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Ceftibuten, a new orally absorbed cephalosporin with a novel side chain, has broad in vitro activity against most of the important respiratory pathogens including Streptococcus pneumoniae and both beta-lactamase-negative and beta-lactamase-positive Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Furthermore it has high activity against Enterobacteriaceae, which contain classic TEM-1 beta-lactamases and those containing the new extended spectrum beta-lactamases, which hydrolyze parenteral third generation cephalosporins. Studies have shown that ceftibuten has a postantibiotic effect comparable to that of other beta-lactams against S. pneumoniae, H. influenzae and M. catarrhalis. Blood levels achieved after a single 400-mg dose given once daily or 9 mg/kg/day taken once daily for children yield blood levels and postantibiotic inhibition for the majority of a dosing period. The in vitro and pharmacokinetic data can be correlated to provide reasonable dosing programs for the new oral cephalosporins.

A review of the published literature detailing the clinical use of amoxycillin/clavulanic acid spanning the period 1979 to 1992 was undertaken to assess the clinical efficacy of the product and to determine whether any changes had occurred during this time. In the 415 publications meeting the selection criteria a total of over 38,500 patients were treated with amoxycillin/clavulanic acid. Analysis of the data confirms the efficacy of amoxycillin/clavulanic acid over a wide range of clinical indications and annual and triennial groupings of publications suggests that there has been little change in the clinical effectiveness of amoxycillin/clavulanic acid. Clinical efficacy rates (cure or improved) with amoxycillin/clavulanic acid were 88% and 92% in comparative and uncontrolled trials, respectively. Gastro-intestinal side effects are the most common adverse event but have been relatively infrequent. Amoxycillin/clavulanic acid should continue to be a useful antibiotic for upper and lower respiratory tract infections, skin structure infections, dental, head and neck infections, and selected urinary tract infections.

There is and has been continued change in organisms causing infection in the hospital. In the past few years, although Gram-negative bacteria have remained a major cause of mortality, Gram-positive bacteria and fungi have become increasingly important. This has caused organisms such as methicillin-resistant staphylococci, enterococci, Xanthomonas maltophilia and multiply resistant Pseudomonas aeruginosa to be common pathogens. Can this difficult state of affairs be changed by better antimicrobial prescribing practices? Yes and no. Virtually any agent will select MRSA and MRSE since the chromosomal location of the resistance of multiple-antibiotics makes such selection common and explains the rapid rate of the fluoroquinolones as therapy of MRSA. Restriction of oral vancomycin will markedly reduce the pressure to select Enterococcus faecium and thus limit the spread of the organisms and delay transmission of glycopeptide resistance to S. aureus. Judicious use of antibiotics in the intensive care environment will be major factor in "saving" antibiotics for other patients since the ICU patient goes to other parts of the hospital carrying with him/her the baggage of resistant Staphylococcus haemolyticus, klebsiella, P. aeruginosa, acinetobacter, enterobacter, xanthomonas and Pseudomonas cepacia. All of these organisms have the potential to become resistant to the agents heretofore used to treat them and are common in ICU patients.

The synthesis of large numbers of antibiotics over the past three decades has caused complacency about the threat of bacterial resistance. Bacteria have become resistant to antimicrobial agents as a result of chromosomal changes or the exchange of the exchange of genetic material via plasmids and transposons. Streptococcus pneumoniae, Streptococcus pyogenes, and staphylococci, organisms that cause respiratory and cutaneous infections, and members of the Enterobacteriaceae and Pseudomonas families, organisms that cause diarrhea, urinary infection, and sepsis, are now resistant to virtually all of the older antibiotics. The extensive use of antibiotics in the community and hospitals has fueled this crisis. Mechanisms such as antibiotic control programs, better hygiene, and synthesis of agents with improved antimicrobial activity need to be adopted in order to limit bacterial resistance.

This chapter reviews the chemistry, microbiology, pharmacology, and clinical use of the fluoroquinolone antimicrobial agents. The molecular and clinical problems of bacterial resistance are reviewed. The clinical areas in which fluoroquinolones have been investigated are detailed, with particular attention to areas of appropriate and inappropriate use.

