sulbactam in the treatment of upper and lower bacterial respiratory tract infections

International Journal of Antimicrobial Agents 18 (2001) 199– 209 www.ischemo.org

Review

Role of sultamicillin and ampicillin/sulbactam in the treatment of upper and lower bacterial respiratory tract infections H. Lode * Pneumologie I (Infektiologie and Immunologie), Lungenklinik Heckeshorn, Zum Heckeshorn 33, 14109 Berlin, Germany Received 12 January 2001; accepted 6 June 2001

Abstract The emergence of b-lactamase-mediated resistance to b-lactam antibiotics among key respiratory tract pathogens has threatened the usefulness of the b-lactam agents familiar to physicians as being clinically effective and well tolerated. This article reassesses the clinical usefulness of ampicillin when administered in combination with the b-lactamase inhibitor sulbactam, either intravenously or orally (as the mutual prodrug sultamicillin), in the treatment of upper and lower respiratory tract infections. Numerous clinical studies and several meta-analyses indicate that ampicillin/sulbactam and sultamicillin are clinically effective and well tolerated in both adults and children, in agreement with published North American and European guidelines. © 2001 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Respiratory tract infection; Ampicillin; Sulbactam; Sultamicillin

1. Introduction Bacterial respiratory tract infections continue to represent a major source of morbidity and mortality, despite continuing improvements in diagnosis and the development of new antibiotic classes. In 1998, respiratory tract infections accounted for more than three million deaths worldwide, i.e. 6.4% of all deaths and more than 85 million disability-adjusted life years, i.e. 6.2% of global disease burden [1]. Nearly all of these outcomes were attributable to lower respiratory tract infections which comprised the third leading cause of mortality (after ischaemic heart disease and cerebrovascular disease), and the leading cause of infectious disease burden [1]. Therefore, in both the community and hospital setting, there is a continuing need for safe and effective parenteral and oral empiric antibiotic therapy that provides coverage against the wide variety of possible pathogens. * Corresponding author. E-mail address: [email protected] (H. Lode).

Experience has taught physicians that b-lactam antibiotics, in particular the penicillins (including aminopenicillins) offer clinical efficacy against a broad spectrum of respiratory pathogens with few serious adverse events [2]. Unfortunately, the emergence of b-lactamase-mediated bacterial resistance among many common pathogens [3–6] has threatened the usefulness of b-lactam agents in prophylaxis and therapy. The Alexander Project, a global antibiotic resistance surveillance programme involving 21 centres, gives a good indication of the current scale of the problem [7]. With regard to clinical isolates collected during 1996, ampicillin resistance, for example, was observed in 21% of Streptococcus pneumoniae isolates (n= 2160), 16% of Haemophilus influenzae isolates (n= 2820), and 90% of Moraxella catarrhalis isolates (n= 655). b-Lactamase production was confirmed as the principal mechanism of resistance among H. influenzae and M. catarrhalis, occurring in 14 and 90% of isolates, respectively. One successful approach to overcoming b-lactam resistance among b-lactamase-producing pathogenic strains is the co-administration of a b-lactamase inhibitor [2,6]. Of the many b-lactamase inhibitors that

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have been evaluated, three (sulbactam, tazobactam and clavulanic acid) are in clinical use as a number of b-lactam/b-lactamase inhibitor combinations: ampicillin/sulbactam (Unasyn®), cefoperazone/sulbactam, piperacillin/tazobactam, ticarcillin/clavulanic acid and amoxycillin/ clavulanic acid [6]. In some countries, sulbactam is also available as a single agent for parenteral use in combination with b-lactams of the physician’s choice. A review of early studies with ampicillin/sulbactam established the clinical usefulness of parenteral formulations in the therapy and prophylaxis of a wide variety of infections, including respiratory tract infections [8]. Later reviews described the good clinical efficacy and tolerability of oral ampicillin/sulbactam, administered as the mutual oral prodrug sultamicillin, in treating respiratory tract infections in adults [9] and children [10]. However, these reviews and the studies discussed within them, pre-date the emergence of b-lactamase resistance among respiratory tract pathogens demonstrated by surveillance studies such as the Alexander [7] and Artemis [11] surveillance projects. Accordingly, this article reassesses the role of ampicillin/sulbactam in the treatment of upper and lower respiratory tract infections, with reference to recent clinical studies and meta-analyses.

1.1. In 6itro antimicrobial acti6ity Although all b-lactamases catalyze the same reaction, a number of different types have been characterized [6]. These vary according to gene location (chromosome or plasmid), substrate specificity and inhibitor susceptibility, as well as other characteristics. For example, the commonly used Bush– Jacoby – Medeiros classification scheme [12] comprises four groups of enzymes. Groups 1 and 2 include the broader-spectrum b-lactamases, encoded by chromosomal and plasmid genes, respectively, whereas, Group 3 includes carbapenem-specific b-lactamases and Group 4 enzymes are poorly inhibited by the b-lactamase inhibitor clavulanic acid [6]. Sulbactam is a potent, highly specific inhibitor of a wide variety of b-lactamases produced by commonly occurring Gram-positive and -negative aerobes and anaerobes [13]. Sulbactam effectively inhibits most plasmid-mediated b-lactamases and some chromosomal blactamases [13–15], and is more resistant to degradation by b-lactamases than clavulanic acid [14,15]. Sulbactam also possesses direct antimicrobial activity against Bacteroides fragilis and Acinetobacter species [13]. Thus, co-administration of sulbactam with ampicillin extends its activity to include b-lactamaseproducing strains of many common pathogens. Susceptibility studies in vitro have shown that ampicillin/sulbactam has antimicrobial activity against Gram-positive, Gram-negative and anaerobic bacteria

