Beta-lactamase Inhibitor Combinations Research Articles

Comparative In Vitro Evaluation of Piperacillin/Tazobactam in a Tertiary Care Hospital

Bacterial resistance is usually a serious problem in tertiary care hospitals. The aim of this In Vitro study was to evaluate the beta-lactamase inhibitor combination piperacillin/tazobactam in a hospital environment with high bacterial resistance rates and compare it with other beta-lactam agents. Three hundred and sixty-two isolates from various clinical materials were studied during the period March-August 1996. Material for culture was collected from patients of all the wards of our hospital, with the majority being from the Intensive Care Unit (45%). Pathogenic Gram-positive and Gram-negative bacteria with high resistance rates and beta-lactamase production were studied (staphylococci, enterococci, Enterobacteriaceae, Pseudomonas). Significant bacterial resistance rates were identified for ceftazidime (50% for Klebsiellae, 60% for Enterobacter spp, 60% for Proteus spp, 33% for Pseudomonas spp, 75% for Acinetobacter spp) and ciprofloxacin (33% for both Klebsiellae and Enterobacter spp, 67% for Pseudomonas spp, 50% Acinetobacter spp). Fifty percent of Enterococcus isolates were resistant to ciprofloxacin but all of them were susceptible to piperacillin/tazobactam, amoxicillin/ clavulanate and imipenem. The antibacterial activity of piperacillin/tazobactam (susceptibility rates 83 to 100% for Enterobacteriaceae, 83% for Pseudomonas spp and 75% for Acinetobacter spp) was higher than that of ceftazidime, piperacillin and ciprofloxacin. Imipenem, being mostly a reserve product, showed higher activity against Acinetobacter, Klebsiella and Enterobacter species.

Comparative activity of twelve beta-lactam drugs tested against penicillin-resistant Streptococcus pneumoniae from five medical centers: Effects of serum protein and capsular material on potency and spectrum as measured by reference tests

A total of 152 strains of Streptococcus pneumoniae from diverse geographic areas in the United States and with different levels of penicillin resistance were tested against five broad-spectrum cephalosporins, ampicillin, piperacillin, ticarcillin, and three beta-lactamase inhibitor combinations. Also, the effect of human serum proteins on the activity of selected “third-generation” cephalosporins was examined. The overall rank order of activity among the cephalosporins against penicillin-susceptible strains was: ceftriaxone (MIC 90, 0.03 μg/mL) > cefotaxime > ceftizoxime = cefuroxime > ceftazidime (MIC 90, 0.5 μg/mL). Only cefotaxime and ceftriaxone exhibited significant activity against penicillin-intermediate or -resistant isolates. Ampicillin, piperacillin, and penicillin were generally eight- to 16-fold more potent than ticarcillin and no increase in the effectiveness of these agents was observed with the addition of the beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam). Ceftriaxone potency was significantly decreased (⩾four-fold) by the modest addition of 25% pooled human serum proteins and this change modified the rank order of potency against nonpenicillin-susceptible pneumococci to favor cefotaxime (41% resistant versus 71% for ceftriaxone; MICs at ⩾2 μg/mL). Induced high-level capsular production had no measurable effect on the MIC results of tested agents. These results confirm the continued activity advantages of cefotaxime and ceftriaxone against various populations of pneumococci compared to other alternative beta-lactams. The predictive value, however, of the utilized breakpoint concentrations of the cephalosporins, remains in question for pneumococcal infections other than those in the central nervous system and at unaltered, “usual” dosing.

Trends in antimicrobial susceptibility of bacterial pathogens of the respiratory tract

Rates of antimicrobial resistance have been increasing in bacteria responsible for community-acquired lower respiratory tract infections in the United States. Nearly 100% of clinical isolates of Moraxella catarrhalis now produce beta-lactamase, an enzyme that renders this pathogen resistant to such agents as penicillin, ampicillin, and amoxicillin. However, this organism remains nearly uniformly susceptible to alternative oral antimicrobials, such as cephalosporins, macrolides, tetracyclines, beta-lactamase inhibitor combinations, and the combination of trimethoprim/sulfamethoxazole. The susceptibility of M. catarrhalis to these agents is not expected to change markedly in the next few years. A linear increase in the prevalence of beta-lactamase-mediated ampicillin resistance has been evident among isolates of nontypeable Haemophilus influenzae during the past decade in the United States. By the year 2000, 45-50% of isolates are likely to produce beta-lactamase. Although the susceptibility of this organism to alternative oral antimicrobials varies, rates of resistance to cefuroxime axetil, cefpodoxime, cefixime, azithromycin, and perhaps clarithromycin remain < 1%. The rate of penicillin resistance among isolates of Streptococcus pneumoniae, which has increased steadily in recent years, currently stands at approximately 25% in the United States and will likely reach 40-50% during the next 5-10 years. Because of cross-resistance, in general all beta-lactam antimicrobials have reduced activity against penicillin-resistant strains of S. pneumoniae. A 1994-1995 survey found that 3.4% of S. pneumoniae isolates were highly resistant to cefotaxime, and 4-8% were resistant to chloramphenicol, tetracycline, and the macrolides. Resistance to these antimicrobials has usually followed the emergence of penicillin resistance in other countries. Therefore, S. pneumoniae resistance to these drugs is expected to increase markedly during the next few years in the United States.

