Drug Evaluation

Ampicillin-sulbactam: an update on the use of parenteral and oral forms in bacterial infections
1. 2. 3. 4. Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by HINARI on 10/08/10 For personal use only. 5. 6. 7. 8. Introduction Chemistry Pharmacokinetics, in vitro activity, resistance Clinical trials Infections due to Acinetobacter spp Safety and tolerability Conclusions Expert opinion

Alex P Betrosian & Emmanuel E Douzinas

Athens University, Evgenidion Hospital, 3rd Department of Critical Care, 20 Papadiamantopoulou Street, 11528, Athens, Greece

Ampicillin-sulbactam has a wide range of antibacterial activity that includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. However, the drug is not active against Pseudomonas aeruginosa and pathogens producing extended-spectrum -lactamases. The combination could be considered particularly active against Acinetobacter baumannii infections due to the intrinsic activity of sulbactam. The drug is indicated as empirical therapy for a broad range of community acquired infections supervened in adults or children and is effective in either parenteral (ampicillin-sulbactam) or oral (as a mutual prodrug sultamicillin) form. In clinical trials, sultamicillin has proved clinically and bacteriologically effective in adults and children against a variety of frequently encountered infections, including mild upper and lower respiratory tract infections, urinary tract infections, diabetic foot and skin and soft tissue infections. Furthermore, adverse effects rarely occur with the diarrhoea to represent the most commonly reported. The parenteral ampicillin-sulbactam is indicated for community infections of mildto-moderate severity acquired infections such as intra-abdominal or gynecological. Moreover, it seems to represent the alternative of choice for the treatment of A. baumannii infections for carbapenem-resistant strains in the nosocomial setting. Thus, ampicillin-sulbactam remains a valuable agent in the physicians armamentarium in the management of adult and pediatric infections.
Keywords: Acinetobacter baumannii, bacterial infections, ampicillin-sulbactam, sultamicillin Expert Opin. Drug Metab. Toxicol. (2009) 5(9):1099-1112

1. Introduction

In the era of global emergence and spread of bacterial resistance and in the absence of development of new effective antimicrobial agents, the correct use of the currently available antibiotics, in particular the penicillins, is of great significance. After the introduction and the widespread use of -lactam antibiotics, many organisms initially susceptible to penicillins and derivatives developed resistance due to the ability to produce -lactamases enzymes that hydrolyze the -lactam ring, and, therefore, to destroy the antimicrobial activity of the antibiotics [1]. A highly effective and proven approach for tackling -lactamase-mediated resistance to -lactams is the use of -lactam/-lactamase-inhibitor combinations [2]. Such combinations have gained great success and have proven to be among the most effective antibiotic strategies [3]. Of the many -lactamase inhibitors that have been evaluated, three inhibitors (sulbactam, tazobactam and clavulanic acid) are currently in clinical use in various combinations, including ampicillin-sulbactam, cefoperazone/ sulbactam, piperacillin/tazobactam, amoxicillin/clavulanic acid and ticarcillin/ clavulanic acid [4]. Sulbactam is also available as a single agent in some countries.

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Ampicillin-sulbactam

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Ampicillin/sulbactam is a -lactam/-lactamase-inhibitor combination that was first developed and marketed in US in 1987. Since then, our knowledge on the effectiveness in the treatment of community and hospital-acquired infections comes mainly from the use of its parenteral form applied in severe infections. However, an interest for the oral administration of the combination has been developed for milder cases surveyed in several clinical studies. The therapeutic efficacy of parenteral and oral formulations of ampicillin-sulbactam has been demonstrated in a wide variety of infections, including upper and lower respiratory tract infections, intra-abdominal infections, urinary tract infections, gynecological infections, skin and soft tissue infections [5-7]. This article aims primarily to concentrate on studies dealing with the treatment of various infections by the two available forms (parenteral and oral) of the ampicillin/sulbactam combination. As it is obvious for the treatment of severe infections, the main body of evidence relies on information coming from studies with the parenteral form of the combination. Information for the treatment of infections of milder severity comes from the use of the oral form of the drug, that is, sultamicillin.
2. Chemistry

pharmacokinetics of sulbactam and vice versa [11]. Both agents have similar time-to-peak plasma concentrations, no interaction in between occurs and both have similar profile of elimination half-time ( 1 h), which supports a 6 8 h i.v./ intramuscular dosing schedule and an optimal application form of 3 4 h infusion [8]. Peak plasma concentrations of both sulbactam and ampicillin are proportional to dose, and accumulation has not occurred in short-term multiple-dose trials [12]. The average adult daily dose for the parenteral form depends on infection severity and ranges from 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g/1 g, respectively) every 6 h with sulbactam usually not exceeding 4 g/day. However, in particularly severe infections, these dosages have been exceeded [13]. The pediatric dosage of the combination is 200 mg ampicillin/100 mg sulbactam per kilogram of body weight/day. Sultamicillin dosage for adults and infants of > 30 kg is 375 750 mg every 12 h, and for infants of < 30 kg 25 50 mg/kg in two divided doses [12].
3.1 Absorption and distribution

