Drugs 50 (1): 62-72, 1995

PRACTICAL THERAPEUTICS 0012-o667/95/0007-Q062/S11.00/0

© Adis International Llmtted, All rights reserved.

A Guide to the Treatment of Lower

Respiratory Tract Infections
Friedrich Vogel
Krankenhaus Hofheim, Hofheim im Taunus, Germany

Contents
Summary 62
1, Aetiology 63
2, Diagnosis 64
3, Therapy 65
3,1 Bronchitis, 65
3,2 Primary Pneumonia , 68
3,3 Secondary Pneumonia 68
4, Special Pharmacokinetic and Dosage Recommendations 69
4,1 Cephalosporins 69
4.2 Macrolides, 70
4,3 Quinolones 70
5. Conclusions , , , 71

Summary Acute bronchitis is usually a viral infection which, unless there is a special dispo-
sition, does not require antibiotic therapy. For the initial oral chemotherapy of bacte-
rial infections of the lower respiratory tract (chronic bronchitis, pneumonia) the
effective and well tolerated cephalosporins, macrolides and amoxicillin plus ~­
lactamase--inhibitor are recommended. In complicated cases with severe underlying
disease, longer history or frequent exacerbations, quinolones should be given if Gram-
negative infections are suspected or if initial therapy with other substances has failed.
If Legionella, Mycoplasma or Chlqmydia spp., so-called 'atypical' pathogens, are
involved, macrolide antibiotics are the therapy of fIrst choice. Special attention should
be given to the increase in resistance against cotrimoxazole (trimethoprim-
sulfamethoxazole) and tetracyclines. In hospitals where primary pneumonias are
treated preferentially by intravenous medication, therapy should be switched to oral
antibiotics as soon as feasible (follow-up therapy).
For severely ill patients with secondary pneumonia and underlying disease,
second generation cephalosporins with aminoglycosides, or monotherapy with
third generation cephalosporins are recommended. In very severe, high-risk
cases, third generation cephalosporins, combinations with high-dosage quino-
lones or ureidopenicillins plus ~-lactamase-inhibitors are suitable. Future devel-
opment in th~antibiotic treatment of respiratory infections will follow the current
trend of lower dosages, with the clear objective of shortening treatment periods
and achieving earlier discharge from hospital.
Lower Respiratory Tract Infections
The identification of the relevant pathogens be-
fore or during antibiotic therapy of lower respira-
tory tract infections (LRTIs) is still a serious prob-
lem. In most cases, treatment will be selected and
started according to clinical and anamnestic cri-
teria without the results of a bacteriological diag-
nosis. According to our own investigations on the
relevance of microbiological findings from 100
hospitalised patients at the University Hospital in
Bonn, Germany, a positive microbiological result
was obtained in only 34.5% of cases. Drug therapy,
however, was started in more than 90% of cases
before these results were available, and was chosen
according to the patient's symptoms and the expe-
rience of the physician.
In 91 % of the total cases, a substantial improve-
ment was achieved. Despite improvement of inten-
sive care and an increase in the availability ofther-
apeutic measures, nosocomial pneumonias still
have a poor prognosis in patients treated in inten-
sive care units. The mortality ranges from 5 to 24%
for Gram-positive pathogens and up to 70% for
infections caused by Pseudomonas Spp.[l,2] Miss-
ing cough and swallowing reflexes causes perma-
nent exposure to organisms from the rhinopharynx[3]
and the gastrointestinal tract.f4 ]
1. Aetiology
LRTIs can be grouped according to their clinical
picture and differing aetiology: bronchitis (acute
bronchitis, exacerbation of chronic bronchitis) and
pneumonia [primary (community acquired), sec-
ondary (nosocomial), atypical]. Additionally, se-
vere cases of LRTIs (mostly pneumonia) should be
treated according to the degree of severity:
Stage 1: Severe purulent bronchitis or broncho-
pneumonia in patients without severe underlying
disease, without pronounced clinical symptoms or
respiratory insufficiency.
Stage 2: Patients with underlying diseases or
elderly patients with pronounced clinical symp-
toms, with tachypnoea, dyspnoea and hypoxaemia,
renal and hepatic impairment and possible septic
complications.
Stage 3: Severe pneumonia combined with se-
© Adis International Limited. All rights reserved.
63
vere underlying disease where patients must be ar-
tificially respirated. Frequently, septic complica-
tions are present, and renal and hepatic function is
impaired. Predominantly, patients treated in inten-
sive care or oncology units belong to this group.
Acute bronchitis is most commonly of viral
aetiology and does not require antibiotic treatment
unless there are special risk factors (e.g. underlying
diseases, age, etc.). Primary bacterial infections or
secondary superinfections occur with an incidence
of only 5 to 20%. In such cases pneumococci,
Haemophilus inJluenzae, Moraxella catarrhalis
~d staphylococci are the commonest and most im-
portant infective agents. Mycoplasma and Chlamy-
dia spp. are rare.£5,6] During acute exacerbations of
chronic bronchitis the same organisms dominate as
in acute bronchitis (tables I and II).
To differentiate between viral and bacterial in-
fections, differential diagnostic methods are re-
quired, which are summarised in the following
paragraphs.
Primary, community-acquired pneumonia in pa-
tients without underlying disease can be treated in
outpatient settings by appropriate oral antibiotics.