Activity of beta-lactamase inhibitor combinations on Escherichia coli isolates exhibiting various patterns of resistance to beta-lactam agents.

The efficacy of the clinically available beta-lactam/beta-lactamase inhibitor combinations (amoxicillin/clavulanic acid (CA), ticarcillin/CA, amoxicillin/sulbactam, and piperacillin/tazobactam) was evaluated on 300 amoxicillin-resistant Escherichia coli isolates having the main patterns of beta-lactam resistance. The patterns, which reflect the production of various beta-lactamase enzymes, were analyzed by a principal component analysis of susceptibility to 11 beta-lactam antibiotics or beta-lactam/beta-lactamase inhibitor combinations. Sixty-two percent of strains were not very susceptible to penicillins, cephalothin, or any beta-lactam/beta-lactamase inhibitor combinations except for piperacillin/tazobactam; these strains may represent high-level broad-spectrum beta-lactamase (so-called penicillinase) production phenotype or inhibitor-resistant TEM-like enzyme production phenotype. Of the strains, 14.7% were resistant to amoxicillin and ticarcillin compatible with low-level broad-spectrum beta-lactamase production phenotype; 5.7% were cefoxitin resistant and were postulated to present a high-level cephalosporinase production phenotype; and 2.6% were resistant to cephalothin only, attributable to a low-level cephalosporinase production phenotype. Three percent of strains were intermediate or resistant to cefotaxime and may produce an extended-spectrum beta-lactamase, and the remaining strains (12 %), resistant to all tested antibiotics except for cefotaxime and piperacillin/tazobactam, were hypothesized to produce both broad-spectrum beta-lactamase plus cephalosporinase. The minimal inhibitory concentration (MIC) for these phenotype patterns indicated that combinations of CA plus amoxicillin or ticarcillin, or sulbactam plus amoxicillin, restored the activity of penicillins against phenotype 1 strains, whereas these combinations remained inactive against the other phenotype strains. Piperacillin plus tazobactam showed the best in vitro effect against the strains of all resistance phenotypes.

NEWER PENICILLINS AND BETA-LACTAMASE INHIBITORS

Penicillins continue to be essential antibiotics for the treatment and prophylaxis of many infectious diseases. Recent advances have resulted in compounds with favorable new antimicrobial and pharmacologic properties. This article reviews the spectrum of activity, toxicity, pharmacokinetics, and clinical uses of the extended spectrum penicillins and the beta-lactamase inhibitor combination agents.

Beta-lactamase inhibitor combinations

The beta-lactamase inhibitor combinations present a novel approach to the problem of beta-lactamase-induced resistance to antibiotics. These agents are derived from the generally safe beta-lactam class of antibiotics. They are all principally excreted through the kidneys and require dosage adjustment in the face of significant renal insufficiency. They show significantly increased activity against methicillin-sensitive S. aureus, H. influenzae, B. catarrhalis, and B. fragilis. The activity against Enterococcus, Pseudomonas, and most gram-negative bacilli, however, remains limited to that of the respective antibiotic component. Although shown to be clinically useful in a variety of clinical situations, they appear to be most useful for skin and soft tissue infections and lower respiratory tract infections as well as intra-abdominal and gynecologic infections caused by susceptible pathogens.

Beta-Lactamase types amongst Staphylococcus aureus isolates in relation to susceptibility to beta-lactamase inhibitor combinations.