Ampicillin and sulbactam is an injectable combination consisting of the semisynthetic antibiotic ampicillin and the -lactamase inhibitor sulbactam sodium for intravenous (i.v.) and intramuscular administration (Figure 1). Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid with the following chemical formula C16H18N3NaO4S. Sulbactam sodium is a derivative of the basic penicillin nucleus. Chemically, sulbactam is sodium penicillinate sulfone and its chemical formulation is C8H10NNaO5S [8]. Sultamicillin (formerly known as CP-49,952) is an oral form of the antibiotic combination ampicillin/sulbactam [9]. It contains esterified ampicillin and sulbactam and is marketed under a number of trade names. It is chemically designated as [(2R)-3,3-dimethyl-4,4,7-trioxo-46-thia-1-azabicyclo[3.2.0] heptane-2-carbonyl]oxymethyl (2R)-{[(2S)2amino-2-phenyl-acetyl] amino}-3,3-di methyl-7-oxo-4-thia-1-azabicyclo [3.2.0]heptane2-carboxylate and has a chemical formulation C25H30N4O9S2 (Figure 1). It is a mutual prodrug that was developed to overcome the poor oral absorption of sulbactam. It is a double ester linkage of sulbactam with ampicillin, which is readily absorbed orally and hydrolyzed by enzymes in the intestinal wall, releasing equimolar proportions of sulbactam and ampicillin to provide effective antibacterial activity [10].
3. Pharmacokinetics, in

resistance

vitro activity,

The pharmacokinetic profiles of ampicillin and sulbactam are similar and favor their co-administration either parenterally or orally (Tables 1 and 2). Ampicillin has no effect on
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Either agent given alone has limited oral bioavailability, with the sulbactam oral absorption being very poor [10]. This problem has been overcome with the combination of ampicillin and sulbactam in one oral prodrug, sultamicillin [10,14]. Sultamicillin is absorbed readily (> 80% bioavailability) leading to high serum concentrations of both agents. Although the ratio of ampicillin:sulbactam differs between parenteral and oral forms (2:1 versus 1:1), both formulations have similar efficacy as shown by comparable bioavailability of ampicillin and sulbactam (administered as oral sultamicillin) when equivalent quantities of the individual components are given intravenously [10,11,14]. In two studies in which 500 mg of sultamicillin was compared with 500 mg of ampicillin alone, the peak serum concentrations of ampicillin were twice as great for the prodrug [10]. In a study with human volunteers, Hampel et al. [15] found increased bioavailability of ampicillin co-administered with sulbactam (orally and parenterally) when compared with amoxicillin plus clavulanic acid and concluded that the effect of sulbactam in increasing the oral bioavailability of ampicillin is greater than the effect of clavulanic acid on the oral bioavailability of amoxicillin. The protein binding of ampicillin and sulbactam in serum is similar, attaining the level of 28%. High body tissue and fluid concentrations of sulbactam and ampicillin are obtained when these agents are administered parenterally and orally [8]. Steadystate volumes of distribution have been shown at the level of 0.32 l/kg for ampicillin and 0.34 l/kg for sulbactam, but tissue drug concentrations were not measured [12]. High tissue/fluid concentrations, which exceed the MICs of important bacterial pathogens, have been demonstrated in cerebrospinal fluid with sulbactam to increase ampicillins penetration, particularly in the presence of inflamed meninges [16]. Similarly, high concentrations have been reported in costal cartilage [17] and middle-ear fluid. Sufficient penetration in peritoneal fluid, intestinal mucosa,

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Sultamicillin
O S O

N NH2 C H O O S CONH N C O O CH2 O C O

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Esterase Ampicillin
O S S N NH2 O N COOH O O HO

H CHCONH

Sulbactam

Figure 1. Chemical structures of sultamicillin, ampicillin and sulbactam.

Table 1. Pharmacokinetic properties of intravenous ampicillin-sulbactam in healthy adults [14].

Parameter Cmax (g/ml) Vds (l/kg) t1/2 AUC (g/(h ml)) Clearance (ml/min) Renal clearance (ml/min) Ampicillin (2 g) 82 15 31 9 1 0.2 120 16 281 34 144 64 Sulbactam (1 g) 42 7 30 10 1 0.2 72 9 236 27 136 58

prostatic and appendiceal tissue, sputum and peritonsillar abscess pus has also been shown [11]. Again, the tissue/fluid concentrations attained were generally in excess of the MICs for common pathogens associated with infections at these sites. The high bioavailability of sultamicillin assures that these high tissue concentrations are achievable with oral therapy [10]. Furthermore, good tissue penetration of sultamicillin supports its use in a twice-daily dosing regimen [10].
3.2 Metabolism and elimination

Vds: Volume of distribution at steady-state.

Table 2. Pharmacokinetic parameters (mean s.d.) for ampiciln and sulbactam administered as sultamicillin* to healthy volunteers [85].
Parameter Cmax (g/ml) tmax (h) AUC (g/(h ml)) t1/2 (h) Urinary recovery (% of dose) Ampicillin 9.1 3.6 0.92 0.30 17.8 0.2 0.96 0.25 59.4 7.1 Sulbactam 8.9 3.4 0.96 0.29 16.7 1 2.5 1.11 0.69 66.3 6.7

*Oral sultamicillin (750 mg) equivalent to 440 mg ampicillin and 294 mg sulbactam.