We determined the efficacy and safety of orally administered ofloxacin, 400 mg twice daily, in the treatment of infections due to multiply-resistant bacteria. Patients (n = 99) were treated for 84 infections in 82 patients evaluable for efficacy with a bacteriologic response of 71%. Organisms treated included Pseudomonas aeruginosa (39), Staphylococcus aureus (11), Serratia marcescens (9), Enterobacter species (7), five each of Escherichia coli, Citrobacter, Salmonella, Klebsiella, and other organisms. The overall clinical responses was 89%: 28 (90%) of 16 osteomyelitis, 10 (83%) of 12 urinary tract infections, and three of three bacteremias. Insomnia occurred in 27% and responded to dose reduction. Resistance of P. aeruginosa to ofloxacin developed in 15% of isolates. No hepatic, renal, or hematologic toxicity developed in spite of long therapy, 283 days. Ofloxacin was an effective therapy for lower respiratory, urinary, bone, and soft tissue infections due to multiply-resistant Gram-negative bacteria and is effective for selected Staphylococcus aureus infections.

The quinolone antimicrobial agents are important therapeutic compounds for many infections. They have potential as substitutes for many parenteral agents, particularly in treating urinary tract, diarrheal, bone and joint, and some respiratory tract infections. The quinolones are important prophylactic agents for neutropenic patients. Adverse reactions to these compounds have been exceedingly infrequent. Important drug-drug interactions occur, and the absorption of the compounds can be markedly impaired by antacids. Resistance to quinolones is already a serious problem in some countries. Improper use in the United States will rapidly make the new quinolones ineffective treatment for staphylococcal, Pseudomonas, and even some Enterobacteriaceae infections. Careful attention to those situations in which resistance has been shown to develop is necessary.

Fluoroquinolones have been in use for the past five years. The agents inhibit Enterobacteriaceae, Pseudomonas aeruginosa, and staphylococci, but some agents lack activity against streptococci and none of the commercially available agents inhibits anaerobic species. The fluoroquinolones possess many pharmacological advantages which have made them excellent therapy for urinary, selected respiratory, gastrointestinal, skin, soft tissue, bone, and sexually transmitted infections. They have also proved useful as prophylaxis in neutropenic patients. A major problem for the future is that inappropriate and indiscriminate use of quinolones will cause rapid development of resistance, particularly among staphylococci and P. aeruginosa.

Agents approved for clinical use in the past five years and others most likely to be available in the near future are evaluated in this two-part review. This installment is devoted entirely to the beta-lactam antibiotics--penicillins, cephalosporins, monobactams, and carbapenems. There are more similarities than differences among them, but the variations give each agent a range of appropriate uses.

beta-Lactamases have been known since the early 1940s when they were recognized as a major mechanism of resistance in Staphylococcus aureus. The synthesis of semisynthetic penicillins provided agents that overcame the resistance of staphylococci, but as gram-negative bacteria became increasingly important as the cause of infections, plasmid-mediated beta-lactamases were recognized in the Enterobacteriaceae, Haemophilus, and chromosomally mediated beta-lactamases in Klebsiella, and Bacteroides were found to be the mechanism of resistance of these species to ampicillin and related penicillins. Two approaches to the problem have been developed. One is to make stable compounds. This has been possible in the cephalosporin family. The other method has been to find inhibitors of beta-lactamases. Clavulanate is a beta-lactamase inhibitor that, in combination with amoxicillin, allows the combination to inhibit many of the organisms that are resistant to amoxicillin. Similarly, clavulanate has been combined with ticarcillin to provide a parenteral agent to inhibit beta-lactamase-producing bacteria and retain activity against Pseudomonas. Sulbactam has been combined with ampicillin. The combination of suicide inhibitors with other beta-lactams has provided agents that inhibit many of the bacteria present in mixed cutaneous infections. Clinical studies have established the efficacy of the clavulanate-amoxicillin and clavulanate-ticarcillin combinations in skin and skin-structure infections. These agents offer an alternative to other drugs when treating cutaneous infections.

