Ampicillin–Sulbactam: Antimicrobial Activity, Susceptibility, Administration and Dosage, Clinical Uses etc.

Ampicillin–sulbactam (AMP/S) is a beta-lactam/beta-lactamase inhibitor that was developed to overcome the increasing resistance of various bacteria to ampicillin. AMP/S is marketed under various trade names, such as Unasyns and Begalins. It is an antibacterial combination of the semisynthetic antibiotic ampicillin sodium and the beta-lactamase inhibitor sulbactam sodium.

Ampicillin sodium is derived from 6-aminopenicillanic acid (i.e. the penicillin nucleus). The detailed chemical structure of AMP/S is monosodium (2S, 5R, 6R)-6 [(R)-2-amino-2-phenylacetamido]-3, 3- dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate and it has a molecular weight of 371.3. The chemical formula of ampicillin sodium is C16H18N3NaO4S. Sulbactam sodium is a derivative of the basic penicillin nucleus. Its chemical structure according to the manufacturer is sodium penicillinate sulfone, i.e. sodium (2S, 5R)-3,3 dimethyl-7-oxo-thia-1-azabicyclo[3.2.0] heptan-2-carboxylate 4,4- dioxide. The molecular weight of sulbactam sodium is 255.2 (Unasyns package insert, Pfizer). The chemical structure of these two drugs is shown in Figure 15.1.

The antibacterial spectrum of AMP/S encompasses Gram-positive and Gram-negative aerobic bacteria as well as anaerobic bacteria (Jones, 1988). AMP/S has no activity against mycoplasma, fungi, viruses, or parasites. It has some activity against Chlamydia trachomatis (Martens et al., 1993); however, it suppresses rather than kills C. trachomatis (Segreti et al., 1992). Similarly, it has some in vitro bactericidal activity against Mycobacterium tuberculosis (Herbert et al., 1996; Chambers et al., 1998; Prabhakaran et al., 1999).

Figure 15.1 Chemical structure of ampicillin and sulbactam.

ANTIMICROBIAL ACTIVITY

Gram-positive bacteria

Gram-positive bacteria that are susceptible in vitro to AMP/S include methicillin/oxacillin-susceptible Staphylococcus aureus, methicillin-susceptible S. epidermidis, methicillin-susceptible S. saprophyticus, Streptococcus pyogenes, S. pneumoniae, S. viridans, and Enterococcus faecalis. However, one must be aware that for methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci, beta-lactam agents, including beta-lactam/beta-lactamase inhibitor combinations, cephems, and carbapenems may appear active in vitro but are not effective clinically (CLSI, 2007).

Gram-negative bacteria

Susceptible Gram-negative bacteria include Haemophilus influenzae (beta-lactamase and non-beta-lactamase producing), Moraxella catarrhalis (beta-lactamase and non-beta-lactamase producing), Escherichia coli (beta-lactamase and non-beta-lactamase producing), Klebsiella species, Proteus mirabilis (beta-lactamase and non-beta-lactamase producing), P. vulgaris, and Neisseria gonorrhoeae (beta-lactamase and non-beta-lactamase producing). In general, P. mirabilis strains are more likely to be susceptible to AMP/S than P. vulgaris strains.

Anaerobic bacteria

Anaerobes that are susceptible to AMP/S include Clostridium species and Peptococcus species, as are Peptostreptococcus species and Bacteroides species, including B. fragilis (Rafailidis et al., 2007).

b. Emerging resistance and cross-resistance

Strains of MRSA are not susceptible to AMP/S since their resistance mechanism is related to altered penicillin-binding proteins rather than to production of beta-lactamase. Among staphylococcal strains, MRSA constitute as many as 60% of the total number of strains in patients presenting to emergency departments with staphylococcal infections in some settings (Jacobus et al., 2007). An increasing number of Gram-negative pathogens have developed resistance to multiple classes of antibiotics, including beta-lactam/ beta-lactamase inhibitor combinations such as AMP/S (Asada et al., 1995; Herna´ndez-Alle´s et al., 2000; Livermore et al., 2000; Bradford, 2001; Paterson and Bonomo, 2005; Fedler et al., 2006). Carbapenems are regarded as appropriate for treatment of severely ill patients with extended-spectrum beta-lactamase (ESBL)-producing pathogens (Paterson et al., 2004; Peterson, 2008), whereas antibiotics such as fluoroquinolones, beta-lactam/beta-lactamase inhibitor combinations, and aminoglycosides have been used successfully in some cases (Tumbarello et al., 2006). When an ESBL-producing strain shows susceptibility to beta-lactam/beta-lactamase inhibitors, beta-lactam combinations with tazobactam and clavulanate may have a theoretical advantage over sulbactam (Weber and Sanders, 1990; Bush et al., 1993).