Half-lifes of both agents are similar and approximately equal to 1 h. They are eliminated primary by urinary excretion: 65% of ampicillin and 46% of sulbactam from sultamicillin are recovered intact in the urine [11]. Tubular secretion plays a major role in excretion of sulbactam, while biliary excretion is minor [8]. Co-administration of probenecid results in an increase in the half-lifes of both ampicillin and sulbactam, demonstrating that tubular secretion is a significant component of their renal excretion [18]. Based on half-life, a dosing schedule of 6 8 h is indicated for the parenteral route [8] and a twice-a-day oral dosing schedule of sultamicillin is sufficient to achieve high serum levels of ampicillin and sulbactam into the circulation [10]. Given that both agents are primarily eliminated by renal excretion, the t1/2 and serum concentration in patients with renal impairment are increased [11]. As a result, the frequency of dosing is reduced according to creatinine clearance in
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patients with renal impairment (from three or four times daily to twice or once daily). Hemodialysis removes 30% of the given doses of ampicillin-sulbactam, and supplemental doses are recommended after dialysis [8,19]. In women during pregnancy, a more frequent administration scheme (every 4 h) is more appropriate due to a decreased elimination half-life [11].
3.3 Pharmacokinetics in pediatric patients

and Klebsiella spp. (73% susceptible), in a multi-center study with a total of 3.134 aerobic and facultative Gram-negative bacilli [25]. The drug is not active against Pseudomonas aeruginosa [25]. It should be noted that most -lactamase inhibitors lack significant antimicrobial activity, except for sulbactam which is active against Bacteroides fragilis, Neisseriae (meningitides and gonorrhoeae) and Acinetobacter spp. [26-28].
3.6 Mechanism of resistance

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Pharmacokinetic properties of ampicillin-sulbactam are comparable in children and adults [12]. In children, age has no effect on the pharmacokinetics of ampicillin or sulbactam and the results were also independent of dose and gender [12]. Oral administration of a single dose of sultamicillin (42.5 mg/kg of sultamicillin equivalent to 25 mg/kg ampicillin and 16.6 mg/kg sulbactam) resulted in greater peak serum concentrations and AUC of ampicillin than those achieved with equivalent dose of ampicillin alone in children whose weights ranged from 8.6 to 19.9 kg [20]. Additionally, in children with otitis media, higher middle ear concentrations of ampicillin, administered as sultamicillin, were reported than after equivalent dose of ampicillin alone.
3.4 Pharmacodynamics

Antibiotic pharmacodynamics describes the impact of an antimicrobial agent on a target pathogen and is based on the drugs pharmacokinetics and microbiologic activity toward that pathogen, together with the pathogens susceptibility to the drug. The bacteriological efficacy of -lactams agents, and as such of ampicillin-sulbactam, is particularly dependent on the time (T) that free serum concentration of the drugs exceed the MIC for the target pathogen (T > MIC) [21]. For ampicillinsulbactam, a T > MIC of 30 40% of the dosing interval is required for maximal bacteriological efficacy against respiratory pathogens, including Streptococcus pneumoniae [22]. The postantibiotic effect (PAE) or persistent suppression of bacterial growth after brief exposure of a bacterial culture to an antimicrobial agent is a well-established phenomenon [23]. Most -lactams agents, including ampicillin, produce a short PAE when tested against Gram-positive cocci [24]. Specifically, sultamicillin produced prolonged PAE (about 3 days) for exposures of 50 100 g/ml for > 2 h [23].
3.5 In

vitro antimicrobial activity

Early studies have shown a good in vitro activity of ampicillin-sulbactam in a wide range of Gram-positive (e.g., S. pneumoniae, Staphylococcus aureus, Streptococcus enterococci), Gram-negative (including Haemophilus influenza, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii) and anaerobic bacterial pathogens (Bacteroides fragilis, Bacteroides spp.) [5]. However, recent trials have indicated increasing resistance to the drug [25]. Ampicillin-sulbactam was found to be the least active agent among 12 antibiotics tested against E. coli (56% susceptible)
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In general, the resistance to -lactam antibiotics of an organism is brought about by a complex interaction between the permeability of the bacterial cell to the antibiotic, the presence, range of activity, level of production of -lactamases, the presence and efficiency of efflux mechanisms, and the affinity of the antibiotic to the penicillin-binding protein (PBP) target site [29,30]. For Gram-negative bacteria, the main mechanism of resistance to ampicillin involves inactivation by -lactamases, which hydrolyze the -lactamic ring by forming of an acidic derivative of -lactam deprived of antibacterial activity. Regarding Gram-positive bacteria, the primary mechanism of resistance to this drug is mediated by changes in PBP [29,30]. During the last decade, resistant isolates among -lactamase inhibitors have been developed and their in vitro and clinical efficacies compromised. The mechanisms involved in and responsible for resistance are several [31,32]. Most bacteria with depressed class C -lactamases are resistant to inhibitor combinations including ampicillin-sulbactam. Overproduction of the class A penicillinases TEM-1 and TEM-2 and production of low affinity enzymes, such as inhibitor-resistant TEM and the OXA enzymes, are other ways of resistance [32]. Overproduction of -lactamases is due to either a point mutation in the promoters for the genes encoding TEM-1 and TEM-2 or to multicopy, plasmid-borne genes [31]. Over the past decades, the incidence of infections caused by penicillin-resistant pneumococci has increased worldwide. Using data from Alexander Project, the prevalence of penicillin resistance in S. pneumoniae increased between 1992 and 2001, with the greatest increase seen in France (1992, 7.7%; 2001, 35.8%) and the US (1992, 5.6%; 2001, 20.4%) [33]. In Europe, over this 10 year period, an overall average increase in penicillin resistance in S. pneumoniae was observed [33]. Although the principal mechanism of aminopenicillin resistance observed in H. influenzae is -lactamase production, a number of -lactamase-negative ampicillin-resistance strains have emerged is some countries, particularly in Japan. These resistant isolates usually evade the action of -lactams by producing one of two -lactamases [34]. The rate of resistance to ampicillin-sulbactam among anaerobic pathogens such as B. fragilis and other species of the Bacteroides group is increasing worldwide [35,36]. However, an 8-year period national survey in the US revealed that only 1.7% of the B. fragilis isolates were resistant to the

