Experience with ampicillin/sulbactam in severe infections

The emergence of beta-lactamase-mediated resistance to established beta-lactam antibiotics prompted the development of beta-lactamase inhibitors for co-administration. Ampicillin has been combined with sulbactam for both parenteral and oral (as the mutual pro-drug sultamicillin) administration. The combination is active in vitro against a wide variety of Gram-positive and Gram-negative pathogens, including aerobic and anaerobic organisms. In clinical trials, ampicillin/sulbactam has proved clinically and bacteriologically effective against a variety of frequently encountered pediatric infections, including mild-to-moderate upper respiratory tract infections (acute otitis media, sinusitis, pharyngitis, and tonsillitis), severe post-operative and intra-abdominal infections, periorbital infections (which, left untreated, can lead to blindness, brain abscess, or death), acute epiglottitis, bacterial meningitis, and brain abscess. Ampicillin/sulbactam has also proved effective in the prevention of post-operative surgical infections in pediatric patients. The clinical efficacy profile of ampicillin/sulbactam and sultamicillin, combined with their excellent tolerability profile, make these agents attractive options for the management of many life-threatening infections in pediatric patients.     

Pharmacokinetics of sultamicillin in mice, rats, and dogs.

The irreversible beta-lactamase inhibitor sulbactam has been combined chemically via ester linkages with ampicillin to form sultamicillin . Upon oral absorption, sultamicillin is completely hydrolyzed to equimolar proportions of sulbactam and ampicillin, thereby acting as an efficient mutual prodrug. In rats, sultamicillin delivered 2 to 2.5 times greater total bioavailability for ampicillin and sulbactam than when each was used individually. Actual plasma or serum concentrations (measured in micrograms per milliliter) of ampicillin and sulbactam produced by sultamicillin were generally equivalent in rats, mice, and beagle dogs. Further studies also indicated that the components of sultamicillin were widely distributed in the various tissues of rats. These findings suggest that sultamicillin might be an effective agent against a variety of infections produced by both beta-lactamase-resistant and beta-lactamase-susceptible microorganisms.     

Beta-lactam resistance: clinical implications for pediatric patients

The emergence of resistance to established antibiotic agents such as beta-lactams has been reported worldwide and poses a serious challenge to the management of pediatric infections. The most common mechanism of resistance involves the production of an enzyme that inactivates the antibiotic before it can be effective. Streptococcus pneumoniae, the most common cause of pediatric respiratory tract infections, exhibits variable resistance to penicillins and aminopenicillin due to alterations in its penicillin-binding proteins (PBPs). Haemophilus influenzae and Moraxella catarrhalis show moderate and high beta-lactamase-mediated resistance to aminopenicillins, although they remain susceptible to beta-lactam/beta-lactamase inhibitor combinations. Methicillin-resistant Staphylococcus aureus, a frequent cause of skin and soft-tissue infections, has shown PBP-mediated beta-lactam resistance, prompting the wide-spread use of vancomycin to eradicate this pathogen. Finally, PBP-mediated resistance has been observed in a large proportion of isolates of coagulase-negative staphylococci, which account for a high proportion of nosocomial infections, particularly in neonatal intensive care units. The challenge is to control the emergence of beta-lactamase-mediated resistance by using beta-lactams judiciously. In this regard, the beta-lactam/beta-lactamase inhibitor combinations have an important role to play in extending the usefulness of established beta-lactam agents.     

Combating bacterial resistance in skin and skin-structure infection: importance of beta-lactamase inhibition.

Serious skin and skin-structure infections may require parenteral antibiotic therapy. Such infections are generally polymicrobial, and they often involve both gram-positive and gram-negative aerobes as well as anaerobic bacteria. Effective treatment thus requires the use of a broad-spectrum antibiotic or combination therapy. The development of antibiotic resistance by clinically important pathogens has significantly increased the difficulty of treating skin and skin-structure infections. One of the major mechanisms of resistance observed in organisms likely to be associated with such infections is the development of beta-lactamases that inactivate beta-lactam antibiotics. Two approaches have been taken to combat this problem: the use of beta-lactam/beta-lactamase inhibitor combinations and the development of beta-lactamase-stable drugs. Both strategies have resulted in treatments that are clinically and bacteriologically effective in patients with skin and skin-structure infections. The use of one beta-lactam/beta-lactamase inhibitor combination, ampicillin/sulbactam, has been demonstrated to be more cost-effective than treatment with beta-lactamase-stable antibiotics, such as cefoxitin and imipenem/cilastatin, for this indication.     