The most frequently occurring pathogens of bacte-
rial pneumonia are pneumococci, followed by H.
inJluenzae and staphylococci (table III). Atypical
pneumonias are caused by Legionella spp., Myco-
plasma spp. and Chlamydia pneumoniae. The fre-
quency of Legionella spp. varies between 1 and
15%. Data on the frequency of mycoplasma infec-
tions vary according to epidemiological situation
and season between 5 and 35%. Infections caused
by C. pneumoniae are reported to occur with a fre-
quency of 5 to 6%.£6-8]
Secondary, nosocomial pneumonia, which is
Table I. Frequency of causative organisms of chronic bronchitis[5]
Organism No. (%) ~-Lactamase­
positive (%)
Pneumococci 1079 (40) o
Haemophilus influenzae 781 (29) 2
Moraxella catarrhalis 311 (12) 41
~-Haemolysing streptococci 261 (10) o
Staphylococcus aureus 241 (9) 74
Drugs 50 (1) 1995
 64 Vogel

Table II. Causative organisms of lower respiratory tract infections only possible if cross-contamination of bronchial
(outpatients). 206 of 480 individuals were tested microbiologically. secretion with organisms from the upper respira-
114 isolates from 91 patients showed the following spectrum[6]
tory tract can be avoided. Once the patient has been
Isolate Organism No.
(%of given appropriate instructions, suitable specimens
cases) can be obtained by expectoration of bronchial se-
Bacterial Streptococcus pneumoniae 62(30)
cretion from the lower respiratory tract. Other, less
(n =92) Haemophilus influenzae 16 (8)
H. parainfluenzae 2 (1)
frequently used methods are transtracheal aspira-
Moraxella catarrhalis 4(2) tion or bronchoscopy. The sputum should be ob-
Haemolysing streptococci 4(2) tained following adequate mouth hygiene during a
Staphylococcus aureus 2 (1) cessation hiatus in the therapy; morning sputum is
Pseudomonas aeruginosa 1 (0.5)
usually preferred.
Mycobacterium malmoensii 1 (0.5)
The sputum work-up investigation should be
Viral causatives Influenza virus a + b 12 (5)
(n = 19) Respiratory syncytial virus 5(2)
performed rapidly - within 3 to 4 hours. If this is
Adenovirus 1 (0.5) not possible, it must be chilled immediately after
Rhinovirus 1 (0.5) sampling and must be transported without interrup-
'Atypical' causatives Mycoplasma pneumoniae 1 (0.5) tion of the refrigeration chain.l1]
(n =2) Coxiella bumetii 1 (0.5)
Since the result is important for the choice of
therapy, differential diagnostic methods must be
used to distinguish between bronchitis of viral and
mainly treated by parenteral antibiotic administra-
bacterial origin. Bacterial infection usually mani-
tion, shows a different aetiology and pathogene-
sis.[9] The spectrum of causative organisms differs fests as an acute, severe illness, whereas viral in-
substantially from that seen in primary pneumonia, fections cause milder symptoms in the early stage.
with staphylococci, Pseudomonas spp., Entero- In contrast to viral infections where the fever is
bacter spp., Klebsiella spp., H. inJluenzae and low, bacterial infections tend to cause high fever
Streptococcus pneumoniae occurring most fre- and frequently chills. Tachycardia and tachypnoea
quently[7,1O-12] (table IV). are also more frequent. The sputum of bacterial

2. Diagnosis
Table III. Causative organisms (%) of primary pneumonia[7]
The microbiological diagnosis in bronchial in- Organism Institution
fections causes substantial problems, and several Grady Milwaukee Hartlor!
Memorial County General Hospital
groups recommend starting antibiotic therapy
Hospital Hospital 1980 to
without bacteriological investigation in less severe 1967 to 1968 1967 to 1970 1981
cases. An exception should be the clinical situation (n = 167) (n = 111) (n = 204)
where the microbiological diagnosis can be or- Pneumococci 62 71 36
Staphylococcus 20 10 8
ganised more easily and where respiratory infec-
aureus
tions are frequently secondary. In these cases, spu- Haemophilus 8 4 15
tum analysis and even bronchoscopy should be influenzae
performed where possible. Enterobacteria 19 13 16
In general, a microbiological diagnosis is indi- Pseudomonas 3
aeruginosa
cated if the primary antibiotic therapy has failed, if
Serratia 2
acute attacks accumulate in short intervals (2 marcescens
months), if an acute attack occurs during therapy Acinetobacter spp. 1
or if the history reveals frequent failure of anti- Legionella spp. 14
biotics. A definitive bacteriological diagnosis is Anaerobic organisms 3 4

© Adls International Umlted. All rights reserved. Drugs 50 (1) 1995

Lower Respiratory Tract Infections 65

Table IV. Causative organisms of primary and secondary pneu- choscopy, transtracheal aspiration and blood cul-
monia in 109 hospitalised patients[B]
tures are also of little value. Serological tests are
Organism Total Primary Secondary more helpful in identifying the causative organ-
Streptococcus pneumoniae 13 8 5
isms of atypical pneumonia and best results are
Staphylococcus aureus 5 5
achieved if samples taken during the early stage of
Streptococci b, d 7 6
Haemophilus influenzae 8 8 infection are compared with those from a later
Pseudomonas spp. 7 7 stage.
Klebsiella spp. 7 7
Enterobacter cloacae 5 4 3. Therapy
Proteus mirabilis 3 3
Escherichia coli 7 7
3.1 Bronchitis
Legionella spp. 3 2
Mycoplasma pneumoniae 7 6 1
Respiratory viral infections are very common in
Parainfluenza a, b 6 5
humans, occurring most frequently in the winter.
