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Pneumonia and Lower Respiratory Tract Infections Richard Brown To cite this article: Richard Brown (1991) Pneumonia and Lower Respiratory Tract Infections, Hospital Practice, 26:sup5, 37-42, DOI: 10.1080/21548331.1991.11707742 To link to this article:

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Date: 27 July 2017, At: 10:37

Pneumonie and Lower Respiratory Tract Infections R 1C HA R D BR0 W N Tufts University

Although a large number of organisms can cause lower respiratory infections, they can be categorized according to disease, patient age, and where acquired. Exacerbations of chronic bronchitis, for example, primarily involve Streptococcus pneumoniae, Hemophilus injluenzae, and, less often, Moraxella catarrhalis.1.2 Pneumonia in young adults most frequently involves S. pneumoniae, Mycoplasma pneumoniae, and, perhaps, the 1WARgroup of Chlamydia (1WAR pneumoniae). Community-acquired pneumonia in the elderly is usually caused by S. pneumoniae, H. injluenzae, and mixed oropharyngeal flora ("aspiration" pneumonia), with variable roles for Legionella pneumophila, gram-negative bacilli, Staphylococcus aureus, and others. 3 ·4 Pneumonia, particularly in the elderly, may also be categorized according to whether it is acquired in the community, nursing home, or hospital. Causative organisms acquired in nursing homes are likely to be skewed toward the gram-negative enteric bacilli, especially Klebsiella pneumoniae; however, S. pneumoniae, mixed oropharyngeal flora, and S. aureus also play a considerable role. 5 Nosocomial pneumonia in patients of any age is llkely to be caused by gram-negative bacilli, S. aureus, and occasionally L. pneumophila. Such

infections may be polymicrobial. Mixed aerobic, community-acquired bacterial pneumonia may be on the increase. A few studies have been published (an early one by Maxwell Finland in 1924 ), and a careful reading of the data suggests that perhaps 10% to 15% of community-acquired pneumonias may be due to mixed aerobes rather than a single pathogen. The list of possible mixed aerobes that cause pneumonia is wide ranging. We have seen several cases ofLegionella plus pneumococcal pneumonia and pneumococcal plus Klebsiella pneumania. Other combinations reported in the literature include multiple gram-negative bacteria, S. pneumoniae and H. injluenzae, S. pneumoniae and S. aureus, and the influenza virus and bacteria, to list only a few of the combinations and permutations. Finally, there are patients in whom no pathogen can be identified. 1 recently tabulated the organisms identified in several hundred patients with community-acquired pneumonia from five major reviews published in the last five years (see Figure 1 ). 6· 10 Despite the relative sophistication of these studies, 20% to 67% of pneumonias were caused by "unknown" pathogens. The diagnosis of pneumonia should, of course, be guided by information obtained from history and physical examination as

well as by results of appropriate microbiologie studies. In patients with a productive cough, the gram stain provides immediate, inexpensive, and potentially valuable information. 6 Results of sputum cultures may be less useful because of contamination with oropharyngeal flora and methodologie difficulties with identification of such pathogens as H. irifluenzae and M. catarrhalis. Furthermore, many patients cannat produce satisfactory sputum specimens. Although blood and pleural fluid cultures provide important information when positive, recent evidence shows that they are often negative, except in severe pneumonia. 6 Need for hospitalization is usually guided by the severity ofillness. But inpatient or outpatient, 25% to 60% of therapy is probably empiric, guided by the most likely etiologie organisms. Such treatment should be safe, cast-effective, and well tolerated.

EarlyData Ceftriaxone is a /3-lactamase stable third-generation cephalosporin with bath in vitro and in

Dr. Brown is Associate Professor of Medicine, Tufts University School of Medicine, Boston, and Chief, lnfectious Disease Division, Baystate Medical Center, Springfield, Mass.


