by mouth 50 mg. per kilogram of body weight daily in 4 doses by mouth
SAUL KRUGMAN CHLORAMPHENICOL: SULFADIAZINE
9
120
same dose as erythromycin
)
SULFISOXAZOLE TRIPLE SULFON-
J
200 mg. per kilogram of body weight daily in 4 doses
AMIDES
Many cases of pneumococcal pneumonia can be treated effectively with a single injection of a mixture of aqueous procaine penicillin, 600,000 units, and benzathine penicillin G, 600,000 units. The dramatic response to this therapy in a nine-year-old boy with pneumococcal tonsillitis and pneumonia is described in the following case report and illustrated in Figure 25. CASE REPORT. T.A., a 9-year-old boy, was seen on his first day of illness (9/20/1960) after sudden onset of fever, sore throat, anorexia and vomiting. Physical examination revealed fever (104.5 F.), follicular tonsillitis and a polynucleosis ( 30,000 white blood cells with 93 per cent polymorphonuclear leukocytes). The initial clinical impression was streptococcal tonsillitis. Accordingly, the patient was inoculated with a single intramuscular dose of a 2-m!. mixture containing aqueous procaine 0
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PENICILLIN
Fig. 25. Treatment of type 1 pneumococcal tonsillitis and pneumonia with a single injection of a penicillin preparation containing 600,000 units of aqueous procaine penicillin and 600,000 units of benzathine penicillin C. Note the dramatic subsidence of fever, the clearing of the exudative tonsillitis and pulmonary consolidation, and the rapid elimination of the type 1 pneumococci from the throat and blood. The penicillin blood level at 11 days (0.04 unit per mI.) still exceeded the sensitivity of the patient's type 1 pneumococcus «0.025 unit of penicillin per mI.).
1210
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
Fig. 26. A, Roentgenogram of chest (patient T.A., Figure 25) taken on third day of illness, showing consolidation of the posterior segment of the right upper lobe. B, Roentgenogram taken on eleventh day of illness, showing clearing of the consolidation. penicillin, 600,000 units, and benzathine penicillin G, 600,000 units. The following day (9/21/1960) the admission throat culture and blood culture were reported positive for pneumococci, type l. No additional therapy was given. Blood cultures obtained on September 21 and 22 were negative. A roentgenogram of the chest taken on September 22 (third day of illness) revealed a consolidation of the posterior segment of the right upper lobe (Fig. 26, A).
SAUL KRUGMAN
1211
Fever subsided within 24 hours after initiation of penicillin therapy. The exudate disappeared from the tonsils by the fifth day. In spite of roentgen evidence of pneumonia, no cough was present. Pulmonary consolidation showed considerable clearing by the eighth day and was gone by the eleventh day (9/30/1960), as indicated in Figure 26, B. Blood levels were determined 3, 8 and 11 days after the single injection of penicillin. As indicated in Figure 25, the levels of 0.155,0.056 and 0.04 unit per milliliter exceeded the penicillin sensitivity of the patient"s type 1 pneumococcus.