Especially susceptible are children and the elderly,
where acute respiratory infections cause 10 to 20%
infections is purulent and plentiful; in viral infec-
of the total mortality. Other risk factors for viral
tions it is mucous and rare. Bacterial infections are infections are asthma, diabetes, a hyperreactive
associated with leucocytosis and a shift to. the left bronchial system, chronic obstructive lung disease,
in the differential blood count, which is less fre- congestive heart failure and immunosuppression.
quently seen in viral infections. The cough is Besides the general immunological status, local
mostly dry during viral infections, whereas in bac- damage to the mucous membranes caused by in-
terial bronchitis it is frequently combined with pu- halative smoking, restricted or obstructive ventila-
rulent expectoration. tory impairment and pulmonary congestion are
Similarly to bronchitis, the bacteriological iden- modifying factors.
tification of pneumonia pathogens also causes dif- Viral respiratory infections usually take a be-
ficulties. Investigations carried out in Great Britain nign course and the symptoms decline after 7 to 10
during the past 20 years showed that up to 50% of days. Except for susceptible patients, as mentioned
the pathogens in community-acquired pneumonia above, antibiotic treatment is not indicated; in most
could not be identified. [13] Our own experience ob- cases physical rest, administration of mucolytic,
tained from different hospitals, from general prac- secretolytic or antipyretic drugs and inhalative or
tice and from one University hospital revealed an parenteral administration of corticosteroids in
identification rate below ~O% under routine clini- more severe cases are sufficient. For reasons of
cal conditions. cost effectiveness and wastage reduction, oral an-
In primary pneumonia the following methods tibiotics are gaining more importance in the treat-
for specimen collection can be used: pharyngeal ment of hospitalised patients.
swabbing, sputum analysis, transtracheal aspira- For at-risk patients with acute bacterial bronchi-
tion, bronchoscopy and blood culture. It should be tis or patients with an acute exacerbation of chronic
mentioned, however, that in most cases antibiotic bronchitis, several effective drugs with different
treatment will be started before the causative or- antibiotic spectra are available. Oral penicillins
ganism can be identified. have fully maintained their efficacy against Gram-
Five to 30% of primary pneumonias are atypical positive cocci and are the first choice for treatment
infections caused by Legionella spp., Mycoplasma of infections caused by pneumococci and strepto-
spp. and Chlamydia spp.l14,15] Since these organ- cocci in adults and children.l 19]
i~ms are difficult to culti~ate, throat swabs and spu- Aminopenicillins (ampicillin, amoxicillin)
tum have little significance for diagnosis. Bron- broaden the penicillin spectrum and are also active

© Adis International Limited. All rights reserved. Drugs 50 (1) 1995

66
Table V. Recommendations for the therapy of bacterial infections in adults[16]
Diagnosis Most frequent pathogens
Acute bronchitis Primary: viral
Secondary: superinfections with
bacteria
Acute exacerbation of Pneumococci
chronic bronchitis Haennophilusinfluenzae
Moraxella catarrhalis
Staphylococci
Pneumonia Pneumococci
Haennophilus influenzae
Staphylococci
Mycoplasnna
Chlannydia spp.
Legionella spp.
against Haemophilus injluenzae, enterococci, list-
eria, salmonelli, shigelli and, partly, Escherichia
coli and Proteus mirabilis (table V). Among these
drugs the better absorbed derivatives, amoxicillin
and bacampicillin, should be preferred. To eradi-
cate ~-lactamase-producing strains of staphylo-
cocci, M. catarrhalis, H. injluenzae, E. coli and P.
mirabilis, aminopenicillins should be given in
combination with a ~-lactamase-inhibitor such as
clavulanic acid or sulbactam. Erythromycin per-
forms well against streptococci, pneumococci, My-
coplasma spp., Chlamydia spp. and Legionella
spp.
Depending upon the strain, eradication of staph-
ylococci and H. injluenzae is not always suffi-
cient.[16,17] Modern macrolides, such as clar-
ithromycin and roxithromycin, are comparable
with erythromycin in antimicrobial activity but
possess improved pharmacokinetic properties and
are well tolerated.[16,18] Azithromycin, anew azalid
compound, is characterised by an extraordinarily
long half-life and high tissue concentrations.[19]
Cotrimoxazole (trimethoprim-sulfamethoxazole)
and similar combinations are widely used thera-
peutic agents for respiratory infections, but cannot
be recommended without reservation because of
the increasing resistance of H. injluenzae and
staphylococci strains, the lack of efficacy against
streptococci and occasional severe adverse effects.
The low cost tetracyclines are commonly used
in hospital and general practice for respiratory tract
© Adis Intemational Umlted. All rights reserved.
Vogel
First choice Alternatives
Aminopenicillin (e.g. amoxicillin) Aminopenicillin + ~-Iactamase
inhibitors, or macrolides, or
cephalosporins
Cephalosporins, or aminopenicillin Quinolones
± ~-Iactamase inhibitors, or
macrolides
Cephalosporins, or Quinolones
aminopenicillin ± ~-Iactamase
inhibitors, or macrolides
infections but, because of increasing resistance in
several frequently occurring causative organisms,
they cannot be recommended for this indication.
Moreover, investigations have shown that tetracy-
cline is no more effective than placebo in the ther-
apy of acute exacerbations of chronic bronchi-
tis PO]
Because of their broad spectrum coverage, good
clinical efficacy and excellent tolerability, oral
cephalosporins are nowadays the first-line treat-
ment for LRTIs. Except for cefalexin and cefa-
droxil, which are no longer recommended for the
empirical treatment of purulent exacerbations of
bronchitis, oral cephalosporins provide several ad-
vantages for empirical antibacterial chemotherapy
(recommendations of the Paul Ehrlich Society,
Germany[16]). An overview of the antibacterial
activity of different cephalosporins is given in
table VI.
The oral first generation cephalosporins,
cefalexin, cefadroxil, cefradine and cefaclor, are
effective against Gram-positive organisms such as
streptococci, pneumococci and staphylococci but
not against enterococci, and they show restricted
efficacy against enterobacteria, except for the ma-
jority of E.coli, Klebsiella spp. and P. mirabilis
strains. The susceptibility of H. injluenzae is low,
with the exception of cefaclor, which is also more
active against streptococci and pneumococci but
ineffective against Pseudomonas, Enterobacter,
Drugs 50 (1) 1995
Lower Respiratory Tract Infections
and Serratia spp., P. vulgaris, Citrobacter spp. and
Bacteroides fragilis. [21,22]
Among the more recently approved cephalo-
sporins, cefuroxime axetil is effective against
Gram-positive pathogens such as staphylococci
and streptococci, including pneumococci, as well
as the Gram-negative organisms, H. inJluenzae,
M. catarrhalis, Klebsiella spp., E. coli, and P.
mirabilis. Clearly, the improved ~-lactamase sta-
bility that broadens the antibacterial spectrum is an
advantage over older compounds of this class.[23]
Cefixime, like the other third generation cephalo-
sporins, is predominantly active against Gram-
negative bacteria. The lack of efficacy against
Staphylococcus au reus and S. epidermidis is a dis-
advantage. Although M. catarrhalis and H. in-
Jluenzae are susceptible, activity against penicil-
lin-resistant pneumococci is less pronounced. [24-26]
Cefpodoxime shows good activity against Gram-
negative organisms, except for Enterobacter spp.,
Serratia marcescens and Pseudomonas aerugin-
osa. Good efficacy is also observed against H.
