A P Ballf

S Mehtar

CiteSeerX

Journal of Antimicrobial Chemotherapy (1985) 15, 765-771
Intravenous Augmentin in bacteraemia and severe invasive polymicrobial sepsis
S. Mehtar* and A. P. Ballf
* Microbiology Department, North Middlesex Hospital, Edmonton, London, ^Infectious Diseases
Unit, Cameron Hospital, Windygates, Fife, Scotland
An intravenous formulation of Augmentin was used as sole chemotherapy in the
treatment of patients with severe infections. Fourteen of 17 assessable patients (82%)
responded satisfactorily including six with bacteraemia. Adverse reactions occurred
in 38% of patients but in all but one, withdrawn due to diarrhoea, were trivial There
was no significant intolerance.
Introduction
The addition of the /Mactamase inhibitor, clavulanic acid, significantly extends the
spectrum of amoxycillin to include many amoxycillin-resistant organisms which have
the ability to produce /7-lactamases (Reading & Cole, 1977; Neu & Fu, 1978). Formula-
tions of clavulanic acid with amoxycillin (Augmentin) are active against Staphylococcus
aureus, Bacteroides fragilis and many enterobacterial species in vitro (Wise, 1977; Wise,
Andrews & Bedford, 1978; Farrell & Brookes, 1980), and are effective in oral therapy of
urinary, respiratory and soft-tissue infections caused by these organisms (Ball et al.,
1980; Mehtar, 1980; Pines et al., 1980; Ball, Mehtar & Watson, 1982).
Although seriously ill patients, including some with bacteraemia, have been success-
fully treated with oral Augmentin formulations, evaluation of the agent in life-
threatening sepsis has been hampered by the unavailability of a parenteral formulation.
An intravenous preparation is now available for clinical trial and the results of a
preliminary study in seriously ill, infected patients are presented.
Patients and methods
Twenty-one patients were selected for treatment with Augmentin. Inclusion criteria
were: serious invasive bacterial infection requiring broad spectrum parenteral therapy,
age > 16 years, isolation of one or more amoxycillin-resistant bacteria responsible for
the infection and verbal consent to participate. Ethical committee approval was
obtained prior to commencement of the study. Patients with penicillin allergy, those with
severe chronic renal impairment, pregnant or lactating females, and those with infections
in sites where the components of Augmentin had not at that time been shown to pen-
etrate adequately, e.g. meningitis, were specifically excluded. Patients with infections in
sites requiring more than ten days therapy, e.g. osteomyelitis, were also excluded.
All patients initially received treatment with intravenous formulation of Augmentin
containing 1 g amoxycillin plus 200 mg clauvulanic acid. This preparation, in 20 ml
765
0305-7453/85/060765 + 07 $03 00/0 © 1985 The British Society for Antimicrobial Chemotherapy
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768 S. Mehtar and A. P. Ball
water for injection, was administered, 6-8-hourly, as sole chemotherapy. Intravenous
Augmentin was discontinued, and oral Augmentin, 750 mg (amoxycillin 500 mg;
clavulanate 250 mg), 8-hourly, substituted, after a satisfactory clinical response. The
period of subsequent treatment with oral Augmentin was usually about one week.
Diagnosis was based on clinical and radiographic procedures and microbiological
confirmation was established by relevant cultures of the site of infection including in
some cases blood culture. Clinical isolates were tested against ampicillin (2 or 10 ug disc
strength) alone as well as a combination disc containing amoxycillin plus clavulanic acid
(ratio 2:1) using the Stokes method. Minimum inhibitory concentrations were measured
on DST and Wilkin-Chalgrins agar (Oxoid) (incorporated with amoxycillin, clavulanic
acid and a combination of the two in a ratio of 2:1) for aerobic and anaerobic organisms
respectively. Final inocula of 10*-103cfu were applied by a multipoint inoculator
(Denley) and the plates were incubated overnight at 37°C in the appropriate atmos-
pheres. Where appropriate, cultures were repeated during, and at the end of Augmentin
therapy.
Patients receiving Augmentin were monitored regularly (usually daily) for efficacy and
tolerance. Four hourly temperature readings were made throughout the febrile period.
Toxicological parameters, including full blood counts, renal and liver function tests,
were monitored immediately before treatment, three to five days thereafter, and within
24-48 h of completion of treatment.
Clinical and bacteriological assessment
Patients were assessed as cured if there was satisfactory resolution of fever, toxaemia and
all signs of the underlying infection, and if there was no evidence of persistence of, or
re-appearance of the causative organism at the site of infection.
Patients were assessed as improved if: (1) despite a satisfactory response, significant
adverse effects necessitated withdrawal prior to the completion of the treatment course,
(2) despite clinical cure, the causative organism persisted in the original site(s), or (3)
initial response was followed by Augmentin-resistant superinfection during therapy. All