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ampicillin-sulbactam combination [36]. The drug is currently recommended from the Infectious Diseases Society of America (IDSA) intra-abdominal infection guidelines as first-line agent for mild-to-moderate severity infections [37]. Resistance of the bacterial flora of the host is known to be induced after the prescription of antibiotics. This fact, especially regarding the enteric flora, is of potential interest for the management of urinary tract infections (UTIs). Escherichia coli is the most common agent from the enteric flora to cause UTIs. Oral administration of ampicillinsulbactam was found to induce resistance (before treatment, 21%; after treatment, 37,5%) at a lower rate compared to ampicillin alone (87.5 and 100%, respectively) [37]. Extended-spectrum -lactamases (ESBLs) are extremely broad spectrum -lactamase enzymes found in a variety of Enterobacteriaceae [38]. Most strains producing these -lactamases are K. pneumoniae, other Klebsiella species (i.e., Klebsiella. oxytoca) and E. coli. When producing these enzymes, organisms become highly effective at inactivating most -lactam antibiotics, except carbapenems [39]. Ampicillin-sulbactam should not be used in ESBL-producing bacteria regardless of an in vitro susceptibility being documented.
4. Clinical trials

Ampicillin-sulbactam has been used either parenterally or orally in a wide range of infections. Parenteral use is recommended in cases of community and/or hospital acquired pneumonia, including aspiration pneumonia, and in several mixed infections including intra-abdominal infections such as peritonitis, cholecystitis, endometritis, bacterial septicemia, brain abscesses, bone and soft tissue infections, and pediatric infections such as acute epiglotitis, acute otitis media and periorbital cellulites. Perioperatively, ampicillin-sulbactam has been used for prophylaxis in abdominal surgery [40]. Acquarolo et al. tested the efficacy of a 3-day ampicillin-sulbactam prophylaxis scheme (3 g every 6 h) for the prevention of early-onset pneumonia in comatose mechanically ventilated patients. Prophylaxis with ampicillin-sulbactam resulted in 64% reduction of the relative risk for early-onset pneumonia in the studied population [41]. The oral use of sultamicillin is indicated in less severe infections such as acute exacerbations of chronic bronchitis, acute or chronic sinusitis, otitis media, UTIs and cellulitis, or as a step-down therapy for patients who have improved under parenteral therapy [42-45]. The efficacy and tolerability of sultamicillin in these infections has been extensively evaluated in several comparative and non-comparative studies mainly in pediatric population in the past decades [7]. Despite the lower incidence of diarrhea observed with sultamicillin compared with amoxicillin/glavulanic acid, a relative paucity of studies referring to sultamicillin exclusively is currently observed in the literature [45]. Sultamicillin has not been evaluated in the setting of nosocomial infections caused by Acinetobacter. It is, therefore, unsafe to draw clinical conclusions by extrapolating

data of parenteral use, because sulbactam dosages are quite different between the two formulations. Over the past decades, professional organizations and societies from many countries have developed guidelines for the treatment of infections, with the objective of producing a helpful prescribing tool. The best of these guidelines are evidence-based, with recommendations made only after extensive review and grading of studies in the literature, and supported by expert opinion. Ampicillin-sulbactam has been recommended in nationwide guidelines as monotherapy or in combination with other antibacterials for various respiratory, intra-abdominal, skin and soft tissue infections, and sexually transmitted diseases [46-52]. IDSA and American Thoracic Society recommend the drug in combination with azithromycin or a fluoroquinolone as first-line treatment of patients with community-acquired pneumonia (CAP) admitted to a hospitals intensive care unit and as a second-line treatment of CAP due to infection with Enterobacteriacae or Acinetobacter spp. [46]. American Thoracic Society/IDSA guidelines recommend ampicillinsulbactam as first-line treatment of hospital-acquired pneumonia or ventilator-associated pneumonia in patients with no known risk factors for multi-drug resistance (MDR) pathogens, early onset and any disease severity [47]. IDSA guidelines support the use of ampicillin-sulbactam as an option in the initial treatment of necrotizing skin, fascia and muscle mixed infections, infections following animal or human bites, incisional surgical site infection after intestinal, perineum, axillary and genital tract surgery, moderate diabetic foot infections and for the treatment of mild-tomoderate community-acquired complicated intra-abdominal infections [48-50]. European Respiratory Society and European Society of Clinical Microbiology and Infectious Diseases guidelines recommend aminopenicillin/-lactamase inhibitor ( macrolide) as preferred treatment option for hospitalized patients with CAP and for treatment of ampicillin-resistant H. influenza [51]. US Centers for Disease Control and Prevention recommend the drug as an option in combination with doxycicline as a treatment effective against Clamydia trachomatis, Neisseria gonorrhoea and anaerobes, and for patients with tubo-ovarian abscess [52].
4.1 Efficacy on respiratory tract infections