Sultamicillin--a new antibiotic in the treatment of persistent lower respiratory tract infections caused by Haemophilus influenzae

Haemophilus influenzae is a frequent cause of recurrent or chronic lower respiratory tract infections in patients suffering from cystic fibrosis (CF) and other chronic obstructive pulmonary disease (COPD). Ampicillin and its derivatives are routinely used in treatment, but resistant strains producing beta-lactamase frequently necessitate the use of other antibiotics. Sultamicillin is a compound agent for oral use in which ampicillin and the beta-lactamase inhibitor sulbactam are linked as a double ester. This combination is active in vitro against many beta-lactamase producing bacteria including ampicillin-resistant H. influenzae. Eight CF children and ten children with other COPD suffering from chronic or recurrent H. influenzae infection of the lower respiratory tract were treated with sultamicillin orally, 25 mg/kg, 12-hourly, for two weeks. Nine infections were caused by ampicillin-resistant strains. At the end of the treatment 65% of the patients were free of H. influenzae. The only adverse reaction was diarrhoea which occurred in 14 patients, and necessitated withdrawal of one patient from the study.     

Oral bioavailability of ampicillin and amoxycillin alone and bound in fixed proportions to sulbactam and clavulanic acid

Oral bioavailability of ampicillin when bound to sulbactam (sultamicillin) compared with ampicillin alone and that of amoxycillin with a ligand of clavulanic acid versus amoxycillin alone were assessed in 16 healthy subjects using an open label, multiple crossover study. After a single administration of the drugs, the bioavailability of ampicillin released from sultamicillin was more than twice (2.17) that of ampicillin administered alone, whereas that of amoxycillin was increased by a factor of 1.64 by the presence of clavulanic acid. Higher peak concentrations and areas under the curves, along with shorter lag times, were observed in both cases. The increased oral bioavailability of these aminopenicillins when associated with a beta-lactamase inhibitor was well demonstrated in this study, the bioavailability of ampicillin being more enhanced by sulbactam than that of amoxycillin by clavulanic acid.     

Sultamicillin (CP-49, 952): evaluation of two dosage schedules in urinary infection

The results of a clinical trial of sultamicillin, a novel mutual pro-drug combination of ampicillin and the beta-lactamase inhibitor sulbactam, in ampicillin-resistant urinary tract infections are reported. The majority of infections treated occurred in elderly geriatric in-patients. Two dosage schedules were investigated, both resulting in the same total daily dosage (1500 mg sultamicillin). These were 750 mg sultamicillin, 12-hourly (series I) and 500 mg sultamicillin, 8-hourly (series II), each administered orally for seven days. Short term cure rates (after exclusion of superinfections and reinfections) of 79.5% (series I) and 82% (series II) were obtained one week after therapy, falling to 69% and 50%, respectively, at three to six week follow up. Sultamicillin was well tolerated. Pharmacokinetic studies confirmed intestinal absorption of both constituents in young volunteers and in the elderly.     

Pharmacokinetics and bioavailability of sultamicillin estimated by high performance liquid chromatography

Sultamicillin is an orally absorbed double ester of sulbactam (penicillanic acid sulphone, a semisynthetic inhibitor of the beta-lactamases of many Gram-positive and Gram-negative species) and ampicillin. First-pass hydrolysis of this prodrug liberates equimolar proportions of sulbactam in plasma, saliva and urine is described and was used to determine the absolute bioavailability of sulbactam and ampicillin from sultamicillin in six normal male volunteers who each received a single 750 mg oral dose of sultamicillin or an iv dose of the equivalent amounts of ampicillin (441 mg) and sulbactam (294 mg). Treatments were given in random order with not less than four days intervening. The mean peak plasma concentrations and time to peak of sulbactam and ampicillin following the 750 mg oral half lives, systemic and renal clearances for sulbactam and ampicillin were similar. The bioavailability for both drugs from sultamicillin as estimated from both plasma and urine pharmacokinetics was better than 80%. We conclude that sultamicillin is an extremely efficient prodrug for ampicillin and sulbactam and that the HPLC assay method is accurate, rapid and easier to perform than the differential microbiological assay.     