Compared with aminoglycosides, chloramphenicol, sulfonamides, tetracyclines, and even penicillins, the cephalosporins represent a remarkably safe class of antibiotics. Among the cephalosporins, the extended spectrum, third generation agents developed generally produce few side effects and appear to be less allergenic than the penicillins. Nephrotoxicity has not been a problem at recommended doses. Some third generation agents can cause hypoprothrombinemia if not administered with vitamin K, and disulfiram-like reactions occur with some agents because of the presence of a thiomethyl tetruzole moiety affixed to the cephem nucleus. There is a greater incidence of diarrhea associated with the agents excreted through a primarily biliary route, and this may contribute to the selection of drug resistant bacteria. Some agents are less active against staphylococci and their use may result in an increased incidence of superinfection or overgrowth of enterococci. If attention is given to the potential for adverse effects, many of these problems can be avoided and the third generation cephalosporins can be used safely in hospitals, nursing homes, and home care settings.

The mechanisms of resistance encountered in bacteria causing infection in the patient at risk for infection are diverse. Most resistance currently seen is the result of plasmid transfer rather than mutational events. However, extensive use of antimicrobial agents in the hospital has caused the selection of organisms resistant to many agents by virtue of chromosomally mediated mechanisms. Staphylococcus aureus resistant to beta-lactams due to altered penicillin-binding proteins has become a problem in certain patients such as narcotic addicts and chronic care facility patients exposed to many beta-lactam antibiotics. S. epidermidis has also proved to be a problem in patients with indwelling foreign devices, and altered penicillin-binding proteins also make these organisms resistant to available penicillins and cephalosporins. Streptococcus fecalis has become increasingly resistant to aminoglycosides, erythromycin, and tetracyclines due to plasmid-mediated enzymes. Hemophilus influenzae resistant to both penicillins and chloramphenicol by virtue of beta-lactamases and chloramphenicol transacetylase has been encountered. Beta-lactamase-mediated resistance of Enterobacteriaceae, Escherichia coli, and Klebsiella pneumoniae to beta-lactam antibiotics has increased, and resistance of Serratia marcescens and Pseudomonas aeruginosa to aminoglycosides and penicillins is a widespread phenomenon. Mechanisms to reduce resistance will include not only careful attention to hygienic practices but also more appropriate use of antibiotics selecting the proper agent depending on the type of patient and environment in which the infection develops.

Cefotaxime is a cephalosporin active against most gram-positive and gram-negative organisms, including streptococci, Staphylococcus aureus, Enterobacteriaceae, Proteus, and many Pseudomonas and Bacteroides fragilis--all but the latter two are inhibited at concentrations below 0.5 micrograms/ml. We evaluated cefotaxime as the sole therapy for 32 infections in 31 patients. Infection sites included 18 bacteremias; pulmonary, urinary tract, deep tissue infections; and meningitis. Clinical cures were achieved in 88 percent and bacteriologic cures in 86 percent of the patients--including those with infections due to organisms resistant to cephalosporins, chloramphenicol, carbenicillin and aminoglycosides; and in two patients with meningitis due to multiresistant Klebsiella pneumoniae. Serum and cerebrospinal levels were readily maintained above the inhibitory levels of susceptible organisms. Adverse reactions were minimal. Cefotaxime was a safe, effective antibiotic in the treatment of infections due to susceptible organisms, including those resistant to other agents.

Bacampicillin hydrochloride is an orally administered ester of ampicillin that is rapidly and completely hydrolyzed in vivo to ampicillin. The most notable advantage of bacampicillin over ampicillin is its superior bioavailability--bacampicillin achieves significantly higher blood and tissue levels and attains peak blood levels more rapidly than equimolar doses of oral ampicillin. In addition, the percentage of an oral dose of ampicillin that is absorbed decreases sharply as the size of the dose is increased from 500 mg to 2 g; this phenomenon is not observed with equipotent doses of bacampicillin. The enhanced absorption of bacampicillin in the upper gastrointestinal tract results in a frequency of diarrhea that appears to be markedly lower than that of ampicillin and similar to that observed with amoxicillin. Apart from the sizable differences between bacampicillin and ampicillin with regard to oral absorption, the pharmacokinetic and pharmacologic profiles of these two agents are essentially identical. Twice daily dosing (pulse dosing) with bacampicillin has been shown in numerous clinical trials to be of equivalent efficacy to ampicillin given four times daily or amoxicillin given three times daily in the treatment of infections of the upper respiratory tract, lower respiratory tract, skin and soft tissues, and urinary tract. The unanswered question is whether twice daily ampicillin or amoxicillin would yield similar results.