responsible for many respiratory tract infections [14– 17]. Susceptible organisms include streptococci, staphylococci and enterococci, H. influenzae, M. catarrhalis, many Enterobacteriaceae (including Escherichia coli and Klebsiella pneumoniae) and anaerobes (such as Bacteroides, Clostridium and Fusobacterium species). For most of these target organisms, the minimum bactericidal concentration of ampicillin/sulbactam is only one dilution greater than its minimum inhibitory concentration (MIC) [14,15]. A comparison of ampicillin/sulbactam with ampicillin alone shows that the combination offers particularly marked improvement in activity against most Enterobacteriaceae and methicillin-resistant Staphylococcus aureus compared with ampicillin alone [14]. Sulbactam also extends the activity of b-lactam agents with marginal activity against anaerobic pathogens, in particular members of the B. fragilis group [17]. Therefore, in vitro microbiological data suggest that co-administration of sulbactam with ampicillin has the potential to restore the latter’s activity against b-lactam-resistant pathogens in the clinical setting.

1.2. Pharmacokinetics of ampicillin and sulbactam, alone and in combination The pharmacokinetic profile of sulbactam administered intravenously or orally is similar to that of intravenous or oral ampicillin (Table 1); this favours co-administration within a single formulation [18]. The pharmacokinetic profiles of ampicillin and sulbactam are dose-proportional up to doses of at least 1000 mg [19]. Sultamicillin, the mutual prodrug, delivers ampicillin and sulbactam to the peripheral circulation as efficiently as intravenous ampicillin/sulbactam, thus overcoming the problem of poor oral absorption of ampicillin and sulbactam when administered separately [18]. Sultamicillin is absorbed readily (\80% bioavailability) from the gastrointestinal tract and hyTable 1 Pharmacokinetic parameters for ampicillin and sulbactam administered as oral sultamicillin (©1989 Munksgaard International Publishers Ltd., Copenhagen, Denmark) [18]

Cmax (mg l−1) Tmax (h) AUC (mg h l−1) T1 (h) 2 Urinary recovery (% of dose)

Ampicillina

Sulbactama

9.1 93.6 0.92 9 0.30 17.8 9 3.6 0.96 90.25 59.4 9 7.1

8.9 9 3.4 0.96 90.29 16.7 92.5 1.11 9 0.69 66.3 9 6.7

Cmax, maximum serum concentration; Tmax, time from dosing to Cmax; AUC, area under the serum concentration–time curve; T1, 2 elimination half-life. a Sultamicillin (750 mg), equivalent to 440 mg ampicillin and 294 mg sulbactam, administered orally to young volunteers.

H. Lode / International Journal of Antimicrobial Agents 18 (2001) 199–209

drolyzed rapidly to release equimolar concentrations of ampicillin and sulbactam, at a mass ratio of approximately 3:2 [18]. Indeed, the bioavailability of ampicillin is greater when administered as sultamicillin than when administered alone [18,20]. Both ampicillin and sulbactam are distributed extensively to a variety of tissues and body fluids including those of the respiratory tract [18,19], attaining concentrations generally in excess of the MICs for common respiratory pathogens. Both agents have an elimination half-life of approximately 1 h, which supports a 6– 8 h intravenous/intramuscular (IV/IM) dosing schedule [19]. In addition, in the case of oral dosing, the high serum concentrations achieved, coupled with the synergistic action of ampicillin and sulbactam, permit twice-daily oral dosing [18,19]. The primary route of excretion of ampicillin and sulbactam is renal [19]. Accordingly, the frequency of dosing is reduced routinely (from three or four times daily to twice or once daily) in patients with renal impairment. Therefore, the pharmacokinetic profiles of ampicillin and sulbactam support their co-administration as oral (PO) or IV formulations, according to a twice- or three-times-daily dosing regimen. This, together with the in vitro antimicrobial profile of ampicillin/sulbactam, suggests that the combination should be clinically effective in treating a variety of respiratory tract infections, including infections involving normally ampicillin-resistant strains.

1.3. Efficacy against respiratory infections Comparative clinical studies have established the clinical and bacteriological efficacy of ampicillin/sulbactam in treating a wide variety of infections. In 1986, a meta-analysis of 39 worldwide therapeutic (mostly open and non-comparative) studies provided cumulative efficacy data for 899 patients (adults or children) with a variety of severe infections attributable to b-lactamaseproducing bacteria [8]. Most (85%) patients received ampicillin/sulbactam by short IV infusion or bolus injection (ampicillin/sulbactam was administered intramuscularly to the remainder), and most (84%) also underwent multiple-dose therapy. The vast majority of adult patients received sulbactam 1– 4 g per day (mean daily dose 2.4 g per day) in a 1:2 (54% of patients) or a 1:1 (41% of patients) mass ratio with ampicillin; the remaining 5% of patients were treated with ampicillin/ sulbactam at a mass ratio of between 3:1 and 10:1. Children were given sulbactam 30–100 mg kg − 1 per day (mean daily dose 1.0 g), mostly (58% of cases) in a 1:2 ratio with ampicillin. The mean duration of therapy was 7.6 days (range 2– 28 days) in adults and 4 days (maximum 11 days) in children. Satisfactory clinical efficacy (cure, marked improvement, or moderate improvement, together with bacteri-