inJluenzae and M. catarrhalis, as well as Gram-
positive organisms like streptococci and pneumo-
cocci. Effectiveness against staphylococci is less
pronounced, and no efficacy is seen against en-
terococciPl,27]
Several studies have demonstrated the good
clinical efficacy of the new oral cephalosporins. In
terms of their effectiveness and excellent tolerabil-
ity, the results are comparable with or slightly bet-
ter than standard therapy with arninopenicillins or
older cephalosporins. Cefaclor has usually been
the standard comparative compound since it shows
the broadest antibacterial spectrum of the older
Table VI. Efficacy of oral cephalosporins against the most frequent causative organisms of respiratory tract infections
Streptococcus
pneumoniae
Cefalexin, cefadroxil +++
Cefaclor +++
Cefuroxime axetil +++
Cefixime +++
Cefpodoxime proxetil +++
Symbols: + = poor activity; ++ = intermediate activity; +++ = high activity; - = not effective.
© Adis Intematlonal Limited. All rights reserved.
67
cephalosporins and good clinical efficacy. [22] Com-
parative trials with cefaclor vs cefuroxime axetil re-
vealed an effectiveness at least comparable or
slightly better in the treatment of LRTIs and pneu-
monia with cefuroxime axetil. [28,29]
Compared with amoxicillin with or without a
~-lactamase inhibitor, cefuroxime axetil has also
demonstrated an equivalent clinical efficacy with
superior bacteriological eradication and tolerabil-
ityJ3o-32] The most striking difference in the com-
parison with cefaclor was the much lower dose of
cefuroxime axetil that achieved a similar clinical
effect. Schleupner et al.[29] reported the same clin-
ical efficacy following cefuroxime axetil250mg or
500mg 12-hourly, or cefaclor 500mg 8-hourly.
Surprisingly, the lower daily cefuroxime axetil
dosage was slightly better than the higher dosage.
These findings,[28,29,33] as well as other experi-
ences,[31,34-36] indicate that LRTIs and pneumonia
can be effectively treated with a daily dose of
500mg and Ig of cefuroxime axetil, respectively.
Compared with amoxicillin (3 x 500mg and 3 x
250mg daily) in the therapy of respiratory tract in-
fections, cefixime (1 x 400mg) exhibited a slight
superiority regarding the clinical and bacteriolog-
ical efficacyJ37] Compared with cefaclor (1.5g
daily) the clinical efficacy was similar and the bac-
teriological potency was slightly lower. Similar re-
sults were found in studies in acute bacterial sinus-
itis and otitis mediaP5,26,38]
A comparative study of cefpodoxime (400mg
daily) and ceftriaxone (lg daily intravenously)
showed comparable results with similar bacterio-
logical activity in the therapy of LRTIs.l39] A
comparison of cefpodoxime with amoxicillin-
Haemophilus Moraxella Streptococcus Staphylococcus
influenzae catarrhalis pyogenes aureus
++ +++ +++
++ ++ +++ +++
+++ +++ +++ +++
+++ +++ +++
+++ +++ +++ +
Drugs 50 (1) 1995
68
clavulanic acid in the therapy of primary pneumo-
nia also showed similar results,[40] as did a compar-
ison with amoxicillin in the same indication.[27,40]
The majority of penicillin-hypersensitive pa-
tients do not show cross allergy to cephalosporins.
Exanthemas are rare. Gastrointestinal disorders are
rare with older agents, but occur more frequently
with the newer compounds.[l6] As with penicillins
and erythromycin, oral cephalosporins are suitable
for use during pregnancy and lactation. Respective
contraindications given for novel compounds
should be considered as general precautions and
could not be substantiated in clinical trials.l 16]
Quinolones, especially ofloxacin and ciproflox-
acin, have a very broad spectrum of action and
show good efficacy against Gram-negative en-
terobacteria, P. aeruginosa and Gram-positive
pathogens such as staphylococci. Because of their
poor efficacy against pneumococci and their high
activity against Gram-negative bacteria, they can-
not be considered as drugs of ftrst choice in respi-
ratory tract infections. They are, however, well tol-
erated with an average adverse effect rate of 4%,
predominantly gastrointestinal disorders, and
rarely allergies or CNS symptoms with headache
and vertigo. . In most cases, nosocomial pneumonia is treated
Quinolones should be reserved for severe cases
of respiratory infections in patients with concomi-
tant disease or when infections with Gram-nega-
tive organisms are suspected.
3.2 Primary Pneumonia
The classification into primary and secondary
pneumonia is of great importance in making rec-
ommendations for differential therapy, since the
spectrum of pathogens varies between the 2 cate-
gories and different therapeutic principles must be
applied.
The prognosis of primary pneumonia has im-
proved substantially following the availability of a
variety of effective oral agents that allow a treat-
ment even in an outpatient setting. Owing to the
present incidence of causative organisms in pri-
mary pneumonia (table III), a broad spectrum an-
tibiotic is the therapy of choice. Good clinical evi-
© Adis International Umited. All rights reserved.
Vogel
dence has been obtained with erythromycin and
clarithromycin, [41] which are effective against most
of the causative organisms, including the myco-
plasmas, cWamydias and legionelli. Aminopenicil-
lins can also be used for the therapy of primary
pneumonia if atypical pathogens can be excluded.