Numerous studies in the late 1980s and early 1990s demonstrated the efficacy of ampicillin/sulbactam and sultamicillin in the treatment of upper and lower respiratory tract infections (URTIs and LRTIs, respectively) both in adult and pediatric patients (Tables 3 and 4). For URTIs, ampicillinsulbactam (at i.v. doses of 2 6 g/day, followed by oral sultamicillin in some cases) and oral sultamicillin (1.5 3 g/day), were adequate to achieve clinical success rates of 64 100% and bacteriological eradication rates of 68 100% [53-59]. In that order, clinical success rates for LRTIs were in the range of 60 100% and 56 100%, respectively [60-70]. Recent
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Treatment Clinical efficacy (patients) Bacteriological eradication SM 0.5 b.i.d. p.o., 10 days Amp/Sulb 1.5 g b.i.d. IM 5 10 days AOM: cure 12/19 (63%) Improvement 5/19 (26%) Acute/chronic sinucitis: cure 12/22 (55%) Improvement 10/22 (45%) Cure 46/55 (84%) Improvement 9/55 (16%) Improvement + cure: 28 + 21/66 (74%) Cure at end of treatment (64%), cure at end of evaluation (97%) Relief of symptoms: 41/50 (84%) End of treatment: 47/51 (92%) Follow-up: 36/46 (78%) Cure 93/100 (93%) Improvement 6/100 (6%) Cure 42/49 (86%) Improvement 7/49 (14%) Cure 17/26 (65%) Improvement 9/26 (35%) Effusion-free: end of treatment 43/81 (53%), follow-up 48/84 (57%) Cure 55/55 (100%) Follow-up 40/42 (95%) 24/29 (83%) isolates 17/25 (68%) isolates 22/22 (100%) for acute/ chronic sinucitis SM 0.75 or 1.5 g/d b.i.d. p.o. 5 days SM 375 mg b.i.d. p.o. 5 7 days SM 375 mg b.i.d. p.o. 10 days, evaluation at 30 days SM 50 mg/(kg day) (b.i.d. or t.i.d.), p.o., 10 days SM 50 mg/(kg day) or 500 mg/day (b.i.d. or t.i.d.), p.o., 10 days SM 25 mg/(kg day), b.i.d. p.o., 7days SM 25 mg/(kg day), b.i.d. p.o., 7 days SM 50 mg/(kg day), b.i.d. p.o., 10 11 days SM 50 mg/(kg day), b.i.d. p.o., 10 11 days ND ND ND ND ND 49/49 (100%) isolates 32/44 (74%) patients 23/23 (100%) isolates ND

Table 3. Summary of studies examining efficacy of Amp/Sulb or SM in adult and pediatric patients with URTIs.

Ampicillin-sulbactam

Study

Site of infection

Adults

Federspil et al. [53]

Tonsillitis, pharyngitis, peritonsilar abscess

Nicoletti et al. [54]

Acute AOM or Acute/ chronic sinusitis

Alvart [55]

Acute ear-nose-throat infection (mild/moderate)

Topuz et al. [56]

Acute sinusitis

Ferreira et al. [45]

Acute sinucitis, otitis, pharyngitis

Children

Kaleida et al. [57]

AOM

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Rodriguez et al. [58]

AOM

Raillard et al. [59]

Mild-to-moderate URTIs

Arguello [110]

Mild-to-moderate URTIs

Biolcati [111]

AOM

Chan et al. [112]

AOM

Amp/Sulb: Ampicillin/sulbactam; AOM: Acute otitis media; b.i.d.: Twice daily; ND: No data; p.o.: Oral; SM: Sultamicillin; t.i.d.: Three times daily; URTI: Upper respiratory tract infection.

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Infection Amp/Sulb (i.v.) Pneumonia AECB LRTIs LRTIs Pneumonia AECB LRTIs VAP Aspiration Pneumonia Aspiration Pneumonia Pneumonia Aspiration Pneumonia VAP 9 g q8h 0.75 g b.i.d., p.o. 3 g q8h i.v. MOX 0.4 g/d 0.4 g, p.o. COL 3MIU q8h 9/15 (60%) 9/13 (61.5%) 66.6 61.5 3 g q 12h IMP/CIL 0.5 g/12h 3 g q12h PAPM/BP 0.5 g/12h 1.5 g q12h CLI 0.6 g q12h 3 g q8h CLI CEPH 0.6 q8h IMP/CIL 1.5 3 g q4h TIC/CLA 3.1 g q6h (79%) 13/14 (93%) 27/37 (73%) 19/25 (76%) 21/25 (84%) 32/35 (91%) 32/48 (67%) 3 g q8h MZL 4 g q8h 42/50 (84%) 3 g q8h CFX 1.5 g q8h 31/35 (89%) 3 g q6h CFT 2 g q6h 29/34 (85%) 1.5 3 g q.i.d. CFX 0.75-1.5 t.i.d. 19/19 (100%) 17/18 (96%) 13/16 (81%) 28/35 (80%) 38/46 (83%) (78%) 52/63 (83%) 22/33 (67%) 19/25 (76%) 22/25 (88%) 28/32 (88%) 32/48 (67%) Comparator (i.v.) Amp/Sulb Comparator Antibiotics Clinical efficacy (pts %) Bacteriological eradication (%) Amp/Sulb 100 55.9 84 90.2 60 100 NR 72 68 84 NR 76 80 80 Comparator 94 62.5 82 88.9 71 97 Betrosian & Douzinas

Table 4. Summary of comparative studies examining efficacy of Amp/Sulb or SM in adult patients with LRTIs.

Study

Geckler [60]

Jauregui et al. [61]

Schwigon et al. [62]

Schwigon et al. [63]

McKinnon and Neuhauser [64]

Wood et al. [69]

Allewelt et al. [65]

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Kadowaki et al. [66]

Yanagihara et al. [67]

Ott et al. [68]

Betrosian et al. [70]

AECB: Acute exacerbation of chronic bronchitis; Amp/Sulb: Ampicillin/sulbactam; b.i.d.: Twice daily; CEPH: Cephalosporin; CFT: Cefoxitin; CFX: Cefuroxime; CLI: Clindamycin; COL: Colistin; IMP/CIL: Imipenem/cilastatin; i.v.: Intravenous; LRTI: Lower respiratory tract infection; MIU: Million units; MOX: Moxifloxacin; MZL: Mezlocillin; NR: Not reported; PAPM/BP: Panipenem/betamiprom; p.o.: Oral; q.i.d. Four times daily; SM: Sultamicillin; TIC/CLA: Ticarcillin/clavulanic acid; t.i.d.: Three times daily; VAP: Ventilator-associated pneumonia.