Figure 1. ln five major reviews of community-acquired

pneumonie that have been published since 1987, the

causative organism was not revealed ln 20% to 67% of the patients. (Adapted from References 6 to 10)

MICg~ >64


Usual y obtained for S. aureus (Methicillin Resistant), Enterococci, B.fragillis, B. thetaiotaomicron, P. aeruginosa

2 gm IV




" ?"'"~ 1






32 ~0


~ .......... !'........ ..........

1 gm IV


Acinetobacter spp.


E. c/oacae

C. freundii


u ~

E. aerogenes, S. marcescens, S. aureus (Methicillin Susceptible),

4 E. coli, Klebsiella spp., P. mirabillis, Indole + Proteus, Providencia spp., M. morganii, Salmonella spp., H. inf/uenzae, N. gonorrhaeae, N. meningitis, S. pneumoniae, S. pyogenes

' 1




12 16 Time (Hours)



Figure 2. A single lntravenous dose of 2 gm of ceftrlaxone in

human volunteers produced plasma levels over a 24-hour


period that exceed the inhlbltory levels for 90% of the Enterobacterlaceae. (Adapted from Cleeland R, Squlres E11 )

vivo efficacy agatnst many of the pathogens likely to cause lower respiratory infections, whether acquired in the community, nursing home, or hospital. It is indicated for S. pneumoniae, other streptococcal species (excluding Enterococcusjaecalis and Enterococcusjaecium), S. aureus, H. irifluenzae, Hemophilus parainfluenzae, Klebsiella species, E. coli, Enterobacter aerogenes, Proteus mirabilis, and Serratia marcescens .u· 12 In

vitro activity is also noted agatnst M. catarrhalis.

When compared with other third-generation cephalosporins, ceftriaxone has similar in vitro activities but has the unique pharmacologie advantage of a half-life of sixto eight and a half hours, th us allowing once-daily dosing. 13 Blood levels achieved over the course of24 hours after a 1-gm dose of ceftriaxone surpass the MIC 90s of the majority of pathogens responsible for lower respiratory infections, particularly for pneumonia (see Figure 2 ). 11 Occasional strains of Enterobacter, Serratia, Acinetobacter, and most strains of Pseudomanas aeruginosa are resistant, however. Furthermore, L. pneumophila and TWAR are universally resistant to all cephalosporin antibiotics. Therapeutic levels of ceftriaxone in pleural fluid have been noted for at least 53 hours in seven patients who received 1-gm doses. 14 Sputum levels were at least 1.5 .ug/ml. 15 The drug's excretion by both hepatic and renal routes obviates dosage adjustments in the presence of renal dysfunction. Ceftriaxone is unusually well tolerated for such a broad-spectrum agent. Most commonly noted adverse reactions include eosinophilia (6%), thrombocytosis (5%), leukopenia ( 1%), diar-

rhea (3%), and elevated liver function studies (3%). 16· 1 7 The vast majority ofthese are not clinically signiftcant.

Clinical Trials Published studies of oncedaily ceftriaxone for treatment of lower respiratory tract infections date back to 1983. An early trial involving 133 infections in 127 patients (39 patients with severe refractory pneumonia) used a 2-gm once-daily dose. 18 Cure or improvement (significant reduction in abnormal findings in "reasonable" Ume, but incomplete resolution, possibly related to underlying disease) was 100% in patients with S. pneumoniae (5 patients), Serratia (2), E. coli (2), and K. pneumoniae infections ( 1 ). Four patients with P. aeruginosa infections fared poorly, with only 25% cured/improved. In the remaining 25 patients, etiology

was "unknown," and 4% were failures. Another early trial of patients with pneumonia compared ceftriaxone (49 patients) with amoxicillin(42 patients). 19 As is the case in the real world, 26% of the amoxicillin-treated patients and 24% of those given ceftriaxone were infected with S. pneumoniae, 10% and 6% with "other" pathogens, and 40% and 41% with "unknowns." Ceftriaxone was the more successful drug, curing 44 (90%) patients to amoxicillin's 29 (69%), producingimprovementin two (4%) as compared with five ( 12%), and failingin one (2%) as opposed to six(14%). Sorne interesting data from Canada regarding the comparative efficacy of ceftriaxone and cefotaxime are graphed in Figure 3. 20 A 2-gm once-a-day dose of ceftriaxone compared very favorablywith multiple doses of IV cefotaxime. Susceptibilities of the