The group of oral cephalosporins is becoming of
increasing importance in such cases.
When initial therapy with oral penicillins,
cephalosporins and macrolides is not successful or
when an infection with Gram-negative organisms
is suspected, an oral quinolone like ofloxacin or
ciprofloxacin is indicated.
3.3 Secondary Pneumonia
Because of the particular environment in which
it occurs, nosocomial pneumonia shows a micro-
bial aetiology that differs substantially from com-
munity-acquired primary pneumonia (table
IV).l6,9-12,42,43] The individual patient situation as
well as the speciftc epidemiological and resistance
pattern of each hospital must be carefully weighed
up before a therapeutic decision is reached.
by parenteral drug administration.l9,44] It is worth
mentioning, however, that oral antibiotic therapy,
for reasons of cost containment and wastage reduc-
tion, should be preferred if the severity of the
patient's clinical situation allows. With their excel-
lent clinical efficacy and tolerability, cephalo-
sporins, alone or combined with other antibiotic
agents, are now established as initial therapy of
nosocomial pneumonia (table VII).
Depending upon the degree of severity, the drug
chosen, dosage regimen and combination partners
vary. The different stages of severity (stages 1-3)
have already been described in section 1. Because
of their aetiological spectrum, second-generation
cephalosporins are most suitable for stage 1 pa-
tients and should be administered in low doses. For
cefuroxime, 750mg twice daily is recommended.
Cefotiam, cefamandole and cefoxitin should be ad-
ministered as daily doses of 2 X 19 to 2 x 2g. As
they have low ~-lactamase stability, cefazolin and
Drugs 50 (1) 1995
Lower Respiratory Tract Infections
Table VII. Recommendations for the parenteral therapy of
secondary pneumonia
Severity stage 1
Cephalosporins, second generation
or macrolides
oraminopenicillins (+ ~-Iactamase inhibitor)
Severity stage 2
1. Cephalosporins, second generation + aminoglycosides or
quinolones (oral) orureidopenicillins
2. Cephalosporins, third generation
3. Quinolones
Severity stage 3
Cephalosporins, third generation + aminoglycosides
or quinolones (intravenous/oral) or ureidopenicillins
or monotherapy with ceftazidime
orimipenem
cefazedone are of minor importance in the therapy
of secondary pneumonia.
As an alternative for initial therapy, especially
if Legionella, Mycoplasma and Chlamydia spp.
have to be taken into account, macrolide antibio-
tics can be used, although only erythromycin is
currently available for intravenous administration.
For the treatment of stage 2 patients, second
generation cephalosporins in combination with
other antibiotics are also recommended but the
doses must be adjusted higher: cefuroxime 2 to 3
x l.Sg; cefotiam, cefamandole and cefoxitin 2 to 3
x 2g daily. Since mortality is significantly higher
than in the stage I group, combinations with
aminoglycosides, quinolones (ofloxacin, cipro-
floxacin 400 to 800mg), which are available orally,
or with ureidopenicillins (piperacillin, azlocillin,
mezlocillin) should be administered.
Alternatively, third. generation cephalosporins
can be used as monotherapy: cefotaxime, ceftizox-
ime and cefmenoxime 2 to 3 x 2g; ceftazidime 2
x 2g or 3 x Ig and ceftriaxone 1 to 2 x 2g daily.
Stage 3 comprises patients with severe concom-
itant disease and respiratory insufficiency, where a
high percentage must be artificially respirated.
Septic complications occur frequently in this
group. Third generation cephalosporins at high
dosage are indicated: cefotaxime, cefmenoxime,
ceftizoxime 3 x 2g, ceftazidime 3 x 19 or 2 to 3 x
© Adls International Limited. All rights reserved.
69
2g, ceftriaxone 2 x 2g, all daily.[45,46] For the last
compound, some reservation is recommended in
severely ill patients with renal and hepatic impair-
ment. Because of the high mortality risk of stage 3
patients, the cephalosporins should be combined
initially with aminoglycosides or ureidopeni-
cillins.
Alternatively, ceftazidime or cefepime can be
administered as monotherapy at a dosage of 2 to 3
x 2g daily or combinations with high dose quino-
lones may be used.[45-48] Promising clinical results
have been obtained with monotherapy with im-
ipenem (2 to 3g daily»)45,48] It should be men-
tioned, however, that for severe infections an ini-
tial combination with aminoglycosides or
quinolones is more favourable.
Especially in severe cases of secondary pneu-
monia, parenteral administration of antibiotics
cannot be avoided, since high plasma drug concen-
trations are required initially. It should be pointed
out, however, that parenteral administration should
be replaced by oral medication as soon as possible,
especially in stage I or 2 patients. This follow-up
or 'switch' therapy can now be recommended fol-
lowing the availability of several potent oral anti-
biotics with favourable pharmacokinetics and very
good tolerability.
The early switch to oral medication has proven
its clinical relevance[30,34,49] and offers many ad-
vantages for the patient as well as for the clinical
staff or for the community. Septic complications
caused by infusions or inconvenience for the pa-
tient caused by frequent injections can be reduced
and a large amount of wastage is avoided. Addi-
tionally, many patients can be discharged earlier
from hospital, which contributes substantially to
their personal comfort and to cost containment.
4. Special Pharmacokinetic and
Dosage Recommendations
4.1 Cephalosporins
The older, oral cephalosporins, cefalexin, cefa-
droxil, cefradine and cefaclor, show good bioavail-
ability (approximately 90% and above) and an
Drugs 50 (l) 1995
70
average half-life of 1 to 2 hours. High blood con-
centrations of 10 to 18 mg/L are achieved. At 10 to
25%, the protein binding is low. The urine recovery
rate is high, being 80 to 90% for cefalexin, cefrad-
ine and cefadroxil, and 50 to 75% for cefaclor.