MECHANISM OF DRUG ACTION

Ampicillin inhibits bacterial cell wall synthesis by binding to penicillinbinding proteins (PBPs), enzymes that contribute to the formation of the cell wall structure. Ampicillin acts as a structural analog of acyl-D-alanyl-D-alanine and acylates the transpeptidase enzyme responsible for the final stage of the formation of the peptidoglycan, which is the main component of the cell wall (McKinnon and Freeman, 2005). Sulbactam, a beta-lactamase inhibitor obtained by oxidation of the thiazolidine sulfur of penicillanic acid, lacks signifi- cant antibacterial activity, except for Neisseria species and Acinetobacter (Urban et al., 1993; Jimenez-Mejias et al., 1997; Corbella et al., 1998; Pandey et al., 1998; Levin et al., 2003), but increases the activity of ampicillin as it protects it from hydrolysis by beta-lactamases (Labia et al., 1986). Sulbactam is recognized by the beta-lactamases as normal substrate and forms an acyl enzyme by reacting with the active site serine hydroxyl group. This intermediate can then undergo (a) deacylation and hydrolysis of the enamine liberated, which leads to the formation of smaller products; (b) tautomerization to enamine, leading to a transiently inhibited form of the enzyme; and (c) transamination reaction or reaction with serine 130, which leads to an irreversibly inhibited enzyme form (Sandanayaka and Prashad, 2002).

MODE OF DRUG ADMINISTRATION AND DOSAGE

a. Adults

AMP/S is licensed for parenteral use. It can be given by slow intravenous (i.v.) injection over at least 10–15 minutes or can also be delivered in greater dilutions with 100 ml of a compatible diluent as intravenous infusion over 15–30 minutes. AMP/S can also be given by deep intramuscular injection. The recommended dose is 1.5 g AMP/S (1 g of AMP and 0.5 g of S) up to 3 g (2 g ampicillin as the sodium salt and 1 g of the sulbactam salt) every 6 hours.

b. Newborn infants and children

The recommended daily dose of AMP/S for pediatric patients 1 year of age or older is 300 mg per kilogram of body weight (200 mg of ampicillin plus 100 mg/kg of sulbactam) administered via intravenous infusion in equally divided doses every 6 hours. The safety and efficacy of AMP/S for intramuscular injection have not been established in pediatric patients. Pediatric patients weighing 40 kg or more should be dosed according to recommendations for adults and the total amount of sulbactam should not exceed 4 g per day.

c. Altered dosages Impaired renal function

Dosage adjustment is necessary for AMP/S when impaired renal function is present, as excretion is primarily by the renal route. Specifically, for a creatinine clearance (CLCr) of Z30 ml/min/1.73 m2, 1.5–3.0 g every 6–8 hours is suggested. For various grades of renal impairment the following regimens are recommended: CCL 15–29 ml/ min/1.73 m2, 1.5–3.0 g every 12 hours; CLCr 5–14 ml/min/1.73 m2, 1.5–3.0 g every 24 hours.

PHARMACOKINETICS AND PHARMACODYNAMICS

a. Bioavailability

Poor bioavailability is present when ampicillin and sulbactam are administered separately by the oral route. The mean serum half-life of ampicillin and sulbactam is approximately 1 hour (Foulds, 1986). However, in premature neonates and the elderly, the mean serum halflife is increased, and thus the frequency of administration needs to be adjusted in these groups. Approximately 28% of ampicillin and 38% of sulbactam is bound to human serum protein (Foulds, 1986).
The poor bioavailabilty of AMP/S led to the formation of the therapeutic prodrug sultamicillin, which is a combination of ampicillin and sulbactam for oral use. Sultamicillin has a bioavailability of over 80%.The impact of food is significant on the absorption of AMP/S; this effect is more pronounced in comparison to amoxicillin–clavulanate.

b. Drug distribution

The drug distribution and pharmacokinetics of AMP/S have been reviewed in detail by Foulds (1986). Following a 15-minute infusion of 3 g AMP/S (2 g ampicillin, 1 g sulbactam) in healthy males, peak serum concentrations were 122 mg/ml ampicillin and 59 mg/ml sulbactam; and after infusion of 1.5 g AMP/S (1 g ampicillin, 0.5 g sulbactam) the corresponding values were 58 mg/ml ampicillin and 30 mg/ml sulbactam. Intramuscular injection leads to a maximum concentration (Cmax) of 18 and 13 mg/ml for ampicillin and sulbactam, respectively. Blackwell et al. (1990) examined the pharmacokinetics of AMP/S in six noninfected CAPD patients who were given 3 g AMP/S (2 g ampicillin, 1 g sulbactam), either intravenously or intraperitoneally, in a randomized two-way crossover study (Blackwell et al., 1990). The mean peak ampicillin and sulbactam serum concentrations following intravenous dosing were 170.3 and 87.5 mg/ml, respectively. The mean peak serum concentrations of ampicillin and sulbactam following intraperitoneal dosing were 48.0 and 27.8 mg/ml, respectively. Absolute bioavailabilities of the intraperitoneal ampicillin and sulbactam doses were 60% and 68%, respectively.