Staphylococcal Pneumonia. In infants this illness usually begins as an upper respiratory tract infection. The symptoms progress rapidly with increasing cough, tachypnea, dyspnea, subcostal retractions, and fever. Subsequently there may be abdominal distention, pallor, cyanosis, prostration and possibly death. The physical findings vary with the pulmonary involvement, e.g. consolidation, abscess formation, pneumatoceles, empyema, pneumothorax or pyopneumothorax. The typical roentgen findings of rapidly changing infiltration, pneumatoceles, pneumothorax and empyema are illustrated in Figure 24. Staphylococcal pneumonia in an infant is an acute medical emergency. The chances for survival will be significantly improved by early, optimum and intensive antimicrobial therapy. Delay in therapy may be followed by an irreversible chronic suppurative process. The various antistaphylococcal drugs recommended for the treatment of severe infections are listed in Table 36. As a general principle it may be wise to use one of the bactericidal drugs (penicillin, bacitracin, vancomycin or kanamycin) plus one of the bacteriostatic drugs (chloramphenicol, erythromycin, novobiocin or ristocetin). Streptomycin and tetracyclines have been less effective in recent years. Sodium dimethoxyphenyl penicillin, a new penicillin which is not inactivated by staphylococcal penicillinase, has minimized the need for combination therapy.3 The patient's clinical response and the results of sensitivity tests will influence subsequent changes in therapy. The duration of antimicrobial therapy must be individualized. It may range between two weeks and two months, dependent upon the extent of pulmonary involvement and the presence or absence of complications. Hemophilus Influenzae Pneumonia. The clinical manifestations are similar to those of pneumococcal pneumonia. Failure to respond to penicillin therapy· may provide the first clue to the correct diagnosis, which is confirmed by a positive nasopharyngeal or blood culture. Chloramphenicol or streptomycin therapy is indicated. Viral Pneumonia. Most viral pneumonias are self-limited infections which are not affected by antimicrobial therapy. Psittacosis, one of the larger viruses, will respond to tetracycline therapy. A recent study has indicated that demethylchlortetracycline is an effective therapeutic
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TABLE
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36. Antimicrobial Drugs for Therapy of Severe Staphylococcal Infections* Oral
Penicillin: Aqueous crystalline Sodium dimethoxyphenyl
Bacitracin
Intramuscular
Chloramphenicol (Chloromycetin)
2000 units/kg. of body 600-1000 units/kg. of body weight/day in weight/day in 4 doses 3 doses Maximum: 50,000 units/day
g ~
Rare in children Poor gastrointestinal absorption Poor gastrointestinal absorption
~ ~ >< Z [;l
en >0
100 mg./kg. of body 25-50 mg./kg. of body weight/day in 4 doses weight/day in 3 doses Maximum: 2 gm./day 100 mg./kg. of body weight/day in 3 doses Maximum: 2 gm./day
~
::0
Nephrotoxic
40-50 mg./kg. of body weight/day in 2 doses Maximum: 2 gm./day
100 mg./kg. of body weight/day in 4 doses Maximum: 2 gm./day
REMARKS
Intravenous
8-12 million units/day 8-12 million units/day in 4 doses in 6 doses 100 mg./kg. of body 100 mg./kg. of body weight/day in 4 doses weight
Vancomycin (Vancocin)
Kanamycin (Kantrex)
TOXICITY
DOSEt
DRUG
Pain at site of injection Phlebitis
Poor gastroin testinal absorption
Nephrotoxic Deafness
Poor gastrointestinal absorption
i "J
~
"J
sa
en t"l
100 mg./kg. of body weight/day in 3 doses Maximum: 2 gm./day
Aplastic anemia (very rare)
Excellent gastrointestinal absorption
~
t"l
en
Erythromycin (Erythrocin; Ilotycin)
50 mg./kg. of body weight/day in 4 doses Maximum: 2 gm./day
Novobiocin (Albamycin; Cathomycin)
25-40 mg./kg. of body weight/day in 4 doses Maximum: 1-2 gm./ day
Ristocetin (Spontin)
25 mg./kg. of body weight/day in 2 doses Maximum: 1 gm./day
30 mg./kg. of body Nausea weight/day in 3 doses Vomiting Maximum; 1 gm./day Superinfection (not common)
Good gastroin testinal absorption
25 mg./kg. of body weight/day in 2 doses Maximum: 1 gm./day
Rash Drug fever Diarrhea Granulopenia
Good gastroin testinal absorption
25
Rash Thrombophlebitis Drug fever Neutropenia
Poor gastrointestinal absorption
mg./kg. of body weight/day in 2 or 3 doses Maximum: 2 gm./day
* Staphylococcal pneumonia, osteomyelitis, septicemia, endocarditis or meningitis. t
For premature and newborn infants one fourth of the dose is recommended.