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comparative studies confirm previous findings for both URTIs and LRTIs [45,56,69-71]. Ferreira et al. reported comparable efficacy rates for oral sultamicillin (750 mg daily) when compared with 1.5 g/day of amoxicillin/clavulanic for the treatment of common community URTIs [45]. Likewise, ampicillin-sulbactam (at i.v. doses 3 18 g/day, and rarely up to 36 g/day) followed by oral sultamicillin in some studies is comparable with moxifloxacin, imipenem/cilastatin, clindamycin and colistin for the treatment of LRTIs, including CAP, aspiration pneumonia, lung abscess and ventilator-associated pneumonia (Tables 3 and 4).
4.2 Efficacy on intra-abdominal infections

With regard to pediatric population, the comprehensive reviews by Dajani [77] and Kanra [78] showed that ampicillinsulbactam was as effective as and in some cases superior to the antimicrobials traditionally used for the treatment (including surgical prophylaxis) of intra-abdominal infections [79].
4.3 UTIs

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Several early studies have established the antimicrobial usefulness of ampicillin-sulbactam in patients with intraabdominal infections [6,72,73]. Specifically, Walker et al. [73] compared the efficacy and safety of ampicillin-sulbactam with cefoxitin in a double-blind trial in patients with suspected bacterial intra-abdominal infections. Patients were randomized to receive either 3 g ampicillin-sulbactam or 2 g of cefoxitin every 6 h. One hundred ninety-seven patients were evaluable for clinical efficacy excluding not operated patients, those with absence of microbial documentation of the infection and those with early interruption of treatment. Ampicillinsulbactam demonstrated clinical success of 86% (n = 96) versus 78% of cefoxitine (n = 101) with no differences in the nature or frequency of side effects observed in the two groups. In fact, only 30% of patients in each group presented mild symptoms such as nausea, vomiting, diarrhoea and rush [73]. The report from the study group of intraabdominal infections showed that ampicillin-sulbactam had comparable efficacy rates (cure plus improvement) with gentamicin plus clindamycin (87 versus 97%, respectively), comparative bacteriological eradication rates (83 versus 66%) and concluded that no difference between the two antibiotic regimens existed [74]. A review of randomized-controlled trials examining patients with intra-abdominal infections and/or peritonitis showed that sultamicillin had comparable clinical success rates when compared with all antibiotic regimens (cefoxitin, gentamycin/ ampicillin, ticarcillin/clavulanic) with the exception of one (clindamycin plus gentamycin), which showed significantly higher efficacy rates than ampicillin-sulbactam in the treatment of gangrenous and perforated appendicitis [72,75]. Furthermore, bacteriological eradication rates were comparable in all studies providing relevant data except for one, in which the eradication rates achieved with ticarcillin/clavulanic were significantly inferior (p = 0.001) to those achieved by ampicillinsulbactam [64]. Recently, in a multi-center study comprising 2150 patients, the initial choice of antimicrobial therapy on the length of stay for patients with complicated intra-abdominal infections was assessed. Mean length of stay analyzed by initial antimicrobial therapy and stratified by diagnosis showed to be significantly shorter for sultamicillin compared with levofloxacin, ceftriaxone and piperacillin/tazobactam [76].
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Several studies in the past decades found that treatment with ampicillin/sulbactam or sultamicillin was effective for various UTIs [80-82]. Schutz showed that sultamicillin (750 mg twice daily) had similar clinical efficacy when compared to amoxicillin/clavulanic (625 mg thrice daily; t.i.d.) and concluded that administration of sultamicillin was advantageous due to simplest daily scheme [81]. Similar cure and eradication rates were also found in a study comparing ampicillin-sulbactam (6 12 g/day) and ticarcillin/clavulanic (12.4 g/day) [64]. As referred earlier, Levin et al. in a recent non-comparative study reported 100% clinical (cure plus improvement) rates in six patients with UTIs treated with a median 9 g/day of ampicillin-sulbactam [28]. Lower UTIs are very common in infancy and childhood. The predominantly renal route of excretion for ampicillinsulbactam and high urinary concentrations favor the eradication of common urinary pathogens, such as E. coli [77].
4.4 Soft-tissue infections

Ampicillin-sulbactam has been considered a useful agentcombination in treating various soft skin tissue infections including diabetic foot [83-85]. In the treatment of limbthreatening infections in diabetic patients, ampicillinsulbactam provided clinical response comparable with imipenem/cilastatin (81% (n = 48) versus 85% (n = 48)) [86]. Talan et al., in a randomized, double-blind comparative trial, reported equal effectiveness (cure or improvement) of ampicillin-sulbactam (2/1 g q6h) versus cefoxitin (2 g q6h) regarding clinical and bacteriological success, in patients with or without a history of injection drug abuse who presented with cutaneous or other soft tissue infections [85]. Bacterial eradication was achieved in 100% of patients receiving ampicillin-sulbactam versus 97.9% of the comparator agent. Other studies demonstrated that ampicillin-sulbactam (doses from 4 to 12 g/day) had comparable efficacy to clindamycin, ticarcillin/clavulanic, imipenem/cilastatin and piperacillin/ tazobactam, with clinical efficacy > 80% and eradication rates of 41 100% [64,86,87].
4.5 Gynecological/obstetrical infections

Numerous comparative and non-comparative studies in the past decades demonstrated the efficacy of ampicillinsulbactam (including sultamicillin in some cases) in the treatment of obstetric and gynecological infections. Although ampicillin-sulbactam is not considered the first-line treatment option for the so-called pelvic inflammatory disease, results from comparative studies demonstrated equivalent clinical efficacy to comparator agents (81 95% versus