Relationships between beta-lactamase type and antimicrobial susceptibility were investigated for Staphylococcus aureus isolates collected recently at UK and Irish hospitals, and for reference producers of types A, B, C and D enzymes. Producers of types A and C beta-lactamases predominated amongst the isolates. Tazobactam and clavulanate combinations were studied, as previous observation showed that these inhibitors incompletely reversed the in-vitro amoxycillin and piperacillin resistance of beta-lactamase-positive staphylococci. Further penicillins and cephalosporins served as controls. Organisms with type C beta-lactamase were less susceptible than those with type A enzyme to piperacillin/tazobactam and amoxycillin/tazobactam in disc and MIC tests, and to co-amoxiclav in disc tests only. Conversely, producers of type A enzyme were less susceptible to cephazolin than those with type C enzyme. Kinetic assays showed that type A enzymes bound piperacillin and amoxycillin less tightly than did type C enzyme (higher Kmapp), and were more susceptible to inhibition by clavulanate and tazobactam (lower I50s). However, the susceptibility to beta-lactamase inhibitor combinations for the few producers of types B and D enzymes tested could not be similarly explained by Kmapp and I50 data. It therefore seems that other factors besides beta-lactamase affinity co-determine the susceptibility of the staphylococci. Possible variables include the exact chemistry of the enzyme-inhibitor interaction, and the degree of beta-lactamase induction. Both tazobactam and clavulanate induced staphylococcal types A and C penicillinases.

Feline Neonatal Sepsis

When bacterial infections exceed or overcome the ability of a kitten's immune system to provide protection, life-threatening illnesses such as neonatal sepsis often occur. Many kittens with neonatal sepsis show unusual presentations or a wide variety of clinical presentations that may not be immediately recognized as being associated with sepsis. Because neonatal sepsis causes unexpected sudden death, kittens suspected of having sepsis should be treated immediately. In most instances, initial antimicrobial therapy is selected empirically. Kittens are treated by giving intravenous or intraosseous fluids for dehydration, oxygen to counter tissue hypoxemia, and glucose if hypoglycemia is present. The beta-lactam antimicrobial agents such as the penicillins, cephalosporins, and the combination of beta-lactam antimicrobials and beta-lactamase inhibitors are considered to be the first choice in the treatment of any septicemic kittens.

Determinants of the activity of beta-lactamase inhibitor combinations.

Inhibitor combinations provide one strategy to overcome beta-lactamase-mediated resistance. Their success depends, obviously, on the inhibitor being able to bind and inactivate the beta-lactamase molecules. Clavulanate, sulbactam and tazobactam are irreversible inactivators of many beta-lactamases, forming covalent complexes which resist hydrolysis. 'Suicide' kinetics are seen with some, but not all, enzymes. All three compounds inactivate staphylococcal penicillinase, the chromosomal beta-lactamases of Proteus vulgaris and Bacteroides spp., and the Class IV beta-lactamases present in some klebsiellae. Tazobactam, but not the other compounds, has moderate activity against some Class I (AmpC) chromosomal beta-lactamases, notably that of Morganella morganii, but not that of Enterobacter cloacae. Both clavulanate and tazobactam are strong inhibitors of the widely distributed TEM and SHV plasmid-mediated beta-lactamases; sulbactam is a weaker inhibitor. Other factors, aside from the affinity of the inhibitor for the enzyme, co-determine the success or failure of inhibition. Potentiation is most readily achieved if little enzyme is produced, and if the organism is very permeable to the inhibitor. Thus, resistance to inhibitor combinations is rare in strains of Haemophilus influenzae and Neisseria gonorrhoeae that produce TEM-beta-lactamase, but is commoner in enterobacteria that produce this enzyme, since these are less permeable and sometimes manufacture very large amounts of enzyme. The partner beta-lactam agent is also important. Irrespective of the inhibitor used, piperacillin is easier to protect against TEM beta-lactamases and the M. morganii Class I enzyme than are ampicillin, amoxycillin or ticarcillin. This may relate to the lower affinity of piperacillin for these enzymes, or to its greater affinity for the bacterial penicillin-binding proteins. Finally, pH can affect the degree of inhibition achieved with sulphones for some beta-lactamases, notably TEM-1.