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Table 2 Meta-analysis of clinical efficacy (cure or improvement) of intravenous or intramuscular ampicillin/sulbactam and comparative agents in clinical trials Infection

Satisfactory efficacy (% of evaluable patients) Ampicillin/sulbactam All studies

Respiratory Urinary Gynaecological Septicaemia Skin/skin structure Bone/joint Intra-abdominal

83 94 79 92 92

(n= 86) (n =71) (n =19) (n =13) (n =113)

90 (n =10) 90 (n =70)

Ear/nose/throat 96 (n =23) Other 100 (n =1)

Comparator

Comparative studies

100 (n = 113)

100 (n = 1)a

89 (n = 9) 96 (n =45)

50 (n = 6)a 100 (n = 32)b 78 (n =9)c

©1986 by The University of Chicago Press [8]. Satisfactory efficacy was defined as clinical cure, marked improvement or moderate improvement, together with bacteriological eradication. a Comparative agents were: Cefotaxime; b Clindamycin–gentamicin; c Gentamicin–metronidazole.

ological eradication) was observed in 83% of ampicillin/sulbactam-treated patients with respiratory tract infections, 79% of patients with gynaecological infections and 92% of other patients (Table 2). Nearly all (93%) pathogens identified at baseline were eradicated. Forty-three percent of the isolates were resistant to ampicillin but sensitive to ampicillin/sulbactam; of these ampicillin-resistant strains, 95% were eradicated at the end of treatment. The efficacy of oral sultamicillin in the treatment of various respiratory tract infections has also been assessed. Sultamicillin 50 mg kg − 1 per day was administered for 3–13 days (mean 5.3 days) to 48 children with various respiratory tract infections, including pharyngotonsillitis, acute bronchitis, bronchopneumonia, obstructive bronchitis and pneumonia [21]. A satisfactory clinical response was seen in 46/48 (96%) patients. Those with fever experienced a defervescence on the second day of therapy.

1.3.1. Upper respiratory tract infections Several clinical studies have demonstrated the efficacy of oral sultamicillin or intramuscular ampicillin/ sulbactam in treating upper respiratory tract infections (URTIs) in both adults and children (Table 3). In adults, two open-label, comparative studies with oral sultamicillin have demonstrated successful clinical response (cure or improvement in signs and symptoms) rates of 100% at end of treatment [22,23] and 95% at

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follow-up [23]; these compared favourably with corresponding rates of 93 and 94% for amoxycillin [23], and 95% (at end of treatment) for cefuroxime axetil [22]. Bacteriological eradication rates for sultamicillin and amoxycillin were similar at end of treatment and at follow-up. A third non-comparative study with intramuscular ampicillin/sulbactam yielded a similar response rate of 89% in adult patients with acute otitis media (AOM) and 100% in patients with acute or chronic sinusitis [24]. An eradication rate of 100% among the 22 bacteriologically evaluable patients with sinusitis was remarkable, given that 44% of the 36 strains isolated at baseline were b-lactamase producers, including all strains of staphylococci, M. catarrhalis and Pseudomonas aeruginosa, and 40% of H. influenzae isolates. Strains of the most commonly isolated organisms (S. pneumoniae, H. influenzae, M. catarrhalis, and staphylococci) showed 100% susceptibility to ampicillin/sulbactam in vitro [24]. In children, two similar non-comparative studies involving 100 and 49 patients yielded an end-of-treatment clinical response rate for sultamicillin of 99 and 100%, including cure rates of 86 and 93% [10,25]. These clinical responses were characterized by a high bacteriological eradication rate of 100% of isolates in one study [10] and in the other, a lower eradication rate of 74%,

which could be corrected to 32/35 (94%) if 10 bacteriologically unevaluable patients were excluded from the bacteriological analysis [25].

1.3.2. Paediatric AOM Among studies that have evaluated oral sultamicillin in the treatment of mild-to-moderate URTIs, a large number have addressed the treatment of paediatric AOM (Table 4). Three open studies featuring a 10– 11day course of sultamicillin dosed twice or three times daily, yielded clinical response rates of 82–100% at end of treatment and 78–100% at follow-up [26–28]. Two of these studies were comparative and showed similar clinical response rates for sultamicillin versus amoxycillin [27] and sultamicillin versus cefaclor [28]. A fourth double-blind study demonstrated similar clinical response rates for sultamicillin and amoxycillin/clavulanic acid [29]. All four studies featured small study populations and a low incidence of b-lactamase-positive bacterial strains among baseline isolates. 1.3.3. Lower respiratory tract infections In the case of IV ampicillin/sulbactam, many openlabel clinical studies [30–37] have demonstrated its effectiveness in the treatment of adults with serious non-specific lower respiratory tract infections (LRTIs) (Table 5). Clinical and bacteriological response rates