~
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1214
ANTIMICROBIAL THERAPY IN RESPIRATORY TRACT DISEASES
agent for the treatment of cold-agglutinin-positive primary atypical pneumonia caused by the Eaton (PAP) virus. 7 A diagnosis of viral pneumonia is usually made by exclusion. Consequently, antimicrobial therapy would be indicated until a bacterial etiology can be definitely excluded. Tetracycline therapy would be in· dicated for cold-agglutinin-positive primary atypical pneumonia. Pneumonia of Unknown Etiology. Antimicrobial therapy should be aimed at the most probable bacterial causes of the infection. In infants the suspects would be pneumococci, Hemophilus influenzae and staphylococci. Therefore a possible initial choice of drugs would be a combination of penicillin plus chloramphenicol or streptomycin. In older children the most common bacterial causes would be pneumococci, streptococci or cold-agglutinin-positive primary atypical pneumonia. Therefore it may be wise to initiate therapy with penicillin. In the absence of a clinical response, tetracycline may be added. Otitis Media
A discussion of antimicrobial therapy for diseases of the respiratory tract would be incomplete without a brief consideration of otitis media. Acute purulent otitis media requires early, optimum therapy. In infants most cases are due to pneumococci and Hemophilus influenzae. In older children pneumococci and hemolytic streptococci are the most common causes. Consequently a useful and effective combination includes penicillin and a sulfonamide. If the clinical response is not satisfactory, the sulfonamide may be replaced with chloramphenicol or tetracycline. REFERENCES
1. Andrews, C. H., Bang, F. B., Chanock, R. M., and Zdanov, V. M.: Parainfluenza
2. 3. 4. 5. 6. 7. 8.
Viruses 1, 2 and 3. Suggested Names for Recently Described Myxoviruses. Virology, 8:129, 1959. Beem, M., Wright, F. H., Hamre, D., Egerer, R., and Oehme, D.: Association of the Chimpanzee Coryza Agent with Acute Respiratory Disease in Children. New England J. Med., 263:523, 1960. Bunn, P. A., Knight, R., and Amberg, J.: Some Notes about a New Synthetic Penicillin for Staphylococcal Disease. New York State J. Med., 60:3074, 1960. Chanock, R. M., and others: Newly Recognized Myxoviruses from Children with Respiratory Disease. New England J. Med., 258:207, 1958. Dingle, J. H., and others: Study of Illness in Group of Cleveland Families. Am. J. Hyg., 58:16, 1953. Huebner, R. J., Cole, R. M., Beeman, E. A., Bell, J. A., and Peers, J. H.: Her· pangina: Etiologic Studies of a Specific Infectious Disease. l.A.M.A., 145:628, 1951. Kingston, J. R., and others: Eaton Agent Pneumonia. l.A.M.A., 176:118, 1960. Krugman, S., and Ebin, E. V.: Improved Local Tolerance to Penicillin. Pediatrics, 21:243, 1958.
SAUL KRUGMAN
1215
9. Mortimer, E. A., Jr., and Watterson, R. L.: Bacteriologic Investigation of Otitis Media in Infancy. Pediatrics, 17:359, 1956. 10. Osaki, F. A., Salitsky, S., and Barness, L. A.: Steroid Therapy in Bronchiolitis: A Double Blind Study. Abstract. American Pediatric Society Meeting, Atlantic City, May 2, 1961. 11. Parrott, R. H.: Newly Isolated Viruses in Respiratory Disease. Pediatrics, 20: 1060,1957. 12. Powers, G. F., and Boisvert, P. L.: Age as a Factor in Streptococcus. J. Pediat., 25:481, 1944. 13. Scott, T. F. M., Steigman, A. J., and Convey, J. H.: Acute Infectious Gingivosto· matitis; Etiology, Epidemiology and Clinical Picture of a Common Disorder Caused by the Virus of Herpes Simplex. J.A.M.A., 117:999, 1941. 14. Vargosko, A. J., and others: Association of Type 2 Hemadsorption (Parainfluenza 1) Virus and Asian Influenza A Virus with Infectious Croup. New England f. Med., 261:1,1959. 550 - 1st Ave. New York 16, N.Y.
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