Figure 3. Ceftriaxone at a once-daily dose of 2 gm was as effective in the treatment of 55 patients with pneumonia as was cefotaxime at a dose of 2 gm every four hours ln 51 patients. (Adapted from Manden LA211)


and seemed to be producing excellent results, we did a retrospective study of 250 patients. Not surprisingly, we found that 167 patients were being treated for a wide variety oflower respiratory infections (see Figure 6). 22 Fiftypercentofthe 167were elderly patients (older than 69 years) who were receiving ceftriaxone for pneumonia, either community- or nurstng-home acquired ( 10%). Another 10% were younger than 69 years but had also acquired the disease in a nursing home. 1\venty-nine percent were younger patients who had community-acquired pneumania, and 11% had bronchitis.

Figure 4. Compared here are the eradication rates for ceftrlaxone, 2 gm/24

hours, and cefotaxime, 2 gm/6 hours, agalnst the causative organisms ln patients with pneumonia. (Adapted from Manden LA211)

organtsms identified are listed in Ftgure4. Dosing regtmens for ceftriaxone in lower respiratory infections have been compared in a number of trials (see Table ). 21 The outcomes with 1 gm or 2 gm a day appear to be equally good agprnnsttheorganismscommonly seen in community-acquired pneumonias, such as S. pneumoniae, H. influenzae, and S. aureus. To my knowledge, there are no data on the efficacy of the 1 gm/day regimen against the

Klebsiella-Enterobacter-Serratia (IŒS) group. But 2 gm/day eradicated KES orgamsms in 27 of29 patients. The bacteriologie efficacy of a 1-gm dose of ceftriaxone was at least as good as a 2-gm dose. Clinical efficacy demonstrated similarly good results with 1 gm every 24 hours, 2 gm every 24 hours, and 1 gm every 12 hours (see Figure 5). Because the 1 gm/day ceftriaxone regimen had become extremely popular at our hospital

Efficacy of Ceftriaxone in Lower Respiratory Infections

Mortality was very low, the drug was well tolerated, and the once-a-day dosage was appreciated by the nursing staff, the pharmacy, and the patients. In our hospital we occasionally isola te L. pneumophila from severely ill patients. So one of our common antibiotic cocktails is ceftriaxone, 1 gm/day, with intravenous erythromycin. Now we have designed a protocol of even lower doses of ceftriaxone for patients with reasonably straightforward community-acquired pneumonias. Their gram stains must show common pathogens, H. influenzae or M. catarrhalis, that are likely to be sensitive to ceftriaxone. We are, of course, obtaining informed consent. To date, we have enrolled eight patients and all have done well, with no adverse reactions at 30-day follow-up.

Dose 1 gm q24 hr

2 gm q24 hr



Hemophilus influenzae



Staphylococcus aureus






Streptococcus pneumoniae

Klebsiella-Enterobacter-Serratia Adapted from Roche Scientific Summary2



Summary One gram once daily of ceftriaxone is as effective as 2 gm for the common causative organisms of community-acquired and nosocomial pneumonias. It should not be used alone agprnnst

Figure 5. Response to ceftriaxone of organisms lsolated from patients wlth lower respiratory infections was similarly good at dosages of 1 gm/24 hours, 2 gm/24 hours, and 1 gm/12 hours. (Adapted from Roche Scientlflc Summary2 1)

Figure 6. Among 167 patients hospitalized with lower resplratory infections, 50% were older than 69 years. Most had acquired pneumonie in the community, 10% in nursing homes. (Adapted from Brown RB, Sands M22)


L. pneurrwphtla, the 1WAR pneu-

pathogens. Ceftriaxone is safe,

moniae, and possibly anaerobie pathogens. Preliminary study suggests that a regimen of 500 mg a day may be effective in selected patients with simple pneumanias caused by sensitive

weil tolerated, and cast-effective,

which means it can play a signiftcant therapeutic role in nursing homes and other long-term care facilities as well as in outpatient therapy. D

References 1.