Table 3 Clinical efficacy of ampicillin/sulbactam in the treatment of upper respiratory tract infections (URTIs) Authors (year)

Infection

Adults Alvart (1992) [22] Mild-to-moderate acute ear, nose and throat infections

Federspil et al. (1989) [23]

Nicoletti et al. (1991) [24]

Children Raillard et al. (1992) [10] Arguello (1992) [25]

Tonsillitis, pharyngitis, peritonsillar abscess

Acute otitis media (AOM), acute or exacerbated chronic sinusitis

Treatment regimens

Clinical efficacy (patients)

Sultamicillin 0.75 or 1.5 g per day bid PO, ]5 days Cefuroxime axetil 0.5 or 1.0 g per day bid PO, ]5 days

Cure 46/55 (84%), improvement 9/55 (16%) Cure 38/55 (69%), improvement 14/55 (25%)

Sultamicillin 0.5 g bid PO, 10 days Amoxycillin 0.5 g tid PO, 10 days

End of treatment 55/55 (100%), follow-up 40/42 (95%) End of treatment 40/43 (93%), follow-up 29/31 (94%)

Ampicillin/sulbactam 1.5 g bid IM, 5–10 days

AOM: cure 12/19 (63%), improvement 5/19 (26%)

Bacteriological eradication

End of treatment 24/29 (83%) isolates, follow-up 17/25 (68%) isolates End of treatment 17/22 (77%) isolates, follow-up 16/19 (84%) isolates

Acute/chronic sinusitis: cure 12/22 (55%), improvement 10/22 (45%)

Acute/chronic sinusitis: end of treatment 22/22 (100%) patients

Mild-to-moderate URTIs

Sultamicillin 25 mg kg−1 per day bid PO, ]7 days

Cure 93/100 (93%), improvement 6/100 (6%)

49/49 (100%) isolates

Mild-to-moderate URTIs

Sultamicillin 25 mg kg−1 per day bid PO, ]7 days

Cure 42/49 (86%), improvement 7/49 (14%)

32/44 (74%) patients

Clinical efficacy is given as the satisfactory response (cure or improvement) rate, unless otherwise indicated. All clinical efficacy and bacteriological eradication data relate to end of treatment, unless otherwise indicated. IM, intramuscular; PO, oral.

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Table 4 Clinical efficacy of sultamicillin in the treatment of paediatric acute otitis media Authors (year)

Treatment regimens

Clinical efficacy (patients)

Kaleida et al. (1986) [26]

Sultamicillin 50 mg kg−1 per day (bid or tid) PO, 10 days

Relief of symptoms: 41/50 (84%)

Rodriguez et al. (1990) [27]

Sultamicillin 50 mg kg−1 per day or 500 mg per day (bid or tid) PO, 10 days Amoxycillin 40 mg kg−1 per day or 250 mg per day (tid) PO, 10 days

End of treatment 47/51 (92%), follow-up 36/46 (78%) End of treatment 25/26 (96%), follow-up 17/23 (74%)

Biolcati (1992) [28]

Sultamicillin 50 mg kg−1 per day (bid) PO, 10–11 days Cefaclor 40 mg kg−1 per day (tid) PO, 10–11 days

End of treatment and follow-up: cure 17/26 (65%), improvement 9/26 (35%) End of treatment: cure 19/29 (66%), improvement 9/29 (31%); follow-up: cure 19/27 (70%), improvement 7/27 (26%)

Chan et al. (1993) [29]

Sultamicillin 50 mg kg−1 per day (bid) PO, 10 days Amoxycillin/clavulanic acid 40 mg kg−1 per day (tid), 10 days

Effusion-free: end of treatment 43/81 (53%); follow-up 48/84 (57%) Effusion-free: end of treatment 17/41 (41%); follow-up 26/43 (60%)

Bacteriological eradication

End of treatment 23/23 (100%) isolates End of treatment: 24/25 (96%) isolates

Clinical efficacy is given as the satisfactory response (cure or improvement) rate, unless otherwise indicated. All clinical efficacy and bacteriological eradication data relate to end of treatment, unless otherwise indicated. PO, oral.

for ampicillin/sulbactam at end of treatment were in the range 84– 100% and 44– 100%, respectively. These response rates are generally comparable with the clinical and bacteriological response rates for the comparators, cefuroxime (41–95% and 50– 93%) [31,33,35,36], cefotaxime (81 and 48%) [32], cefoxitin (81 and 76%) [37] and mezlocillin (83 and 89%) [34]. One open-label, comparative study showed that, whereas ampicillin/sulbactam and cefuroxime yielded similar clinical responses (98 and 95%, respectively), the eradication rate for ampicillin/sulbactam was significantly superior (95 versus 50%, P B0.001) [36]. The discrepancy between these data sets might be explained by the high rate of spontaneous clinical recovery that is routinely observed among AOM patients, which is likely to mask the benefits of a bacteriologically effective drug compared with an ineffective drug [40]. Few clinical trials have compared the efficacy of ampicillin/sulbactam with that of another b-lactam/blactamase inhibitor combination. A meta-analysis of clinical trials involving the use of amoxycillin/clavulanic acid in over 38 000 patients with LRTIs recorded clinical success in 92% of amoxycillin/clavulanic acidtreated patients and 92% of patients who received a comparative agent [41]. More recently, a clinical trial of ampicillin/sulbactam versus ticarcillin/clavulanic acid recorded a satisfactory clinical response in 83 and 78% of patients with RTIs, respectively [42]. The corresponding rates of bacteriological efficacy were 62 and 71%. These data suggest that ampicillin/sulbactam, amoxycillin/clavulanic acid and ticarcillin/clavulanic acid are equally effective in the treatment of LRTIs. The clinical usefulness of oral sultamicillin, administered either following IV ampicillin/sulbactam [38] or