The emergence of beta-lactamase resistance in respiratory pathogens

Bacteria have evolved a variety of mechanisms to express resistance to beta-lactam antibiotics. beta-Lactamase-induced hydrolysis of the beta-lactam ring is the principal and most important mediator of clinically significant resistance. Almost 200 beta-lactamases have now been identified, of which class 1 chromosomal beta-lactamases, class 2b plasmid-mediated beta-lactamases (especially TEM-1) and class 2be extended-spectrum beta-lactamases (ESBLs) are among the most important in respiratory pathogens. The combination of enzymatic and non-enzymatic resistance mechanisms has led to a steady rise in the prevalence of resistance to beta-lactams among isolates of the major respiratory pathogens, and, in turn, increasing rates of treatment failure, increased mortality, and prolonged morbidity. The combination of a beta-lactam antibiotic with a beta-lactamase inhibitor such as sulbactam, which protects the antibiotic from beta-lactamase destruction and so restores its activity, provides an innovative solution to this problem.     

Clinical results with sulbactam/ampicillin in a multicenter study of 425 patients

In an open, non-comparative multicenter study, efficacy and toleration of sulbactam/ampicillin for therapy of various infections were investigated. 42 centers in the Federal Republic of Germany and West-Berlin participated in this study. In total, 425 patients were included, 112 of whom suffered from renal/urinary tract infections, 103 from respiratory tract infections, 84 from intraabdominal infections, and 73 from skin/soft tissue infections. Moreover, 43 female patients had gynecological infections. More than 95% of the patients received three daily dosages of 3 g sulbactam/ampicillin via intravenous short-infusion. Mean duration of therapy was 7.3 days. In 280 patients, in total, pathogens were initially identified, among them were 87 patients with mixed infections. At study onset, 393 pathogens were identified, after completion of the trial 63 germs could still be made evident. In 234 cases (= 83.6%) pathogens were eradicated by therapy, in 19 patients superinfection occurred, and in 27 patients pathogenic organisms persisted. 419 patients were included into evaluation of clinical efficacy of sulbactam/ampicillin therapy. In 391 cases (= 93.3%) therapy was successful with 293 patients cured and 98 improved. Therapy failed in 28 patients (= 6.7%) which, in 23 cases, led to discontinuation of treatment. Sulbactam/ampicillin was well tolerated. In total, 55 adverse drug reactions were observed, 22 of which were exanthemas (= 5.2% of all patients). In seven patients (= 1.6%) therapy had to be discontinued due to adverse events. The combination of sulbactam, a beta-lactamase inhibitor, with the reliable antibiotic agent ampicillin has proved to be successful in therapy of infections of different localizations with excellent toleration.     

Cefdinir: an oral cephalosporin for the treatment of respiratory tract infections and skin and skin structure infections

Cefdinir is an oral third-generation cephalosporin (also known as an advanced-spectrum or generation cephem) with good in vitro activity against the pathogens responsible for community-acquired respiratory tract infections and uncomplicated skin and skin structure infections. The drug distributes very well in respiratory tract tissues and fluids, as well as skin blisters and ear fluids; its pharmacokinetic profile allows once- or twice-daily administration. Oral cefdinir 300 mg twice daily or 600 mg once daily in adults and adolescents, or 14 mg/kg/day in one or two daily doses in pediatric patients, administered for 5 or 10 days, has shown good clinical and bacteriological efficacy, at least equivalent to that of other oral agents in randomized controlled trials conducted in patients with community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, sinusitis, acute otitis media, pharyngitis and uncomplicated skin and skin structure infections. Cefdinir is well tolerated and the oral suspension has shown superior taste or palatability over other comparator oral antimicrobial agents. Thus, cefdinir continues to represent an important cephalosporin option for the treatment of adult, adolescent and pediatric patients with mild or moderate respiratory tract or cutaneous infections, especially in areas with elevated rates of beta-lactamase production in Haemophilus influenzae and where resistance to other commonly used agents has emerged (e.g., macrolides, penicillins, tetracyclines, fluoroquinolones and trimethoprim-sulfamethoxazole).     