This low recovery rate for cefaclor is caused by
the relative instability of the compound, which
leads to a loss of activity of 50% after 6 hours at
37°C.[22] Among the newer oral cephalosporins,
cefuroxime axetil has a bioavailability of 50 to
60%; absorption is facilitated by administration af-
ter a meal. Consequently, the urine recovery rate is
lower (45 to 55%). The protein binding is 30 to
50% and the half-life 1 to 2 hours. A correlation of
the in vitro activity with the plasma concentration
shows that MICgo (minimum inhibitory concentra-
tion for 90% of strains tested) values of cefuroxime
axetil are exceeded for a significantly longer time
compared with cefadroxil and cefaclor in spite of
the lower bioavailability of cefuroxime axetil.
Concentrations in sputum and bronchial mucosa
are 2 to 3 mg/L at a blood concentration of 10 mg/L,
which is well above the MICgo values of the clini-
cally relevant pathogens of respiratory infec-
tions.l50]
Cefixime has a bioavailability of approximately
50%, the urine recovery rate lies between 18 and
25%, and 60 to 65% is bound to plasma proteins.
The low urine recovery indicates a partial biliary
elimination of 4 to 10%. Consequently, an alter-
ation of the intestinal flora was observed in volun-
teers, with a decrease of enterobacteria and an in-
crease of enterococci. The tissue concentrations are
mainly above the MIC values of relevant causative
organisms and amount to 1 mg/L in the lung and
0.05 mg/L in the sputum. The serum half-life of 3
hours is higher than that of older cephalospo-
rins.l24,25]
Cefpodoxime also has a bioavailability of ap-
proximately 50%, the urine recovery is 40% and
the protein binding reaches 30%. The serum half-
life is 2 to 3 hours, depending upon the patient's
age. The tissue concentration is mostly above the
MIC of relevant organisms, except for staphylo-
cocci, and amounts to 0.2 to 0.6 mg/L in the lung
© Adis Intemational limited. All rights reserved.
Vogel
at a serum concentration of 0.4 mg/L. With a serum
concentration of 2 mg/L, a tissue concentration of
0.9 mg/L in the bronchial mucosa was ob-
tained.l27 ,51]
Correlation of in vitro activity and serum or tis-
sue concentrations shows advantages for newer
oral cephalosporins in comparison to the older
compounds. For that reason new oral cephalospo-
rins are effective in lower dosages and permit
longer dosage intervals.
4.2 Macrolides
The pharmacokinetics of macrolides differ con-
siderably: the bioavailability is 10 to 50% and the
serum concentration of roxithromycin and clarith-
romycin is substantially higher than that of
azithromycin and dirithromycin.[52]
Macrolides attain high intracellular concentra-
tions: they accumulate in the lysosomes of the
phagocytic cell. The concentration of macrolides
in body fluids is nonuniform. In general, they can
be found in a range where the relevant bacteria are
impeded. For H. inJluenzae the concentrations are
not always sufficientJ16]
Macrolides are metabolised in the liver and the
metabolites undergo biliary excretion. With the ex-
ception of clarithromycin and dirithromycin the
metabolites have no antibacterial efficacy. The
main metabolite of clarithromycin has in vitro ac-
tivity against H. inJluenzae.l 16 ] The urinary recov-
ery of the macrolides is low. Apart from biliary
excretion,gastrointestinal elimination is assumed,
which may be due to a direct transfer of the mac-
rolides from the blood into the intestine. The longer
half-life of the newer macrolides allows twice- or
once~daily administration.
4.3 Quinolones
Because of their microbiological and pharmaco-
kinetic properties, quinolones can be utilised in a
variety of infections. Good clinical results have
been obtained in the therapy ofLRTIs. The concen-
trations in the sputum, the bronchial mucosa and in
lung tissue exceed those in the blood by several
Drugs 50 (1) 1995
Lower Respiratory Tract Infections
times. An accumulation in alveolar macrophages
has also been reported. [53]
Therapeutically effective plasma concentra-
tions are reached (2 to 5 mg/L), depending upon
the compound. The mean serum half-life of
quinolones is approximately 5 hours (pefloxacin >
ofloxacin > ciprofloxacin > enoxacin > norflox-
acin) and a twice-daily dosage regimen is suffi-
cient. Because of their relatively long half-life and
the preferentially renal elimination, careful dosage
adjustment is required for patients with renal im-
pairment. Ciprofloxacin, however, is an exception
since 15 % of the parent compound is metabolised,
with 15% being excreted through the faeces and
70% renally.
If one elimination pathway is impaired or miss-
ing, this is compensated for by the other respective
mechanism. [54-56]
5. Conclusions
The various antibacterial agents (aminopenicil-
lins, cephalosporins, macrolides and quinolones)
are different according to their antibacterial spec-
trum and pharmacokinetic properties. Drugs of
choice in respiratory tract infection can be consid-
ered according to the most frequently isolated
pathogens. The clinical efficacy and safety is the
main criterion for selection. Therefore, the group
of oral second generation cephalosporins, the
newer macrolides and aminopenicillins with or
without a ~-lactamase inhibitor are of importance
in the therapy of respiratory tract infections such
as primary pneumonia or acute and chronic bron-
chitis. Because of their poor efficacy against pneu-
mococci and their high activity against Gram neg-
ative bacteria, quinolones cannot be considered as
drugs of first choice in these indications. In noso-
comial pneumonia the parenteral cephalosporins,
because of their efficacy and tolerability, are the
basis of initial antibiotic treatment, used either
alone or combined with other antibacterials. In less
severe cases the second generation cephalosporins
can be well recommended. Patients with severe
secondary pneumonia should be treated with a par-
enteral third-generation cephalosporin which
© Adis intemationai Umited. All rights reserved.
71
mostly, at least in the initial situation, should be
combined with an aminoglycoside.