Survey of Antimicrobial Resistance to Oral Antibiotics in Italy

The susceptibility of approximately 4,200 fresh clinical isolates to eleven different orally available compounds was assessed in ten Italian microbiology institutions during summer 1991. A standardized microdilution system including all the material necessary was employed to assess the antibacterial activity of ampicillin, ampicillin plus sulbactam, amoxicillin plus clavulanic acid, cefadroxil, cephalexin, cefaclor, cefuroxime, cefetamet, doxycycline, erythromycin, and clindamycin. The amino-penicillins (including the beta-lactamase inhibitor combinations) were highly active against the streptococci, whereas cefetamet was the most active compound against Enterobacteriaceae, exhibiting good activity against the streptococci as well. The analysis of distribution of susceptibility revealed that there is a good discrimination between susceptible and resistant strains for cefetamet in any case, whereas the discrimination is low for the aminopenicillin/inhibitor combinations and the older cephalosporins in at least some of the gram-negative species.

Changes in the susceptibility of Bacteroides fragilis group organisms to various antimicrobial agents 1979-1989.

The in vitro activity of metronidazole, chloramphenicol, clindamycin and 11 beta-lactam antibiotics against 135 clinical isolates of the Bacteroides fragilis group was compared. In addition, changes in the resistance patterns of members of the Bacteroides fragilis group isolated at the Hospital Universitario San Carlos in Madrid, Spain, between 1979 and 1989 were documented. The most active beta-lactam drugs were imipenem and beta-lactamase inhibitor combinations. In 1989, however, two strains were found to be resistant to imipenem and to all other beta-lactam agents tested. There was no emergence of resistance to metronidazole. Chloramphenicol was very effective: only one resistant strain was detected in 1979 and no chloramphenicol-resistant isolates were found during the rest of the study period. An outbreak of clindamycin resistance was noted in 1982, and the first cefoxitin resistant strains were recovered in 1985. The changing patterns of susceptibility of anaerobic bacteria to antimicrobial agents and the emergence of Bacteroides fragilis strains resistant to new beta-lactam agents suggest that periodic antimicrobial susceptibility tests should be performed in order to guide the selection of antimicrobial agents for therapy.

Comparison of the inoculum effects of members of the family Enterobacteriaceae on cefoxitin and other cephalosporins, beta-lactamase inhibitor combinations, and the penicillin-derived components of these combinations

We compared the inoculum effects of 105 recent clinical isolates of the family Enterobacteriaceae on cefoxitin, other cephalosporins, aztreonam, and three beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) and their penicillin-derived components. Piperacillin and aztreonam showed the largest inoculum effect, and cefoxitin showed the smallest. The other cephalosporins tested (cefotetan, ceftizoxime, and ceftriaxone) showed an intermediate inoculum effect. In general, the inoculum effect was of greater magnitude for the penicillin and beta-lactamase inhibitor combinations than for the cephalosporins tested. Bactericidal activity was assayed and morphologic changes were monitored for selected strains exhibiting a large inoculum effect. MICs correlated with bactericidal activity at an inoculum level of 10(5) CFU/ml, while activity at 10(8) CFU/ml was variable. Cefoxitin demonstrated the least filamentous transformation and the most rapid bactericidal activity. Aztreonam showed the most marked filamentous transformation and was no longer bactericidal at 10(8) CFU/ml. The beta-lactamase inhibitor combinations showed variable bactericidal activity, and regrowth occurred with a number of strains with all three agents tested.

Susceptibilities of anaerobic Gram-negative bacilli to thirteen antimicrobials and β-lactamase inhibitor combinations

Thirteen antimicrobial agents and beta-lactamase inhibitor combinations were tested simultaneously for their in-vitro activity against a range of anaerobic Gram-negative bacilli with a standard reference agar dilution method. Overall, metronidazole, imipenem, ampicillin/sulbactam, ticarcillin/clavulanic acid and cefoperazone/sulbactam, followed by clindamycin, cefoxitin, and piperacillin, had the greatest activity. Cefotetan, ceftizoxime, and cefoperazone were moderately active, while ampicillin and penicillin were least active. Metronidazole was the only drug active against all strains, but only one strain was resistant to imipenem. Resistance was highest among certain members of the Bacteroides fragilis group, but was observed also among numerous other Bacteroides species. beta-Lactamase was produced by 94% of strains in the B. fragilis group, and by 64% of strains overall. The activities of clindamycin and cefoxitin were compared with those in previous surveys since 1982 at our institution. No clear evidence of increasing resistance was demonstrated, but the data emphasized the significant effects resulting from variations in susceptibility testing.