Community-acquired lower respiratory tract infections: clinical experience with beta-lactam/beta-lactamase inhibitors

Once universally susceptible to aminopenicillins and cephalosporins, an increasing percentage of the common respiratory pathogens that cause community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are now resistant to these agents and exhibit cross-resistance to other commonly used antibiotics. In an era of multidrug resistance, guidelines for the management of both CAP and AECB can help to guide appropriate antibiotic prescribing, encourage the rational use of antibiotics, which will help to limit the emergence of resistance, and conserve the use of new antimicrobial agents for more serious infections. Central to all current management guidelines is risk assessment, which includes an appreciation of local antibiotic resistance patterns. beta-Lactam antibiotics are still considered among the drugs of choice for the treatment of CAP and AECB, although their use can be compromised by high rates of resistance. The beta-lactam/beta-lactamase inhibitor combinations, such as ampicillin/sulbactam, provide a means of overcoming such resistance and represent a suitable alternative.     

Beta-Lactamase Production and Resistance to Beta-Lactam Antibiotics in Nocardia

Although ampicillin has been suggested as a useful agent for the treatment of nocardiosis in man, little is known regarding the presence of beta-lactamase in Nocardia or its possible role in determining resistance to ampicillin and the other beta-lactam antibiotics. We have evaluated 55 isolates of Nocardia for susceptibility to five beta-lactam antibiotics and for the presence of beta-lactamase. Nocardia were resistant to penicillin G, cloxacillin, and cefazolin, but 27 and 62% were susceptible to 3.1 and 25 mug of ampicillin per ml, respectively. Almost 90% of these ampicillin-susceptible or intermediate strains were also susceptible to carbenicillin. The combination of ampicillin and cloxacillin was synergistic against many ampicillin-resistant strains. Beta-lactamase was detected in 89% of Nocardia isolates when intact cells were used and in six of six strains after cell fractionation. This beta-lactamase was most active against penicillin G and ampicillin, with lesser activity against carbenicillin and cephaloridine. These studies suggest that beta-lactamase may be present in all clinical isolates of Nocardia and that mechanisms of antimicrobial resistance other than or in addition to beta-lactamase are responsible for resistance of Nocardia to ampicillin and carbenicillin.     

Role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents.

We studied the role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents. beta-Lactamase-positive strains were more resistant than beta-lactamase-negative strains to amoxicillin, ampicillin, and ticarcillin (P less than 0.05). With penicillin G, piperacillin, imipenem, and six cephalosporins, the susceptibility levels were similar for both beta-lactamase-positive and -negative strains. By using spectrophotometric and microbiological assays, the beta-lactamase from three strains hydrolyzed ampicillin, amoxicillin, penicillin G, cloxacillin, and, partially, cephalothin. Ticarcillin and piperacillin were partially hydrolyzed in the microbiological assay. There was no activity against five other cephalosporins or imipenem. Isoelectric focusing of the enzyme showed a pI of 8.8. Tazobactam was the best inhibitor of the enzyme, followed by clavulanic acid, sulbactam, and cefoxitin, while EDTA and p-chloromercuribenzoate had no activity. All beta-lactamase-positive strains became susceptible to amoxicillin and ampicillin with 1 micrograms of clavulanic acid per ml. With the same inhibitor, there was a reduced but significant effect for ticarcillin but no effect for penicillin G or piperacillin. Sulbactam had no effect and tazobactam was effective only at 2 micrograms/ml on amoxicillin and ampicillin. The beta-lactamase of C. jejuni seems to be a penicillinase with a role in resistance for only amoxicillin, ampicillin, and ticarcillin.     

Antimicrobial resistance in respiratory tract pathogens

Antimicrobial resistance has been a problem ever since the introduction of antimicrobial agents 60 years ago. Today, this problem is increasing so rapidly that the end of the antimicrobial era is being predicted. The increasing problems caused by antimicrobial resistance can be illustrated by those seen in bacterial pathogens that cause community acquired respiratory tract infections, which are among the most common and important infections seen by clinicians. Bacterial pathogens causing community acquired respiratory tract infections have a number of resistance mechanisms such as beta-lactamases. Recognition of these resistance mechanisms allows them to be targeted, such as with beta-lactamase inhibitors. Newly recognized resistance mechanisms such as efflux may also be targeted in the future.     

Effect of beta-lactamase inhibitors on the activities of various beta-lactam agents against anaerobic bacteria.