AMP/S penetrates well in the lower respiratory system. Indeed, levels of AMP and S in biopsy samples of bronchial mucosa were 39.7% and 74.7% of those of serum. Lower, although still relatively good, levels have been obtained in empyema samples (Wildfeuer et al., 1994). Excellent AMP/S levels (mean 53% and 61%, respectively) have been obtained in the alveolar lining fluid (Valcke et al., 1990). AMP/S has been measured in the cerebrospinal fluid (CSF) both during meningitis and in the uninflamed state; penetration of AMP/S is greater when the meninges are inflamed. CSF levels of AMP and S reached 39% and 34% of the serum levels, respectively. With uninflamed meninges the CSF levels for AMP and S were 5% and 11% of the serum levels, respectively (Foulds et al., 1987). In another study, similar results were obtained, with ampicillin achieving 41% of the serum concentrations in the CSF while the corresponding percentage for sulbactam was 33% (Stahl et al., 1986).

d. Excretion

Over 75% of both AMP and S is excreted unchanged in the urine (Foulds, 1986). In sharp contrast, less than 1% of sulbactam and less than 3% of ampicillin is excreted in the bile (Morris et al., 1986). Despite the fact that levels of AMP and S in the bile are lower than those of serum, they exceed the MIC for a significant number of organisms and, thus, have proved successful both for surgical prophylaxis for operations involving the biliary tree and for the treatment of biliary infections.

e. Drug interactions

The renal tubular secretion of AMP/S is decreased by probenecid. Thus, increased levels of AMP/S ensue when probenecid is used concurrently. The frequency of skin rashes increases significantly when allopurinol is co-administered with AMP/S. AMP/S and aminoglycosides should not be reconstituted together because of the inactivation of aminoglycosides by ampicillin (Unasyns Package Insert). The high urinary concentration of ampicillin obtained with AMP/S may interact with testing for the presence of glucose in the urine using Clinitestt, Fehling’s solution, or Benedict solution (Unasyns Package Insert).

TOXICITY

AMP/S is generally well tolerated. In data pooled from the manufacturer, injection site pain after intramuscular injection, diarrhea, phlebitis, nausea, and rash were the most common adverse events (Campoli-Richards and Brodgen, 1987). Otherwise, the adverse reaction profile for AMP/S is similar to that of ampicillin (see Chapter 3, Ampicillin, Amoxicillin and Other Ampicillin-Like Penicillins). Similar to all beta-lactams, AMP/S may cause hypersensitivity reactions presenting as anaphylactic reactions, angioedema, and urticaria. Other very rare skin manifestations of toxicity include erythema multiforme, exfoliative dermatitis, and toxic epidermal necrolysis (Arca et al., 2005).

Laboratory changes most commonly reported with AMP/S involve elevated hepatic enzymes (AST, ALT, ALP, LDH). Hematologic abnormalities include anemia, leucopenia, increased or decreased number of platelets and lymphocytes, increase in monocytes, basophils or eosinophils, and positive direct antiglobulin test. A decrease in serum albumin and total proteins levels has also been reported.

CLINICAL USES OF THE DRUG

AMP/S has been used for a wide range of clinical indications, especially including mixed aerobic/anaerobic infections.

a. Respiratory tract infections Lower respiratory tract infections

A significant number of comparative studies have evaluated the role of AMP/S in infections such as pneumonia, acute exacerbation of chronic bronchitis (AECB), and bronchitis (see Table 015.2; Geckler, 1994; Jauregui et al., 1995; Rossoff et al., 1995; Schwigon et al., 1996a; Schwigon et al., 1996b; Castellano and Maniatis, 1998; McKinnon and Neuhauser, 1999; Yanagihara et al., 2006). The majority of the studies compare the effectiveness of AMP/S with second- and thirdgeneration cephalosporins: cefuroxime (Geckler 1994; Rossoff et al., 1995; Schwigon et al., 1996a), cefotaxime (Jauregui et al., 1995), mezlocillin (Schwigon et al., 1996b), and cefoxitin (Castellano and Maniatis, 1998). AMP/S has also been compared with ticarcillin– clavulanate (McKinnon and Neuhauser, 1999) and imipenem– cilastatin (Yanagihara et al., 2006).