alone [39], has also been investigated. In one study, the clinical response rate for IV-to-oral ampicillin/sulbactam was 96%, i.e. comparable to that for IV therapy [38]. The number of bacteriologically evaluable patients was insufficient to enable any meaningful conclusion to be drawn regarding the bacteriological eradication rate. Similarly, in the case of treatment with oral sultamicillin, one study reported a favourable clinical response among all 30 evaluable patients; this was accompanied by eradication of all 52 isolates identified before treatment [39]. Oral sultamicillin has also proved efficacious in treating LRTIs in paediatric patients. A clinical cure rate of 94% and clinical improvement in an additional 2% of patients were reported following the twice-daily administration of low-dose (25 mg kg − 1 per day) sultamicillin to children with mild-to-moderate infections [10]. These studies suggest that oral ampicillin/sulbactam may be a useful treatment option in patients with mild-to-moderate infections or in patients with severe infections who are responding to IV ampicillin/ sulbactam.

1.3.4. Pneumonia A meta-analysis conducted in 1997 confirmed the efficacy of ampicillin/sulbactam to treat patients with severe pneumonia [43]. Zervos et al. carried out a meta-analysis of seven comparative clinical studies to determine the efficacy of ampicillin/sulbactam (2/1 or 1/0.5 g IV four times daily) compared with second- or third-generation cephalosporins (cefoxitin, cefotaxime, cefuroxime, or cefamandole) in the treatment of community-acquired pneumonia (CAP), as well as other LRTIs (Table 6). The observed rate of clinical cure or

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improvement was greater for ampicillin/sulbactam than for comparators (93.3 versus 86.6%, P = 0.019), as was the rate of clinical cure (60.3 versus 54.6%, P= 0.055). Mortality rates in the ampicillin/sulbactam group (6%) and comparator group (4%) were well below the average values reported for patients with CAP with similar risk factors. The bacteriological eradication rate was similar for ampicillin/sulbactam (85.3%) and comparators (83.5%). Other open-label studies that did not satisfy the

criteria for evaluation within the meta-analysis have similarly demonstrated the clinical efficacy of IV, IM and oral ampicillin/sulbactam in treating patients with severe pneumonia [48–52]. In the case of IV ampicillin/ sulbactam, one study showed that the clinical efficacy of twice-daily ampicillin/sulbactam was superior to that of cefotiam (96 versus 75%, P = 0.05) [51]. In another study involving patients with lobar pneumonia, administration of IM ampicillin/sulbactam 1/0.5 g three times daily for 7 days resulted in a decline in fever and rapid

Table 5 Clinical efficacy of ampicillin/sulbactam in the treatment of lower respiratory tract infections (LRTIs) Authors (year)

Infection

Antibiotics

Clinical efficacy (patients)

Bacteriological eradication

Mehtar et al. (1986) [30]

Intra-thoracic infections

Ampicillin 0.5 or 1 g/sulbactam 0.5 g qid IV, ]5 days

Cure or improvement 13/14 (93%)

13/14 (93%) patients

Geckler (1994) [31]

Pneumonia, AECB

Ampicillin/sulbactam 1–2/0.5–1 g qid IV

Cure 5/19 (26%), improvement 14/19 (74%) Cure 5/18 (28%), improvement 12/18 (67%)

22/22 (100%) isolates

Cefuroxime 0.75–1.5 g tid IV Juaregui et al. (1995) [32]

Severe LRTIs

Ampicillin/sulbactam 2/1 g qid IV Cefotaxime 2 g qid IV

Rossoff et al. (1995) [33]

Severe LRTIs

Ampicillin/sulbactam 2/1 g qid IV Cefuroxime 1.5 g tid IV

19/22 (86%) isolates Cure 21/34 (62%), improvement 8/34 (24%) Cure 9/16 (56%), improvement 4/16 (25%)

56/126 (44%) isolates 29/61 (48%) isolates

Cure 16/25 (64%), improvement 6/25 (24%) Cure 10/22 (45%), improvement 8/22 (36%)

16/25 (64%) isolates 15/22 (68%) isolates

Schwigon et al. (1996) [34] LRTIs

Ampicillin/sulbactam 2/1 g tid IV, ]5 days Mezlocillin 4 g tid IV, ]5 days

Cure 25/50 (50%), improvement 17/50 (34%) Cure 25/46 (54%), improvement 13/46 (28%)

46/51 (90%) isolates 48/54 (89%) isolates

Schwigon et al. (1996) [35] Severe LRTIs

Ampicillin/sulbactam 2/1 g tid IV, ]5 days Cefuroxime 1.5 g tid IV, ]5 days

31/35 (89%)