Mezlocillin, a new semisynthetic penicillin chemically related to ampicillin which is more active than carbenicillin against Ps. aeruginosa, B. fragilis and Strep. faecalis and which inhibits many Klebsiella, was evaluated in the therapy of 34 episodes of infection in 26 patients. Infection sites included pulmonary, urinary tract and tissue infections, including peritonitis. Seven patients had bacteremia. Clinical cures were achieved in 83 per cent and bacteria cures in 76 per cent of infections. Cure was achieved with mezlocillin in patients with infections caused by carbenicillin-resistant species. Adverse effects of therapy were minimal, one rash and one episode of reversible neutropenia. Serum and body flevels of susceptible organisms.uid levels were easily maintained above the inhibitory levels of susceptible organisms. Mezlocillin was a safe, well tolerated and effective antibiotic in the treatment of infections due to susceptible organisms.

The pattern of antimicrobial resistance of common bacterial isolates obtained from various groups of patients at a large tertiary-care center was compared with the pattern of resistance seen at a primary-care community hospital. At the tertiary-care center, significant differences in susceptibility were seen between pediatric and adult groups. In the tertiary-care center, the inpatients were more likely than the outpatients to have resistant staphylococcal and enterobacterial strains. Comparison of the overall resistance at the tertiary-care center and the primary-care hospital showed that resistance to cephalosporins, piperacillin, and aminoglycosides was significantly higher at the tertiary-care hospital than at the community hospital. Striking differences were noted in the resistance of nosocomial Enterobacter and Citrobacter isolates. Hospitals should be cautious in extrapolating nationwide data to their particular institutions.

Chemotherapy affects both the host and the microorganism. Antimicrobial agents have a profoundly adverse influence on the surrounding environment if they are improperly employed. In all chemotherapy, it is critical to know what the infecting organisms are, and if that information is not immediately available, to base chemotherapy on those organisms that characteristically produce the infection. It also is critical to have an understanding of the distribution of antibiotic-resistant microorganisms in one's community if the proper antimicrobial agent is to be selected. The host's status and site of the infection will impact upon the choice of drug. Infection in sites in which phagocytic function is poor, such as in heart valves or in the spinal fluid, or in individuals lacking complement, white blood cells, or immunoglobulins, must be treated with bactericidal agents. An understanding of the pathogenesis of infection caused by different microorganisms will provide insights into the type of therapy, duration, and amount of drug that must be used. Ultimately, the chemotherapy of infection should be based on integration of the activity of antimicrobial agents with their pharmacologic properties.

Thirty-four patients were treated with intravenous ciprofloxacin. Thirty infections occurring in 28 patients were assessable for the efficacy analysis. The drug dosage was 300 mg every 12 hours in 19 patients and 200 mg intravenously every 12 hours in nine patients. Twelve patients were also given ciprofloxacin orally after initial intravenous therapy. The mean duration of total therapy was 31 days. The overall clinical response rate was 87 percent, and the bacteriologic response rate was 70 percent. Favorable responses were observed in 10 of 12 patients with osteomyelitis/septic arthritis; seven of eight with soft tissue infection; four of four with pneumonitis; one of two with cystic fibrosis; and four of four with urinary tract infections. Resistance to ciprofloxacin developed in three Pseudomonas aeruginosa isolates. Toxicity was minor: phlebitis occurred in six patients, nausea in six, and rash in one. Intravenously administered ciprofloxacin or intravenous ciprofloxacin followed by oral ciprofloxacin is a safe and effective therapy for serious infections.