Aspiration pneumonia

In the management of aspiration pneumonia, AMP/S is compared with antimicrobials with antianaerobic activity, such as clindamycin and imipenem/cilastatin. Cure rates with AMP/S in aspiration pneumonia were relatively lower in comparison with the cure/improvement rates of AMP/S in clinical trials of lower respiratory tract infections (LRTIs) without aspiration, i.e. 73% (Allewelt et al., 2004) and 76–84% (Kadowaki et al., 2005). Kadowaki et al. (2005) examined the costeffectiveness of AMP/S, clindamycin, and carbapenem in 100 elderly patients with mild to moderate aspiration pneumonia. AMP/S was administered in two different dosage protocols: 3 g twice a day and 1.5 g twice a day. Cure rates in the patients who received 3 g of AMP/S were higher (84%) than the corresponding rates in patients treated with the half-dose and similar to those in the imipenem/cilastatin group (88%), which seemed to be the most effective regimen. It is noticeable, though, that this study was interrupted early owing to the appearance of MRSA in all patient groups except those who received clindamycin. The highest rate of MRSA was noticed in the carbapenem group. Clindamycin was also found to be significantly less expensive than the other three regimens.

b. Gynecologic/obstetric infections

Pelvic inflammatory disease (PID) includes endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. Pathogens commonly responsible for PID are sexually transmitted, including N. gonorrhoeae and C. trachomatis, or they belong to the vaginal flora (e.g. anaerobes, Gardnerella vaginalis, H. influenzae, Gram-negative bacteria, and S. agalactiae). First-line treatment options include cefotetan or cefoxitin plus doxycycline, or clindamycin–gentamicin plus doxycycline (Centers for Disease Control and Prevention, 2006). AMP/S 3 g every 6 hours is recommended as an alternative treatment for PID with clinical effectiveness similar to that of the first-line regimens.

c. Intra-abdominal infections

The mainstay of treatment of intra-abdominal infections is surgical debridement in combination with administration of antibiotics with activity against the anticipated local polymicrobial flora. Common etiologic agents of intra-abdominal infections are facultative and aerobic Gram-negative organisms and anaerobes. In complicated intraabdominal infections it is recommended that AMP/S should be used in mild to moderate community-acquired infections according to Infectious Diseases Society of America (IDSA) guidelines; patients with more severe infections benefit from regimens with broader spectrum against facultative and Gram-negative aerobic bacteria. Healthcare-associated complicated intra-abdominal infections necessitate the use of multidrug combinations (such as a carbapenem in combination with vancomycin) (Solomkin et al., 2003).

d. Diabetic foot infections

A significant cause of morbidity in the diabetic patient population is diabetic foot infection (Lipsky et al., 2004). A double-blind randomized study comparing imipenem–cilastatin (I/C) (0.5 g every 6 hours) and AMP/S (3 g every 6 hours) in limb-threatening infections in diabetic patients found similar results for the two regimens. After 5 days of empiric treatment, improvement was achieved in 94% of 48 AMP/ S-treated infections and in 98% of 48 I/C-treated infections. Cure rates were 81% for the AMP/S group versus 85% for the I/C group; failure rates were 17% and 13%, respectively, and bacterial eradication rates were 67% and 75%, respectively. The episodes of treatment failures were associated with pathogens with antibiotic resistance and acquisition of nosocomial pathogens (Grayson et al., 1994).

e. Skin and soft-tissue infections

AMP/S has proved effective in clinical trials in the treatment of skin and soft tissue infections (SSTIs; see Table 015.5). In a randomized doubleblind trial, the clinical and bacteriologic efficacy of AMP/S (2 g/1 g) and cefoxitin (2 g) administered intravenously every 6 hours were compared in patients with or without histories of injecting drug abuse who presented with cutaneous or other soft-tissue infections. AMP/S and cefoxitin were equally effective for the empirical treatment of cutaneous or other soft-tissue infections in injection drug abusers and patients who did not inject drugs. Cure or improvement occurred in 89.8% of AMP/S-treated patients, compared with 93.6% of cefoxitin-treated patients. The median time to resolution of all symptoms was 10.5 days with AMP/S treatment and 15.5 days with cefoxitin treatment. Mixed aerobic–anaerobic infection was encountered frequently in both groups. Patients with a history of injection drug abuse had a significantly higher percentage of Streptococcus strains than patients without a history of drug abuse (37% vs 19%, respectively). Bacterial eradication was achieved in 100% of patients receiving AMP/S, whereas the eradication rate with cefoxitin was 97.9% (Talan et al., 2000).