32/34 (94%) isolates 38/41 (93%) isolates

Ampicillin/sulbactam 1 g bid IV

Cure 15/56 (27%), improvement 40/56 (71%) Cure 10/42 (24%), improvement 30/42 (71%)

53/56 (95%) patients 21/42 (50%) patients

Cure or improvement: 48/52 (92%) Cure or improvement: 20/23 (87%)

40/60 (67%) isolates 22/29 (76%) isolates

Ozbay and Uzun (1997) [36]

LRTIs

Cefuroxime 0.75 g q12h IV Castellano and Maniatis (1998) [37]

LRTIs

Ampicillin/sulbactam 2 g bid IV, ]4 days Cefoxitin 2 g bid IV, ]4 days

28/35 (80%)

Valcke and Van Der Straeten (1989) [38]

LRTIs

Ampicillin/sulbactam 2/1 g bid IV for 3 days, then 0.75 g bid PO for 10–14 days

Cure 44/50 (88%), improvement 4/50 (8%)

9/9 (100%) patients

Tageldin and Said (1992) [39]

LRTIs

Sultamicillin 375 mg bid or tid PO, 5–14 days

Cure 23/30 (77%), improvement 7/30 (23%)

52/52 (100%) isolates

Mild-to-moderate Sultamicillin 25 mg kg−1 per day (bid) PO Cure 93/100 (93%), LRTIs improvement 6/100 (6%)

49/49 (100%) isolates

Children Raillard et al. (1992) [10]

Clinical efficacy is given as the satisfactory response (cure or improvement) rate, unless otherwise indicated. All clinical efficacy and bacteriological eradication data relate to end of treatment. AECB, acute exacerbations of chronic bronchitis; IV, intravenous; PO, oral.

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Table 6 Meta-analysis of clinical response rates for intravenous ampicillin/sulbactam in the treatment of community-acquired pneumonia Study, comparator drug

Tan and File, cefoxitin [44] Castellano and Maniatis (1997), cefoxitin [37] Jauregui et al. (1995), cefotaxime [45] Rossoff et al. (1995), cefuroxime [33] Geckler (1994), cefuroxime [31] Williams et al. (1994), cefamandole [46] Berk et al. (1993), cefamandole [47] Meta-analysis

Clinical response (% patients)

Difference, 95% CI (%)

Ampicillin/sulbactam

Comparator

96.9 (n=32) 92.3 (n= 52) 85.3 (n=34) 88.0 (n=25) 100.0 (n= 19) 97.3 (n= 37) 96.2 (n= 26) 93.3 (95% CI, 89.0–96.1) (n =225)

95.8 (n = 24) 87.0 (n =23) 81.3 (n =16) 81.8 (n =22) 94.4 (n =18) 81.6 (n = 38) 87.0 (n = 23) 86.6 (95% CI, 76.8–88.7) (n = 164)

1.0 5.4 4.0 6.1 5.6 15.7 9.2 6.2

(−9.0, 11.1) (−10.2, 20.9) (−18.5, 26.6) (−14.4, 26.7) (−5.0, 16.1) (2.3, 29.1) (−6.4, 24.8) (1.0, 11.4)

©1997 Williams and Wilkins, [43].

improvement in other signs and symptoms in 17/20 (85%) patients, with chest radiographs showing complete clearance within 14 days [48]. Single-dose IV therapy has also been shown to be clinically effective. Administration of a single 3– 4 g IV dose to 300 outpatients with CAP led to clinical recovery in all cases [50]. Finally, oral sultamicillin has been used successfully in the treatment of acute pneumonia [52]. Good/satisfactory clinical efficacy was observed in 76.2/19% of patients with acute pneumonia.

1.3.5. Acute exacerbations of chronic bronchitis Few studies have evaluated oral sultamicillin in the treatment of acute exacerbations of chronic bronchitis (AECB). However, those studies that have been conducted have demonstrated good clinical efficacy. For example, an open study of sultamicillin yielded rates of good and satisfactory clinical response of 80 and 16%, respectively, among cases of acute exacerbations of chronic non-obstructive bronchitis, 50 and 30% among patients with acute exacerbations of chronic obstructive bronchitis, and 0 and 70% in patients with acute exacerbations of chronic purulent bronchitis [52]. Two more open studies have shown that the overall clinical efficacy of oral sultamicillin is comparable with that of azithromycin, ciprofloxacin, or cefaclor in patients with acute exacerbations of chronic obstructive pulmonary disease [53,54]. 1.4. Tolerability profile Ampicillin/sulbactam is well tolerated [55]. Comparative clinical studies have demonstrated no difference between the adverse events profile of ampicillin/sulbactam and ampicillin alone [56]. An early meta-analysis examined the tolerability of ampicillin/sulbactam across 45 studies involving 1287 adult or paediatric patients with a variety of respiratory and non-respiratory infections [8]. Only 10% of patients