3. 4. 5. 6.

7. 8.

9. 10.

11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21.



Nlcotra B et al: Branhamella catarrhalts as a lower resptratory tract pathogen ln patients wlth chronlc lung dlsease. Arch Intern Med 146:890, 1986 Schrelner A et al: Bactertologlcal findings ln the transtracheal asptrate from patients wtth acute exacerbations of chrome bronchltis. Infection 6:54,1978 Verghese A, Berk SL: Bacterlal pneumonla ln the elderly. Medicine (Baltimore) 61:271, 1982 Niederman MS, Fein AM: Pneumonta ln the elderly. Gertatr Clin North Am2:241, 1986 Garb JL, Brown RB, Garb JR: Differences ln etiologyofpneumonlas ln nurstnghomeandcommun1typatients.JAMA240:2169,1978 Levy Met al: Communlty-acqutred pneumonla: Importance of initial nonlnvasive bacteriologie and radiographie investigations. Chest 92:43,1988 Fine MJ et al: Prognosts of patients hospitalized wtth commun1ty-acqutredpneumon1a.AmJMed88(Suppl 5):10, 1990 British Thoractc Society: Communlty-acqutred pneumonta ln adults ln British hospltals ln 1982-1983: A survey of aetiology. Q J Med 62:195, 1987 Marrie T Jet al: Communlty-acqutred pneumonla requtrtng hospttallzation: Ftve-year prospective study. Rev Infect Dis 11 :586, 1989 Fang GD et al: New and emergtng etiologies for communlty-acqutred pneumonia wtth Implications for therapy. Medicine (Baltimore) 69:307,1990 Cleeland R, Squtres E: Antlmicroblal activlty of ceftrtaxone: A revlew. Am J Med 77(Suppl4C):3, 1984 Neu HC: Pathophyslologtc basls for the use of thtrd-generation cephalosporlns. Am J Med 88(Suppl4A):3S, 1990 Pate! IH, Kaplan SA: Pharmacoklnetic proffie of ceftrlaxone ln man. AmJMed 77(Suppl4C):17,1984 Benonl G et al: Penetration of ceftrlaxone lnto human pleural tluid. Antlmlcrob Agents Chemother 29:906, 1986 l'raschlni F et al: Human pharmacokinetics and distribution ln vartous tissues of ceftrtaxone. Chemotherapy 32: 192, 1986 Moskovltz BL: Clinical adverse effects durtng ceftrlaxone therapy. Am J Med 77(Suppl4C):84, 1984 Oakes M, Macdonald H, Wilson D: Abnormallaboratory test values durtng ceftrtaxone therapy. Am J Med 77(Suppl4C):89, 1984 Baumgartner JO, Glauser MP: Stngle dally dose treatment of severe refractory Infections wtth ceftrtaxone. Arch Intern Med 143:1868, 1983 Baumgartner JD. Glauser MP: Tolerance study of ceftriaxone compared wlth amoxlclllin ln patients wlth pneumonla. Am J Med 77(Suppl4C):54, 1984 Mandell LA (personal communication) Roche Scientlftc Summary: The clln1cal evaluation ofRocephin (ceftrtaxone sodium/Roche). Hoffmann-La Roche Inc., Nutley, New Jersey, 1988 Brown RB, Sands M: One-gram lntravenous ceftrlaxone use ln a large teachlng hospital. Curr Ther Res 46:285, 1989

Ceftriaxone in treatment of serious infections. Pneumonia and lower respiratory tract infections.

One gram once daily of ceftriaxone is as effective as 2 gm for the common causative organisms of community-acquired and nosocomial pneumonias. It shou...
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