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83 95%), including cefoxitin, cefoxitin/doxycycline, gentamycin/clindamycin, cefotetan, metronidazole/gentamycin and clindamycin alone [88-91]. Specifically, ampicillin-sulbactam showed comparable efficacy with clindamycin/gentamicin (88.7%; 141/159) versus (90.8%; 139/153) against postpartum endometritis infection [89]. Moreover, the Centers for Disease Control and Prevention guidelines suggest ampicillinsulbactam plus doxycycline as one of the alternatives to treat pelvic inflammatory disease [92]. However, it has been shown that doxycycline plus cefoxitine had no advantage over ampicillin-sulbactam in the treatment of pelvic inflammatory disease and both regimens have equal clinical response of about 70% [93]. A retrospective study involving gynecological infections showed that ampicillin-sulbactam (1.5 g in 24 patients in group 1; 3 g in 38 patients in group 2) versus ticarcillin/clavulanic acid (5 patients in group 3) had comparable clinical (overall clinical efficacy 93 versus 100%, respectively) and bacteriological efficacy rates. However, the cost effectiveness was significantly lower in the ampicillin-sulbactam group than in the ticarcillin/clavulanic acid group [64].
5. Infections due to Acinetobacter spp.

Acinetobacter baumannii is a Gram-negative, non-fermentative, non-spore forming, strictly aerobic, oxidase-negative coccobacillary organism that may be isolated from skin, throat and other sites of healthy persons. Acinetobacter baumannii is a major cause of hospital infections including pneumonia, bloodstream infections, meningitis and UTIs [94]. MDR is a growing problem and has been reported in different parts of the world, causing significant difficulties in the treatment of these severe hospital infections, particularly in the intensive care setting [95]. Sulbactam has intrinsic antimicrobial activity against A. baumannii, and is the most active of the -lactamase inhibitors [3,5,96]. Its mode of activity is either bacteriostatic or bactericidal depending on the strain examined, and is mediated through binding to PBP. Studies from the past decades have shown high in vitro susceptibility (using the National Committee for Clinical Laboratory Standards criteria) rates of A. baumannii isolates, including MDR ones, to ampicillin-sulbactam [97-99]. However, in recent studies, the antimicrobial activity of sulbactam against A. baumannii isolates has declined substantially. Still, sulbactam retains its activity against a rather small proportion of carbapenem resistant A. baumannii isolates [100,101]. Favorable clinical outcomes have been reported with ampicillin-sulbactam therapy in patients with various types of nosocomial infections caused by MDR A. baumannii, including ventilator-associated pneumonia, bactaeremia, meningitis and UTIs. Urban et al. [97], showed improvement in 9 (90%) of 10 patients with imipenem-resistant Acinetobacter calcoaceticus infections treated with ampicillin-sulbactam. In a prospective observational cohort study of patients with

A. baumannii bacteremia, Cisneros et al. [98] treated 8 patients with ampicillin-sulbactam and 42 with imipenem, and observed response rates of 83.0 and 87.5%, respectively. Corbella et al. [102] evaluated ampicillin-sulbactam (2 g/1 g t.i.d.) compared with sulbactam alone (1 g t.i.d.) in the treatment of non-life threatening MDR strains and showed that the active drug against A. baumannii in the ampicillin-sulbactam combination is sulbactam. In a non-comparative study of 40 consecutive patients with severe nosocomial infections by MDR A. baumannii, Levin et al. [101] recorded 67.5% of clinical success rate (improvement/care) when treated with 3 18 g i.v. of ampicillin-sulbactam (median 9 g/daily). Wood et al. [103] in a retrospective comparative study of 75 patients with ventilatorassociated pneumonia showed similar treatment efficacy in the ampicillin-sulbactam and imipenem-cilastatin groups (93 versus 83%, respectively). Similarly, Jellison et al. in a retrospective study showed that ampicillin-sulbactam was at least as effective as imipenem-cilastatin based on clinical response at days 2, 7, and end of treatment and was a cost-effective alternative for treatment of A. baumannii infections [104]. In a study of 94 patients with nosocomial A. baumannii bloodstream infections, 54% involved MDR A. baumannii, 81% of which were genetically related. Of the 51 patients with MDR A. baumannii, 65% received ampicillin-sulbactam and 35% received inadequate antibacterial therapy, whereas of 43 patients with non-MDR A. baumannii, 86% were treated according to susceptibility and 14% were treated inappropriately with antibacterials to which these organisms were resistant. Crude mortality was comparable in the adequately treated groups. Respective mortalities among patients treated adequately and inadequately were 41.4 and 91.7% (p < 0.001), respectively. Among severely ill patients, ampicillin-sulbactam therapy significantly decreased the risk of death (p = 0.02; odds ratio = 7.64) [105]. Two late comparative studies evaluated the efficacy and safety of ampicillin-sulbactam versus polymixins (colistin) for treating infections caused by MDR A. baumannii strains. Oliveira et al. [106] retrospectively showed that among existing therapeutic options for infections due to carbapenemresistant Acinetobacter, sultamicillin seemed to be more efficacious therapy than polymixins, which was an independent factor associated with mortality during treatment. Contrariwise, Betrosian et al. [70] in a small prospective trial using high dosing scheme of ampicillin-sulbactam showed comparable efficacy and safety between the two drugs for treatment of critically ill patients with MDR A. baumannii ventilator-associated pneumonia. Notably, high-dose ampicillin-sulbactam regimens have been used with safety as a means to overcome A. baumannii resistance to this agent in patients with ventilator-associated pneumonia [13]. However, data from several studies have showed that lower doses of the drug can be effective against MDR A. Baumannii as well [101,104].
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6. Safety and tolerability