reported adverse events that may have been related to treatment (compared with 6% of comparator-treated patients). Almost half of the events involved pain at the injection site, which was most often reported following IM injection, consistent with clinical experience with other parenteral antibiotics. Of 1287 patients, 15 (1.2%) experienced skin disorders, 21 (1.6%) diarrhoea, and 58 (4.5%) injection-site pain. A more recent guide to the tolerability profile of IV ampicillin/sulbactam is provided by the meta-analysis of ampicillin/sulbactam compared with second- or third-generation cephalosporins (cefoxitin, cefotaxime, cefuroxime, cefamandole) in the treatment of community-acquired pneumonia, as previously described [43]. The proportion of patients reporting adverse events was the same for the ampicillin/sulbactam and comparator groups (16% in each group), and the treatments were comparable with regard to the incidence of specific adverse events (Table 7). No deaths were attributable to administration of ampicillin/sulbactam. With regard to oral sultamicillin, a meta-analysis of the worldwide clinical experience in treating a variety of community-acquired infections has provided evidence for a satisfactory tolerability profile [9]. Side-effects were recorded in 18% of 5947 patients; the most common side-effects were gastrointestinal in nature, including diarrhoea and soft/loose stools (Table 8). Most of these cases were of mild-to-moderate severity, and resolved spontaneously without the need for drug discontinuation. Repeated examination of stools from patients with diarrhoea (n = 620) failed to detect Clostridium difficile or its toxin, except in one patient complaining of watery diarrhoea. Recovery of this patient, who previously had experienced a similar episode associated with clindamycin therapy, was uneventful following vancomycin therapy. Only 5% of patients discontinued therapy due to adverse effects (2.8% due to diarrhoea).

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Table 7 Incidence of adverse events (all causes) among patients with lower respiratory tract infections treated with intravenous ampicillin/sulbactam and comparator agents [43] Adverse event

Death Diarrhoea Rash Other (not specified) Transient liver abnormalities Nausea and vomiting Phlebitis Headache Chest pain Neutropenia Generalized pruritus Exanthema Bullous impetigo Urinary tract infection Congestive heart failure with pulmonary edema Hypotension Eosinophilia Elevated prothrombin time

Incidence (% of n patients) Ampicillin/ sulbactam (n= 353)

Comparator (n= 288)

5.7 2.8 2.3 1.9 0.8

4.2 4.2 1.4 1.4 1.0

0.8 0 0 0.6 0.3 0.3 0.3 0.3 0.3 0

1.0 0.7 0.7 0.3 0.3 0 0 0 0 0.3

0 0 0

0.3 0.3 0.3

Comparator agents included cefoxitin, cefotaxime, cefuroxime and cefamandole.

Clinical laboratory variables have been monitored in over 3000 adult and paediatric patients treated with sultamicillin [9] and in over 1200 patients treated with ampicillin/sulbactam [8]. Abnormalities in liver funcTable 8 Adverse event profile of oral sultamicillin among patients (n= 5947) with community-acquired infections Incidence (% of patients) Diarrhoea Soft stools Loose stools Abdominal pain/cramping Abdominal discomfort Nausea Vomiting Epigastric distress Epigastric pain Dermatitis (rash) Itching Smell/taste change Drowsiness/sedation Anorexia Vaginal discharge Headache Yeast infection Other

10.4 2.3 1.4 1.1 0.3 1.1 0.5 0.2 0.1 0.9 0.4 0.1 0.1 0.1 0.2 0.4 0.6 2.1

©1989 Munksgaard International Publishers Ltd., Copenhagen, Denmark [9].

tion tests were observed in a small proportion of ampicillin/sulbactam-treated patients (serum aspartate aminotransferase, 6.2%; serum alanine aminotransferase, 6.9%) [8]. The frequency and degree of abnormality were similar to those of the comparator group (the comparative treatments included cefazolin/metronidazole, ampicillin/metronidazole, cefoxitin, cefazolin and gentamicin/metronidazole). The corresponding values among sultamicillin-treated patients were 1.9 and 2.3%, respectively [9]. There was no evidence of significant hepatic toxicity [8,9]. By contrast, the use of amoxycillin/clavulanic acid has been associated infrequently with liver damage [57]. Thus, an extensive clinical program has demonstrated that ampicillin/sulbactam, administered intravenously or orally, is well tolerated in adult and paediatric patients with respiratory tract infections.

1.5. Cost-effecti6eness While the studies reviewed above indicate that ampicillin/sulbactam is clinically effective and well tolerated, there is also evidence that treatment with ampicillin/sulbactam is cost-effective. One study examined the efficacy and cost of parenteral ampicillin/sulbactam 1.5 or 3.0 g four times daily compared with ticarcillin/clavulanic acid 3.1 g four times daily in the treatment of 899 hospitalized patients with various bacterial infections and found that the agents did not differ significantly in efficacy for the treatment of most infections [42]. However, the costs of ampicillin/sulbactam, particularly the 1.5 g dose regimen, were lower than those of ticarcillin/clavulanic acid for respiratory tract infections. The mean (9 SD) durations of therapy for ampicillin/sulbactam 1.5 and 3.0 g were 4.79 2.3 and 5.79 2.3 days, and for ticarcillin/clavulanic acid 5.79 2.2 days. The corresponding per patient drug-acquisition costs were US$1639 232, US$4319 523, and US$3129 156 (all treatments differed significantly, PB0.001). The per patient preparation/administration cost did not differ significantly between treatments.