The in vitro activities of several new beta-lactam-beta-lactamase inhibitor combinations (piperacillin plus tazobactam, ceftizoxime and cefonicid with sulbactam and clavulanic acid, and ampicillin plus 8 micrograms of sulbactam per ml) were tested with anaerobic bacteria and compared with known beta-lactam-beta-lactamase inhibitor combinations and other potent antianaerobe agents. All the combinations tested (except for the cefonicid-inhibitor combinations) were active against almost all strains of the Bacteroides fragilis group. This report indicates that beta-lactamase inhibitors may improve the activity of beta-lactam agents with marginal activity against the B. fragilis group.     

Clinical efficacy and safety of sulbactam/ampicillin in patients suffering from chronic liver disease

Sulbactam is a new beta-lactamase inhibitor with pharmacokinetic characteristics in humans similar to those of ampicillin. A total of 41 patients hospitalized in the Clinic of Infectious Diseases, University of Naples, for chronic liver diseases, were treated with sulbactam/ampicillin (ratio 1:2) for urinary, respiratory, biliary tract or soft tissue infections. Sulbactam/ampicillin was administered im or iv at a dosage of 3-9 g/day depending on the site and severity of the infection. All the patients treated with sulbactam/ampicillin had clinical signs and symptoms of infection, and all the organisms isolated were sensitive to sulbactam/ampicillin (MIC less than 16 mg/l). For both Gram-positive and Gram-negative bacteria the sulbactam/ampicillin MICs were much lower than the ampicillin MICs. In agreement with the favourable in-vitro results, we observed good therapeutic efficacy. 85% of the patients recovered or improved within a few days of therapy, with no clinical relapses, and in 81% of the infections the responsible bacteria were completely eradicated. We observed a low number of side effects (3/41 oral candidosis; 3/41 pain at the im injection site) and no change in the blood chemistry tests.     

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.     

Susceptibility trends of haemophilus influenzae and Moraxella catarrhalis against orally administered antimicrobial agents: five-year report from the SENTRY Antimicrobial Surveillance Program

The assessment of orally administered antimicrobial susceptibilities of common pathogens that cause community-acquired respiratory tract infections (CARTI) has become exceedingly important due to the number of office visits for this indication. Numerous local, regional and global studies have documented the susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, the most common CARTI pathogens. SENTRY Antimicrobial Surveillance Program sites in North and Latin America, and Europe were requested to send a combined total of 100 isolates of these pathogens to the local monitor for reference broth microdilution testing (1997-2001). This study compared the susceptibility profiles of H. influenzae and M. catarrhalis isolates (13,370 strains) from the three geographic regions over a five year period. beta-lactamase mediated ampicillin resistance among H. influenzae was highest among North American isolates (27.9%) compared to Latin America and Europe (16.2 to 16.3%), although it was noted that during the five year study period, ampicillin resistance was steadily increasing in the latter two regions. Cefprozil (84.3% susceptible) and clarithromycin (81.1% susceptible) were also less active against North American H. influenzae isolates. Latin American isolates were much less susceptible to trimethoprim/sulfamethoxazole (T/S; 59.3%) compared to the other regions (75.8 to 78.6%). M. catarrhalis isolates were also significantly less susceptible to T/S in Latin America (10.5% resistance). The production of beta-lactamase enzymes among the M. catarrhalis isolates exceeded >95% in all three regions during the five year period. The fluoroquinolones (FQ) remained very active against these two respiratory pathogens with rare isolates with elevated FQ MIC results. It is apparent from this investigation that many commonly prescribed empiric treatments remain viable therapeutic options for CARTI caused by these two Gram-negative respiratory tract pathogens.     

Telithromycin

Telithromycin (Ketek), Aventis Pharma), a ketolide, belongs to a new class of antibiotics that was developed for the treatment of upper and lower respiratory tract infections. The prevalence of penicillin and macrolide resistance among respiratory pathogens is increasing in the USA. Telithromycin is highly active against beta-lactam, macrolide and fluoroquinolone reduced-susceptibility pathogens. Its efficacy has been shown to be equal or superior to comparator agents in numerous studies. It has a broad in vitro spectrum versus usual respiratory pathogens and oral once-daily dosing that increases patient compliance. Telithromycin penetrates rapidly into neutrophils in bronchopulmonary tissue, with peak levels obtained in 1 to 2 h. Results of clinical trials show clinical-esponse rates similar to comparator agents. The most frequent adverse events involve the gastrointestinal system, with mild to moderate diarrhea and nausea. A low rate of discontinuation was observed in the studies. Telithromycin is an effective first-line treatment for mild to moderate respiratory infections in adults.