References
1. Pennington 1. Hospital acquired pneumonia. In: Respiratory
infections: diagnosis and management. 2nd ed. New York:
Raven Press, 1988
2. Bodey GP. Empirical antibiotic therapy for fever in neutropenic
patients. Clin Infect Dis 1993; 17 Supp!. 2: 378-84
3. Atherton SF, Wbite DJ. Stomach as source of bacteria colonis-
ing respiratory tract during artificial ventilation. Lancet 1978;
2:968
4. Finegold SM. Aspiration pneumonia. Rev Infect Dis 1991; 13
Supp!. 9: 737-42
5. Focht J, Klietmann W, Nosner K, et al. In-vitro-Aktivitat von
Cefuroxim im Vergleich mit anderen oralen Antibiotika.
Munch Med Wochenschr 1990; 132: 226-9
6. MacFarlane JT, Colville A, Guion A, et a!. Prospective study of
aetiology and outcome of adult lower-respiratory-tract infec-
tions. Lancet 1993; 341: 511-4
7. Garibaldi RA. Epidemiology of community-acquired respira-
tory tract infections in adults. Am J Med 1985; 78: 32-7
8. Weinke Th, Trautmann M, Soffker K, et al. Die Pneumonie bei
Erwachsenen. Munch Med Wochenschr 1988; 130: 641-3
9. Mandell LA, Marrie TJ, Niederman MS et a!. Initial antimicro-
bial treatment of hospital acquired pneumonia in adults: a
conference report. CanJ Infect Dis 1993; 4: 317-20
10. Ferlinz R, Meyer-Davila A. Epidemiologie ambulant erworbe-
ner und nosokomialer Pneumonien. Atemwegs Lungen-
krankh 1988; 14: 6-14 .
11. Kappstein I, Daschner F. Nosokomiale Pneumonien auf
Intensivpflegestationen.Intensivmed 1988; 25: 95-7
12. Kemmerich B, Rahlwes M, Vogel-Hartmann H, etal. Ambulant
erworbene Pneulnonieri. Dtsch Med Wochenschr 1989; 114:
1471-7
13. MacFarlane JT, Finch RG, Ward MJ, et al. Hospital study of
adult community-acquired pneumonia. Lancet 1982; 2: 255
14. Martin RE, Bates JH. Atypical pneumonia. Infect Dis Clin
North Am 1991; 5: 585-601
15. Kayser PH. Pneumonien in der Praxis. Schweiz Rundsch Med
Prax 1987; 76: 175-9
16. Adam D, Goertz G, Helwig H, et al. Rationaler Einsatz oraler
Antibiotika in der Praxis; Empfehlungen einer Ex-
pertenkommission der Paul-Ehrlich Gesellschaft flir Chemo-
theraphie e.v. Munch Med Wochenschr 1993; 135: 591-9
17. Simmen HP, Siegenthaler W, Liithy R. Erythromycin. Dtsch
Med Wochenschr 1982; 107: 1480
18. O'Neil SJ, Miller ED, Coles SJ, et al. Safety and efficacy of
c1arithromycin in the treatment of acute mild to moderate
respiratory tract infections. Ir Med J 1991; 84: 33-5
19. Peters DH, Friedel AA, McTavish D. Azithromycin: a review
of its antimicrobial activity, pharmacokinetic properties and
clinical efficacy. Drugs 1992; 44: 750-99
20. Nicotra MB, Rivera M, Awe RJ. Antibiotic therapy of acute exac-
erbation of chronic bronchitis. Ann Intern Med 1982; 97: 18
21. Bauernfeind A, Jungwirth R, Schweighart S et a!. Anti-
bakterielle Aktivitat und beta-Laktamase-Stabilitat von elf
Oralcephalosporinen. Infection 1990; 18 Supp!. 3: 155-67
22. Moellering RC, Waldvogel FA, editors. Cefac1or: a decade of
experience. Clin Ther 1988; 11 Supp!. A: 1-94
23. Bingen E, Lambert-Zechovsky N, Doit C et a!. Killing kinetics
of cefuroxime axetil against Haemophilus inJluenzae in an
in-vitro model simulating serum concentration profiles after
oral administration. J Antimicrob Chemother 1991; 28: 533-6
Drugs 50 (1) 1995
72
24. Brogden RN, Campoli-Richards DM. Cefixime: a review ofits
antibacterial activity, pharmacokinetic properties and thera-
peutic potential. Drugs 1989; 38: 524-50
25. Neu HC, McCracken GH, editors. Clinical pharmacology and
efficacy of cefixime. Proceedings of a conference. Pediatr
Infect Dis J 1987; 6: 949-1009
26. Marget W, Benner U, editors. Cefixime. Infection 1990; 18
Suppl. 3: S1l5-68
27. Cefpodoxime proxetil: a third-generation oral cephalosporin
[editorial]. J Antimicrob Chemother 1990; 26 Suppl. 1: 1-101
28. Nolen TM, Phillips HL, Hutchinson J, et al. Comparison of
cefuroxime axetil and cefaclor for patients with lower respi-
ratory tract infections presenting at a rural family practice
clinic. Curr Ther Res 1988; 44: 821-9
29. Schleupner CJ, Anthony WC, Tan J, et al. Blinded comparison
of cefuroxime to cefaclor for lower respiratory tract infec-
tions. Arch Intern Med 1988; 148: 343-8
30. Brambilla C, Kastanakis S. Cefuroxirne versus Augmentin fol-
low-on therapies in the treatment of lower respiratory tract
infections. In: Adam D, Lode H, Rubinstein E, editors. Recent
advances in chemotherapy. Proceedings of the 17th Internat
Congress on Chemotherapy; 1991 Jun 23-28: Berlin.