other patients were assessed as failures.
Results
The clinical and bacteriological results of Augmentin treatment are shown in Table I. A
total of 17 patients were assessable: four being excluded because of failure to isolate a
bacterial pathogen prior to Augmentin therapy. Three of these patients, who were
thought to be bacteraemic on clinical grounds (one related to facial erysipelo-cellulitis,
one to cholecystectomy and one to pericolic abscess in a steroid treated patient with
ulcerative colitis) were cured. The fourth, with a ventilator-associated pneumona,
improved.
The remaining 17 patients suffered from pneumonia (three due to Gram-negative
bacilli, one due to Staph. aureus and Streptococcus pneumoniae), empyema (3), intra-
abdominal abscess, peritonitis and wound infection (6), bacteraemic cholangitis (2) and
bacteraemic pyelonephritis (2). Six patients had proven bacteraemia. At least one
amoxycillin-resistant isolate was present in each patient and three had received
unsuccessful amoxycillin therapy.
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IV Augment™ in severe infections 769
The 17 patients received a mean of 5-2 days IV Augmentin therapy (range 2-7 days)
and a mean of 6-9 days follow-up oral Augmentin therapy (range 0-8 days). The mean
period before abatement of pyrexia was 2-9 days (range 1-6 days).
Fourteen of the 17 patients (82%) responded satisfactorily: eight were cured and six
significantly improved. Patients 4, 5,9 were assessed as failures because of failure to con-
trol the infection (Table I), and persistence of original pathogens or superinfection with
Pseudomonas aeruginosa. Two patients assessed as improved (6, 14) also developed
superinfection with this organism, two had persistence of an original organism in
sputum (1,2), one had a persistent liver abscess requiring operation despite satisfactory
control of bacteraemia (15), and one suffered a relapse of empyema after 12 days clinical
improvement (3).
Bacteraemia was eradicated in six patients, although two could only be assessed as
improved, because of persistence of liver abscess requiring surgery (15) and resistant
superinfection caused by Ps. aeruginosa (14) respectively.
Seven patients had intrathoracic infections of whom two were assessed as failures. In
one patient (4), whose pre-treatment sputum flora included Ps. aeruginosa, a variety of
antibiotic combinations were required before cure was finally attained with gentamicin
plus ticarcillin. In the order (5), who had an underlying oesophageal carcinoma, there
was no clinical response prior to the patient's death of a pulmonary embolus, on day 5 of
therapy. The remaining five patients in this category all improved initially, although one
subsequently relapsed after 12 days treatment for empyema and another died of myo-
cardial infarction complicating prolonged assisted ventilation. Only one, with an
anaerobic empyema (7) was assessed as cured.
The MICs of ampicillin and clavulanic acid alone, and of a 2:1 combination of these
agents were subsequently determined for 38 of the strains isolated. Fourteen isolates,
mainly streptococci and Gram-positive anaerobes, were ampicillin-sensitive. The
remaining 24, mainly coliform bacilli and Bad. fragilis, including at least one isolate
from each patient—were ampicilh'n-resistant /J-lactamase producers. When clavulanic
acid was added a greater than four-fold reduction in ampicillin MIC was observed for 19
of the isolates: MICs ranging from 2-16 mg/1. However, five strains (from patients 1-5)
had MICs for ampicillin-clavulanate of 32-128 mg/1, and two of these isolates, Klebsiella
aerogenes and Escherichia coh (patients 4, 5) showed a greater than two-fold increase in
MIC of the combination during treatment. These findings are reflected in the clinical and
post-therapy bacteriological results given above.
Adverse reactions were assessed in all 21 patients originally selected for IV Augmentin
therapy, and were observed in eight (38%). Most were trivial. Diarrhoea occurred in
four patients (19%) and necessitated withdrawal in one. There was no clinical or bac-
teriological evidence of antibiotic associated colitis in this patient (9). Clostridium diffi-
cile was isolated, in the absence of toxin, from another diarrhoeal patient (14). However,
his diarrhoea settled spontaneously. Elevation of serum transaminases, possibly related
to therapy, occurred in two patients, and a single patient developed jaundice—thought
in retrospect to relate to total parenteral nutrition. A positive Coombs test, with no
evidence of haemolysis, was found in one patient. There was no significant intolerance of
either IV or oral Augmentin.
Discussion
The patients treated in this small series were generally severely ill, elderly and com-
promised by surgery, ventilation, solid tumours or other significant factors The results
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770 S. Mehtar and A. P. Ball
of treatment of infection with intravenous Augmentin reflect these factors, despite which
a response rate of 82% was obtained. Although only eight of 17 patients (47%) were
assessed as cured, eradication was achieved in all six bacteraemic patients and cure was