Perspectives of beta-lactamases inhibitors in therapy of infections caused by Escherichia coli or Klebsiella with plasmidic resistance to third generation cephalosporins

New plasmidic beta-lactamases inactivating so far stable cephalosporins, aztreonam and cephamycins restrict the use of these antibiotics in therapy of infections, e.g., by Escherichia coli and Klebsiella. Thus, combinations of beta-lactamase inhibitors and beta-lactam antibiotics were investigated in vitro with regard to their therapeutic perspectives. Minimal inhibitory concentrations and the kinetics of killing in a pharmacodynamic model were determined. Extended broad spectrum beta-lactamases (EBS-beta-lactamases) representative both for the TEM- and SHV-type were included. None of the available fixed combinations of penicillins and beta-lactamase inhibitors appears useful for therapy of infections caused by producers of EBS-beta-lactamases. In contrast, combinations of piperacillin and tazobactam or sulbactam plus cephalosporins (cefoperazone, cefotaxime, ceftazidime) or aztreonam are highly active (both by their MICs and bactericidal activity) against TEM-type EBS-beta-lactamases, but less promising for the SHV-type EBS-beta-lactamases, and plasmidic cephamycinase. Of the beta-lactams available, the monobactam carumonam and the carbapenems (imipenem, meropenem) remain safe in infections caused by E. coli and Klebsiella EBSBase producers.

Studies to optimize the in vitro testing of piperacillin combined with tazobactam (YTR 830)

The combination of piperacillin and the beta-lactamase inhibitor tazobactam (formerly YTR 830) was studied to determine optimal disk concentrations and dilution testing conditions. In addition, the potency of the combination was compared to that of piperacillin alone. The spectrum of piperacillin was greatly expanded by the addition to tazobactam principally against beta-lactamase producing strains of Haemophilus influenzae, Escherichia coli, Morganella morganii, Proteus vulgaris, Providencia stuartii, Shigella spp., Neisseria gonorrhoeae, and Staphylococcus spp. Tazobactam was active alone against Branhamella catarrhalis (minimum inhibitory concentration [MIC] 50, ⩽1 μg/ml), gonococci (MIC 50, 0.5–4 μg/ml), and N. meningitidis (MIC 50, ⩽1 μg/ml). Studies with beta-lactamase-producing type strains showed tazobactam to have high affinity for plasmid-mediated enzymes (TEM-1 and 2, SHV-1, HMS-1, and some CARB or OXA types) and not chromosomal beta-lactamases. Piperacillin/tazobactam inhibited 93% of fluoro-quinolone resistant strains at ⩽ 64 8 μ g/ml but failed to suppress the growth of 15 strains producing stably derepressed cephalosporinases. Comparisons of piperacillin/tazobactam results determined with 100 10 -, 100 20 -, and 100 30 -μ g disks established the 100 10 -μ g disk as most usable. Among five different MIC combinations the ratio of eight parts piperacillin to one part tazobactam or fixed concentration tests at ⩾4 μg tazobactam/ml were preferred, each producing very low occurrences (≤1.6%) of false-resistance or -susceptibility when compared to disk test results. MICs determined by agar and broth microdilution methods were essentially the same. The recommended breakpoints for piperacillin/tazobactam MICs were identical to those now found in the NCCLS susceptibility testing standards with the following exceptions: (1) for tests with H. influenzae and Staphylococcus spp.—susceptible at ⩾21 mm ( MIC ⩽ 16 2 μ g/ml ) and resistant ⩽20 mm ( MIC ⩾ 32 4 μ g/ml ); and (2) all remaining nonpseudomonas isolates would be interpreted by the NCCLS piperacillin enteric bacilli susceptibility criteria. This newer beta-lactamase inhibitor combination appears to be worthy of further in vivo trials guided by these or similar tentative in vitro susceptibility testing parameters.

Synergism and Antagonism

Among the reasons for use of antimicrobials in combination is the desire to achieve synergistic inhibitory or bactericidal activity. Several methods have been used to test for the presence of synergistic interactions, but virtually all are either very time consuming or nonstandardized. With combinations of cell wall-active agents plus aminoglycosides, bactericidal synergism has been associated with enhanced intracellular uptake of the aminoglycoside. Combinations of beta-lactamase inhibitors with beta-lactams susceptible to enzymatic hydrolysis have yielded synergistic activity against a number of common pathogens. The example of trimethoprim-sulfamethoxazole illustrates the potential value of combination of drugs acting at proximate steps along a single metabolic pathway. By analogy, combinations of antimicrobials active at various steps in peptidoglycan synthesis might also result in synergistic interactions. Use of certain drug combinations does pose the risk, however, of unwanted antagonistic interactions. The clinical importance of synergism in the treatment of bacterial infections has been documented in only a few limited circumstances.