7. Conclusions

Ampicillin-sulbactam (administered intramuscular or i.v.) or sultamicillin have been well tolerated in clinical trials both in adults and children [6,7]. Data on the safety of ampicillinsulbactam collected from 1287 patients from a variety of studies demonstrated adverse reactions at 10% of patients involved compared with 6% of comparator treated patients [6]. Almost 50% of these reactions involved pain at the injection site, especially during intramuscular administration. Other adverse reactions were skin disorders (1.2%), diarrhoea (1.6%) and minor increase in serum transaminase levels (serum aspartate aminotransferase, 6.2%; serum alanine aminotransferase, 6.9%) [6]. Recent studies confirm previous finding regarding safety and tolerability [13,45]. Ferreira et al. [45] reported similar adverse reactions in patients treated with ampicillin-sulbactam versus amoxicillin-clavulanic acid, with the ratio of patients with diarrhoea to be significantly higher in the amoxicillin-clavulanic acid group. Our group used high dosing schemes of ampicillin-sulbactam (27 36 g/day) for treating A. baumannii ventilatorassociated pneumonia, and found that the drug was well tolerated while no major adverse effects were reported [13]. Significant hepatotoxicity has not been reported with the use of ampicillin-sulbactam; however, two case reports of cholestasis associated with the drug have been published in the recent literature [107]. With regard to oral sultamicillin, a summary of data derived from 5947 patients with a variety of communityacquired infections has provided evidence for a satisfactory tolerability profile [7]. Side effects were recorded in 17.9% of patients, with diarrhoea to be the most frequently reported adverse reaction with an overall incidence of 10.4%. Other symptoms included soft stools (2.3%), loose stools (1.4%), nausea (1.1%) and rash (0.9%). Discontinuation of treatment because of diarrhoea was observed in 2.8% of patients. Clostridiun difficile or its toxin was not observed in the stools from patients with diarrhoea in all except one who had previously experienced a similar episode with clindamycin therapy and had uneventful course following vancomycin therapy. Ampicillin-sulbactam has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal evidence of fetal harm. There are, however, no controlled data from human pregnancy studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly indicated [108]. Ampicillin is excreted into breast milk in low concentrations. Milk:plasma ratios have been reported up to 0.2 [109]. Although adverse effects are apparently rare, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant (e.g., allergic response or sensitization) and interference with the interpretation of culture results if a fever workup is required.
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Numerous studies and a number of meta-analyses demonstrated the usefulness of the combination of ampicillinsulbactam (administered parenterally or orally) for a number of clinical indications. Its broad spectrum of activity against several -lactamase-producing pathogens, combined with a favorable safety and tolerability profile, makes this antibacterial a first-line option for the empirical treatment of mild to moderate community acquired infections. Due to the high prevalence of MRSA, pseudomonas and ESBL-producing bacteria in the nosocomial setting, hospital acquired infections should not be treated with ampicillin-sulbactam empirically and treatment should be adapted on the basis of pathogen identification. However, in the era of increasing bacterial resistance, ampicillin-sulbactam preserves its critical place in worldwide updated guidelines for the treatment of various infections including URTIs and LRTIs, sexually transmitted infections, intra-abdominal and skin and soft-tissue infections.
8. Expert opinion

The discovery of the -lactam inhibitor sulbactam and its co-administration with ampicillin as ampicillin/sulbactam allowed the continued use of this antibiotic to treat infections caused by pathogens that had developed resistance due to -lactamase production, thus expanding the range of activity of ampicillin alone. Ampicillin-sulbactam is a -lactam/-lactamase inhibitor combination with a broad spectrum of antibacterial activity that includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. The drug is indicated either parenterally (ampicillin/sulbactam) or orally (sultamicillin) as empirical therapy before the identification of causative organisms, or for disease caused by single or several susceptible bacteria in both adults and children with a broad range of community and hospital acquired infections. One of the specific advantages of using ampicillin/sulbactam combination when compared with other -lactam/-lactamase combinations is the inherent activity of sulbactam against A. baumannii, thus, making the drug a valuable option against multi-resistant isolates. Ampicillin-sulbactam is not active against P. aeruginosa and pathogens producing ESBLs and, therefore, is not recommended for infections due to these organisms. Numerous clinical trials and several meta-analyses have demonstrated ampicillin-sulbactam to be as clinically effective as relevant comparator antibiotics. The drug is effective for the treatment of URTIs and LRTIs, intra-abdominal infections, UTIs, gynecological, diabetic foot and skin and soft tissue infections. Ampicillin-sulbactam is generally well tolerated and its oral form, sultamicillin, provides effective outpatient therapy against many commonly encountered infections. Furthermore, the availability of oral sultamicillin also provides the option of oral follow-on therapy on an outpatient basis after the initiation of treatment with i.v. formulation, thus, improving

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patients compliance. Ampicillin-sulbactam has been recommended in nationwide guidelines as first-line therapy or in combination with other antibacterials for various respiratory, intra-abdominal and skin and soft tissue infections. Bibliography
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Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation
Alex P Betrosian MD & Emmanuel E Douzinas MD Author for correspondence Critical Care Consultant, Athens University, Evgenidion Hospital, 3rd Department of Critical Care, 20 Papadiamantopoulou Street, 11528, Athens, Greece Tel: +30 210 7208116; Fax: +30 210 7208100; E-mail: abetrosian@gmail.com

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