f. Sepsis in pediatric patients

AMP/S appears to be effective in various severe pediatric infections such as periorbital infections, acute epiglottitis, bacterial meningitis, and acute fulminant meningococcemia (Kanra, 2002).

g. Infections due to Acinetobacter baumannii

Multidrug-resistant (MDR) A. baumannii poses a new challenge for physicians worldwide (Choi et al., 2004; Sader and Jones, 2005), especially when managing critically ill patients, as resistance to carbapenems is a particular problem in many countries. Thus, possible treatment options include polymyxins (colistin and polymyxin B) (see Chapter 75, Polymyxins) (Falagas and Rafailidis, 2008), AMP/S (Levin et al., 2003; Higgins et al., 2004; Brauers et al., 2005), and tigecycline (see Chapter 69, Tigecycline). Although experimental data suggest that sulbactam is an important consideration in the treatment of infections due to MDR A. baumannii (Corbella et al., 1998), clinical data do not recommend monotherapy with sulbactam in these severe infections; the majority of clinical data come from studies examining the efficacy of the AMP/S combination. A higher dose of AMP/S than that used in infections due to other bacteria is usually employed in the treatment of A. baumannii (Betrosian et al., 2007; Betrosian et al., 2008). AMP/S has also been successfully used in the treatment of A. baumannii meningitis, although successful treatment is a challenge and i.v. and intrathecal administration of polymyxins is frequently necessary (Kasiakou et al., 2005). Microbiologic data show that A. baumannii is more susceptible to polymyxins than AMP/S (Duenas Diez et al., 2004).

h. Urinary tract infections

AMP/S is effective in the treatment of UTIs due to bacteria resistant to ampicillin (Syriopoulou et al., 1986) and is as effective and safe as trimethoprim–sulfomethoxazole for these infections (Naber and Wittenberger, 1989). However, AMP/S is unlikely to be effective against ESBL-producing Gram-negative pathogens. For example, in a study of complicated UTIs, 77% of ESBL producers were resistant to AMP/S (Taneja et al., 2008). In such settings, treatment with fosfomycin, nitrofurantoin, temocillin, or carbapenems may be necessary (Livermore et al., 2007; Giamarellou 2008). However, if the urine Gram stain reveals a Gram-positive pathogen, then AMP/S is considered appropriate empiric therapy according to IDSA guidelines (Warren et al., 1999).

i. Bacterial endocarditis

The role of ampicillin in the treatment of endocarditis due to Enterococcus spp. with susceptibility to penicillin is well established (Olaison et al., 2002); however, there is a scarcity of clinical data regarding the use of AMP/S for enterococcal endocarditis (Mekonen et al., 1995). In vitro data have supported the role of AMP/S in the treatment of endocarditis due to Enterococcus spp. (Hindes et al., 1989; Lavoie et al., 1993), and AMP/S has been recommended in combination with gentamicin in the treatment of those rare cases of native or prosthetic valve endocarditis caused by beta-lactamaseproducing enterococcal strains that are also susceptible to aminoglycoside. AMP/S has been used to treat endocarditis due to HACEK bacteria (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae), although ceftriaxone and ciprofloxacin are treatment alternatives (Baddour et al., 2005).

j. Gastrointestinal infections

Although AMP/S is likely to be effective in the treatment of gastrointestinal tract infections due to Salmonella spp. (typhi and non-typhi) and Shigella spp., other agents such as ciprofloxacin (see Chapter 93, Ciprofloxacin) or trimethoprim–sulfamethoxazole (see Chapter 83, Trimethoprim, Co-Trimoxazole (Co-T) and Related Agents) are generally preferred.

k. Other infections

AMP/S has been used successfully to treat gonorrhoea due to betalactamase (penicillinase)-producing N. gonorrhoeae strains (Kim et al., 1986; Baddour et al., 1992; Hellman et al., 1995) – indeed, in this setting, AMP/S appears to be as effective as ceftriaxone.

l. Surgical prophylaxis

AMP/S has been used very successfully as prophylaxis against the development of postsurgical infections, including mainly abdominal (Kirton et al., 2000) and gynecologic surgery prophylaxis, as well as various other types of surgery, such as head and neck surgery (Johnson et al., 1997) and neurosurgical patients with external ventricular drain (Zhu et al., 2001). AMP/S appears to be more effective than cefuroxime in elective cholecystectomy for the prevention of enterococcal infections (Dervisoglou et al., 2006).

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