Critical assessment of the newer non-quinolone oral antimicrobial agents

In this issue of The Antimicrobic Newsletter, Dr. Ronald Jones tracks recent developments in the formulation of orally administered therapeutic agents. When last reviewed by Dr. Jones (The AMN, Vol. 5, No. 1, 1988), twelve compounds were discussed, all of the cephalosporin class. In his current work, five antibiotic drug families are referenced, monobactams, penems, beta-lactamase inhibitor combinations, macrolides, and cephalosporins; in all, the activity and potential applications of at least ten In 1987, annual sales for antimicrobial agents topped $3.5 billion. Although the major portion of these expenditures were for the newer, expensive, parenteral antimicrobics such as third-generation cephalosporins, carbapenems (imipenem), or monobactams (aztreonam); the remainder was for oral formulations. Until the release of the first fluoroquinolone, norfloxacin, nearly 4 years ago, the orally administered drugs had been

New Experimental Drugs for the Treatment of Tuberculosis

New antitubercular agents are needed for two main purposes: to further simplify therapy (through reductions in the number of medicaments used, the number of doses administered, and the duration of treatment required), thus facilitating supervision and improving compliance, and to combat resistant mycobacteria. Reduction in the number of medicaments has been achieved by combining two or more drugs in a single tablet while retaining a degree of bioavailability similar to that of the single components. The adverse effects observed with once-weekly high doses of rifampin have limited the development of widely spaced intermittent regimens of treatment. For this reason new rifamycins have been developed that are as active as rifampin against mycobacteria but that also offer the advantage of high and prolonged serum levels and thus have the potential for once-weekly administration. The in vitro and in vivo properties of these drugs have been studied. Three classes of drugs show promise for the treatment of drug-resistant tuberculosis: spiropiperidyl rifamycin, the fluoroquinolones, and combinations of beta-lactam agents and beta-lactamase inhibitors.

The Role of the Newer Antimicrobial Agents in Obstetrics and Gynecology

The new antibiotics include interesting compounds--extended-spectrum cephalosporins and penicillins, combinations of older antibiotics plus beta-lactamase inhibitors, and new classes such as the monobactams and fluoroquinolones. In addition to extended spectrums, some of these compounds offer more favorable kinetics, less toxicity, or decreased cost. Several general conclusions might help place this array of new antibiotics in a useful clinical perspective. The newer antibiotics discussed here are no more effective than what is currently used. However, several have very good in-vitro activity against pelvic pathogens and are reasonable single-agent therapy in mild to moderate postpartum and postoperative infections. These antibiotics include cefoxitin, cefotetan, and piperacillin. Although moxalactam has good activity, its use is limited by concerns regarding bleeding disorders. Cefotaxime and cefoperazone have somewhat less favorable spectra, especially against anaerobes, yet in limited clinical trials are as effective as those cited above. Penicillin/beta-lactamase inhibitor combinations are currently being evaluated and appear to be reasonable choices. Although imipenem has an excellent in-vitro spectrum, it should probably be reserved for resistant cases. Aztreonam offers an alternative to gentamicin. However, in view of its greater cost, its use should be limited to patients in whom renal toxicity is a concern. For serious infections, combination therapy with clindamycin and gentamicin is our preference. For pelvic inflammatory disease, none of the agents is recommended as sole therapy due to the lack of coverage for chlamydia and frequent suboptimal coverage for anaerobes. Many of these agents have been effective for prophylaxis, but none has been shown to be superior to the older, less expensive agents such as cefazolin. Although many are effective in single doses, it is also likely that cefazolin is equally effective as a single dose. In addition, while most of the newer antibiotics are resistant to beta-lactamases themselves, they may induce their formation. This may ultimately result in limitations to the use of the relatively inexpensive prophylactic antibiotics.

Branhamella catarrhalis respiratory infections in The Netherlands.

In the southern Netherlands, Branhamella catarrhalis can be cultured from sputum in more than 20% of patients with purulent lower respiratory tract infections and approximately 40% of strains produce beta-lactamase. With increasing resistance to co-trimoxazole (10%) and erythromycin (6%) this produces many treatment problems, particularly in general practice. Recent results in the treatment of B. catarrhalis respiratory infections with newer antimicrobial agents and new combinations of beta-lactamase inhibitors are presented. Cefotaxime and ceftazidime are predictably effective but, considering their cost and the fact that they require parenteral administration, they need to be reserved for strict indications.