1.6. Role in the treatment of respiratory tract infections b-Lactam antibiotics occupy a central position in recent North American and European guidelines for the management of patients with respiratory tract infections, despite the gradual emergence of in vitro b-lactam resistance among clinical isolates. These guidelines indicate little change in the role of b-lactam/b-lactamase-inhibitor combinations from that outlined in earlier recommendations. Early North American guidelines for the treatment of CAP were broadly in agreement, and recognized the

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emergence and increased prevalence of b-lactamaseproducing pathogens [58]. Thus, Canadian Consensus Conference guidelines [59], published in 1993, recommended the use of b-lactam/b-lactamase-inhibitor combinations to treat non-severe, high-risk infections in outpatients (young and otherwise healthy patients), whereas, 1993 American Thoracic Society guidelines [60] recommended their use to treat high-risk infections in outpatients and inpatients admitted to general hospital wards. Guidelines released in France [61], Italy [62], Spain [63] and the UK [64] at around the same time (1991– 1997) presented treatment recommendations for two patient groups: non-severely ill and severely ill [5]. Penicillin, aminopenicillins, and b-lactam/b-lactamaseinhibitor combinations were all recommended as treatment options in non-severe patients. Guidelines for the management of CAP in adults published by the Infectious Diseases Society of America (IDSA) in 1998 [65] recommend amoxycillin/clavulanic acid (the only oral b-lactam/b-lactamase inhibitor combination currently available in the USA) as one treatment option for CAP in outpatients. In the case of inpatients, a b-lactam/b-lactamase-inhibitor combination is also recommended for the treatment of patients in an intensive care unit, as well as for inpatients with suspected aspiration pneumonia. Interestingly, European guidelines for the management of LRTIs acknowledge an increase in penicillin resistance among streptococci, but consider the clinical relevance of this trend to be a matter for local debate, with the use of penicillins being dependent upon local resistance rates [66]. For outpatients with CAP, antibiotic treatment is usually appropriate and should always offer good activity against S. pneumoniae. Penicillins are considered the treatment of choice and should be used at high dose to combat resistant pneumococci. Aminopenicillins offer superior activity against H. influenzae; it is suggested that the addition of a b-lactamase inhibitor may be necessary in areas of high b-lactamase production. For outpatients with AECB, it is considered likely that antibiotic therapy may be beneficial in patients with Anthonisen type 1 exacerbations (defined by increases in dyspnoea, sputum volume, and sputum purulence) [67] but not in patients with milder exacerbations. From these guidelines, the use of a b-lactam/b-lactamase inhibitor combination would seem appropriate, given the possibility of infection by H. influenzae or M. catarrhalis, both of which are associated with a high proportion of b-lactamaseproducing strains. In the case of inpatients, the European guidelines hold that penicillins remain the treatment of choice for CAP, even when penicillin resistance is common; the recommendation is that pneumonia due to resistant pneumococci (MIC for penicillin not usually higher

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than 4 mg ml − 1) can be managed by increasing the dose [66]. b-Lactam/b-lactamase inhibitor combinations are recommended for the treatment of inpatients not requiring intensive care, including patients with pulmonary abscess, cavitation, or suspected aspiration. For inpatients with AECB, a b-lactam/b lactamase inhibitor combination offers increased activity against M. catarrhalis and H. influenzae, and is a good initial antibiotic choice. Published guidelines, therefore, indicate that the class of b-lactam/b-lactamase inhibitor combinations, has retained an important role in the treatment of URTIs and LRTIs, in agreement with the findings of recent clinical studies, and despite reports of increased in vitro b-lactam resistance. The administration of a combination of ampicillin and sulbactam enables the physician to continue to use this familiar b-lactam antibiotic with confidence. In vitro microbiological data indicate that ampicillin/sulbactam is effective against current key respiratory pathogens, including b-lactamase-producing strains not susceptible to ampicillin in vitro. The extension of ampicillin’s antimicrobial spectrum to include anaerobic pathogens, such as Bacteroides species, is advantageous in the treatment of pneumonia involving aspiration. Furthermore, the availability of an oral formulation (the mutual prodrug sultamicillin) as well as an IV formulation offers the opportunity for simplified IV-to-oral sequential therapy. The availability of ampicillin/sulbactam as a single, twice-daily, oral formulation offers the prospect of convenient outpatient therapy, which may lead to improved patient compliance. Finally, one study has demonstrated that ampicillin/ sulbactam is more cost-effective than ticarcillin/clavulanic acid in the treatment of various bacterial infections. Further studies are required to assess the overall cost-effectiveness of ampicillin/sulbactam in treating respiratory tract infections when the costs of hospitalization and adverse event management are included. However, the evidence reviewed above suggests that ampicillin/sulbactam may offer cost savings in these areas also.

2. Conclusions Many studies, as well as several meta-analyses, demonstrate that intravenous ampicillin/sulbactam and oral sultamicillin have continued to provide clinically effective and well tolerated therapy for a variety of respiratory tract infections in both adults and children, in agreement with the recommendations of published guidelines. Physicians have amassed vast experience in the use of penicillins to treat such infections. The co-administration of ampicillin with sulbactam contin-

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ues to meet the challenge of b-lactamase-mediated resistance, and enables physicians to prescribe with confidence b-lactam agents that remain a desirable treatment option.

[18] [19] [20]

Acknowledgements This review was sponsored by an unconditional education grant from Pfizer inc.

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