obtained in five of seven patients with intra-abdominal sepsis. Failure to control the
infection occurred in only three patients and no deaths occurred related to treatment
failure. Of the six patients assessed as unproved, five had a satisfactory clinical response
despite persistence of the original infecting organism(s) or isolation of a further potential
pathogen.
Persistence of infecting organisms in sputum or empyema fluid occurred in all five of
the patients with intrathoracic infections from whom Gram-negative bacilli were
isolated. In these patients (1-5) at least one organism was isolated which was resistant to
Augmentin in vitro. Failure in patients 4 and 5 directly reflects this. In patients 1-3, who
were clinically improved initially but in whom failure to eliminate Gram-ne"gative aero-
bic bacilli prevented assessment as cure, the treatment result also reflected the presence
of Augmentin-resistant bacteria. The apparently less than optimal results in chest infec-
tions should therefore be interpreted with caution. Previous studies in chest infections,
notably due to /Mactamase producing Branhamella catarrhalis and Haemophilia
influenzae, have shown excellent results after Augmentin therapy (Ninane et al., 1978;
Mehtar, 1980). However, the amounts of clavulanic acid required to inhibit /Mactamases
produced by Gram-negative bacilli, such as Escherichia coli, may be of the order of
2-5-10 mg/1 (Farrell & Brookes, 1980). This compares with sputum concentrations of
this agent of 0-92 mg/1 at 1 h after oral dosage of Augmentin 750 mg (clavulanate
250 mg) found by Kosmidis (1983) and peak pleural fluid concentrations of 31 mg/1 at
4 h after a single oral dose of amoxycillin 1 g with clavulanic acid 250 mg (Kitzis et al.,
1983). Studies of sputum penetration after intravenous Augmentin, currently in
progress, have not been reported.
The overall results suggest that intravenous Augmentin will prove an effective anti-
biotic in the management of bacteraemia and intra-abdominal infection emanating from
the bowel, biliary tract or urinary tract. The less optimal results in intrathoracic infec-
tions suggest that further efficacy studies should be carried out in Gram-negative disease
to fully assess the potential of Augmentin therapy.
References
Ball, A. P., Geddes, A. M., Davey, P. G , Farrell, I. D. & Brookes, G R. (1980). Clavulanic acid
and amoxycillin: a clinical, bacteriological and pharmacological study. Lancet i, 620-3.
Ball, A. P., Mehtar, S. & Watson, A. (1982). Clinical efficacy and tolerance of Augmentin in soft
Ussue infection. Journal of Antimicrobial Chemotherapy 10, 67—74
Farrell, I. D. & Brookes, G. R. (1980). The laboratory efficacy of amoxycillin and clavulanic acid
combinations. In Proceedings of the First Symposium on Augmentin- Clavulanate-potentiated
amoxycillin (Rolinson, G. N. & Watson, A., Eds), pp. 54-7. Excerpta Medica, Amsterdam.
Kitzis, M. D., Kitzis, M. B , Yvelin, C, Acar, J F & Andreassian, B. (1983) The penetration of
Augmentin into the pleural fluid. In Augmentin- Clavulanate Potentiated Amoxycillin
(Croydon, E. A. P. & Michel, M. F., Eds), pp. 261-6. Excerpta Medica, Amsterdam.
Kosmidis, J. (1983). Pharmacokinetic and clinical experiences with clavulanic acid in association
with amoxycillin and ticarcillin. In Proceedings of the 13th International Congree of
Chemotherapy (Spitzy, K. H. & Karrer, K., Eds), Part 22, pp. 50-2.
Mehtar, S. (1980). Respiratory infections caused by beta-lactamase-producing organisms treated
with Augmentin. In Proceedings of the First Symposium on Augmentin Clavulanate-
potentiated amoxycillin (Rolinson, G. N. & Watson, A., Eds), pp. 259-68. Excerpta Medica,
Amsterdam.
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IV Augmentin in severe infections 771
Neu, H. C. & Fu, K. P (1978) Clavulanic acid, a novel inhibitor of beta-lactamascs. Anti-
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Ninane, G., Joly, J., Kraytman, M. & Piot, P. (1978). Bronchopulmonary infection due to
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Pines, A , Raafat, H , Khorasam, M. H., Jabbar, N. A. & Sharma, J. C. (1980). Experience with
amoxycillm plus potassium clavulanate in lower respiratory infections. In Proceedings of the
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Watson, A., Eds), pp 277-83 Excerpta Medica, Amsterdam.
Reading, C. & Cole, M. (1977). Gavulanic acid, a beta-lactamase-inhibiting beta-lactam from
Streptomyces clavuligerus. Antimicrobial Agents and Chemotherapy 11, 852-7.
Wise, R. (1977). Clavulanic acid and susceptibility of B fragilis to penicillin. Lancet u, 145.
Wise, R., Andrews, J. M. & Bedford, K. A (1978) Clavulanic acid and CP-45,899: a comparison
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(Manuscript accepted 29 November 1984)
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Intravenous augmentin in bacteraemia and severe invasive polymicrobial sepsis

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Intravenous augmentin in bacteraemia and severe invasive polymicrobial sepsis

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