MUnchen: Futuramed Verlag, 1992: 1640-1
31. Hebblethwaite PM, Brown GW, Cox DM. A comparison of the
efficacy and safety of cefuroxime axetil and Augmentin in the
treatment of upper respiratory tract infections. Drugs Exp Clin
Res 1987; 13: 91-4
32. Spencer RC. A comparison of the efficacy and safety of cefur-
oxime axetil and amoxycillin in the treatment oflower respi-
ratory tract infections. 6th Mediterranen Congress of
Chemotherapy; 1988 May 22-27, Taormina-Giardini, Naxos
33. Vogel F, Maas AB. Clinical and bacteriological experience with
cefuroxirne axetil in the treatment of lower respiratory tract
infections [abstract]. Z Antimikrob Antineoplast Chemother
1989; 7 Suppl. 1: 50
34. Kohl FV, Kohler CO. A multicenter clinical trial to compare two
antibiotic regimes: cefuroxime i.v. followed by cefuroxirne
axetil orally (group 1) versus cefotiam i. v. (group 2). In: Adam
D, Lode H, Rubinstein E, editors. Recent Advances in Che-
motherapy. Proceedings of the 17th Internat Congr Chemo-
ther; 1991 June 23-28: Berlin. MUnchen: Futuramed Verlag,
1992: 2068-9
35. Meyers BR. Management of community acqnired lower respi-
ratory tract infections with cefuroxime axetil: clinical over-
view. In: Emmerson AM, editor. The management of lower
respiratory tract infections with cefuroxime axetil. Royal So-
ciety of Medicine Services International Congress and Sym-
posium Series No. 124; 29 May 1987. London: Royal Society
of Medicine Servia, 1987
36. Vogel F. Orale Cephalosporine bei unteren Atemwegs-
infektionen. FAC 1993; 12-1: 135-47
37. Kiani R, Johnson D, Nelson B. Comparative multicenter studies
of cefixime and amoxicillin in the treatment of respiratory
tract infections. Am J Med 1988; 85: 6-13
38. Dorow P. Safety and efficacy of cefixirne versus cefaclor in
respiratory tract infections. J Chemother 1989; 1: 257-60
39. Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime
proxetil compared with ceftriaxone in vulnerable patients
with bronchopneumonia. J Antimicrob Chemother 1990; 26
Suppl. E: 71
40. Periti P, Novelli A, Schildwachter G. Efficacy and tolerance of
cefpodoxime proxetil compared with co-amoxiclav in the
© Adis Interna~onal Limited. All rights reserved.
Vogel
treatment of exacerbations of chronic bronchitis. J Antimicrob
Chemother 1990; 26 Suppl. E: 63-9
41. Vogel F. Efficacy and tolerability of clarithromycin in the short-
course treatment of acute respiratory infections. Drug Invest
1991; 3: 205-9
42. Heinrich R, Mitschka J. Multicenter, randomized comparative
study of ceftazidime vs. cefotaxime in the treatment of pa-
tients 65 years of age and older with nosocomial bacterial
pulmonary and urinary tract infections. Int J Exp Clin Chem-
other 1991; 4: 40-7
43. Niedermann MS, Bass ]B, Campbell GD et al. Gnidelines for
the initial management of adults with community-acquired
pneumonia. Am Rev Resp Dis 1993; 148: 1418-26
44. Yangco BG, Baird I, Lorber B, et al. Comparative efficacy and
safety of ceftizoxime, cefotaxime and latamoxef in the treat-
ment of bacterial pneumonia in high risk patients. J Anti-
microb Chemother 1987; 19: 239-48
45. Norrby S, Finch R, Glornser M et al. Monotherapy in serious
hospital-acquired infections; a clinical trial of ceftazidime
versus imipenemlcilastatin. J Antimicrob Chemother 1993;
31: 927-37
46. Rubinstein E, Lode H, Grassi C et al. Ceftazidime monotherapy
vs. ceftriaxone/tobramycin for serious hospital-acquired
Gram-negative infections. Clin Infect Dis. In press
47. De Pauw BE, Stanley C, Deresinski MD. ceftazidime compared
with piperacillin and tobramycin for the empiric treatment of
fever in neutropenic patients with cancer. Ann Intern Med
1994; 120: 834-44
48. Freifeld AG, Walsh T, Marshall D et al. Monotherapy for fever and
neutropenia in cancer patients: a randomized comparison of
ceftazidime versus imipenem. J Clin Onco11995; 13: 165-76
49. Konsensuskonferenz der Paul-Ehrlich-Gesellschaft fUr Chemo-
therapie e. V. Cephalosporine zur parenteralen Anwendung.
Chemotherapie J 1994; 3: 101-15
50. James NC, Donn KH, Collins JJ et al. Pharmacokinetics of ce-
furoxime axetil and cefaclor: relationship of concentrations in
serum to MICs for common respiratory pathogens. Anti-
microb Agents Chemother 1991; 9: 1860-3
51. Tremblay D, Dupront A, Ho C, et al. Pharmacokinetics of
cefpodoxime in young and elderly volunteers after single
doses. J Antimicrob Chemother 1990; 26 Suppl. E: 21-3
52. Neu HC. The development of macrolides: clarithromycin in
perspective. J Antimicrob Chemother 1991; 27 Suppl. A: 1-9
53. Lamp KC, O'Baily EM, Rybak MJ. Ofloxacin clinical pharma-
cokinetics. Clin Pharmacokinet 1992; 22: 32-46
54. Bolaeret IM, Valcke Y, Schurgers M, et al. The pharmacokinet-
ics of ciprofloxacin in patients with impaired renal function.
J Antimicrob Chemother 1985; 16: 87-98
55. Gasser TC, Ebert SC, Graversen PH, et al. Pharmacokinetic
study of ciprofloxacin in patients with impaired renal func-
tion. Am J Med 1987; 82 Suppl. 4A: 139-41
56. Wingender W, 'Be~rmann D, Forster D, et al. Mechanism of
renal excretion of ciprofloxacin (BAY 09867), a new
quinolone carbocylic acid derivative in humans. Chemiotera-
pia 1985; 4 Suppl. 2: 403-4
Correspondence and reprints: Professor Dr Friedrich Vogel,
Krankenhaus Hofheim, Lindenstrasse 10, D-65719 Hofheim
im Taunus, Germany.
Drugs 50 (1) 1995