Azlocillin, a semisynthetic ureidopenicillin that inhibits many Gram-negative and Gram-positive bacteria and many Pseudomonas aeruginosa resistant to carbenicillin, was used to treat 23 episodes of infection in 20 patients. The majority of the patients had severe underlying diseases, including marked reduction in renal function in a number of the patients. Infection sites were lung, urinary tract, skin and primary bacteraemia. Seven patients had bacteraemia. Clinical cure or improvement was achieved in 87% of infections, all patients with bacteraemia due to Pseudomonas spp., Escherichia coli, Listeria spp. and Streptococcus faecalis were cured. Cure was achieved with azlocillin against carbenicillin-resistant Ps. aeruginosa infections. Serum and urine levels were easily maintained in excess of the accepted minimal inhibitory concentrations of the susceptible organism (less than or equal to 64 mg/l). Adverse effects were minor. Azlocillin was a safe, well-tolerated and effective agent to treat suspected or proven infections due to Ps. aeruginosa and other susceptible bacteria.

Moxalactam was evaluated as the sole therapy of 45 episodes of infection in 41 patients due primarily to bacteria resistant to older antibiotics. Infections included bacteremias, pulmonary, skin and soft tissue infections, osteomyelitis, and meningitis. Clinical and bacteriological cure was achieved in 69% of infections. Cure was achieved with moxalactam in patients infected with cefazolin-resistant, carbenicillin-resistant, chloramphenicol and gentamicin-resistant organisms. Although adverse reactions were generally mild, diarrhea developed in five patients, a major increase in prothrombin time and bleeding in three patients and a disulfiram reaction in two patients.

Many physicians do not know what they should expect from the microbiology laboratoy. What physicians need from the microbiology laboratory varies according to type of patient and type of physician. The laboratory should provide information that will affect clinical management guidelines for obtaining specimens, microbial identification, antimicrobial susceptibilities, rapid collection of material, and reporting of data and educational updating. Data are needed to establish how the physician responds to microbiologic reports.

Sixty patients were treated with ciprofloxacin: 19 received only intravenous ciprofloxacin, 41 received intravenous followed by oral ciprofloxacin. The mean duration of therapy was 28 days in the intravenous only group and 10 days intravenously and 80 days orally in the intravenous/oral group. Ten (17 percent) patients received 200 mg intravenously every 12 hours and 49 (82 percent) 300 mg every 12 hours. The overall clinical response was 85 percent, with a bacteriologic response of 70 percent. The lowest bacteriologic response (38 percent) occurred in the 13 patients treated for Pseudomonas respiratory infection. Clinical response occurred in 24 of 26 patients with soft-tissue infection, and 10 of 13 patients with respiratory infection. Of three patients with endocarditis, therapy failed in two with resistance developing in Pseudomonas aeruginosa and Staphylococcus aureus. Overall, 19 percent of 26 P. aeruginosa isolates developed resistance to ciprofloxacin. Toxicity was minor, with phlebitis and nausea most commonly reported. Intravenously administered ciprofloxacin or intravenous followed by oral ciprofloxacin is a safe, effective therapy for serious infections due to multiply resistant gram-negative bacteria, including P. aeruginosa and S. aureus.

Articles in this supplement have examined in detail the role of aminoglycosides in the therapy of infections, addressing problems of resistance, toxicity, and efficacy. This article discusses other agents and their potential utility and effect on aminoglycosides. Penem antibiotics, which have activity against only aerobic gram-negative bacteria, have recently been synthesized. These agents have proved effective in animal experiments; to date, however, results of human clinical trials are not available. Carboxypenicillins and ureidopenicillins will still have to be administered with aminoglycosides in patients with serious life-threatening infections or in those institutions in which organisms such as Klebsiella, Enterobacter, and Pseudomonas exhibit high levels of resistance. What will be the role of aminothiazolyl cephalosporins? In some institutions, these agents might be used as sole therapy, particularly if they become less costly as a result of competition. In other settings, concern over the resistance of organisms, such as Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, and Pseudomonas aeruginosa, will result in the use of aminoglycosides with these relatively beta-lactamase-stable cephalosporins. It will be necessary to monitor the development of resistance to the new antibiotics and to determine whether the use of aminoglycosides plus third-generation cephalosporin combinations results in decreased resistance. Other agents to be considered include the directed therapy monobactams aztreonam and carumonam, the broad-spectrum carbapenem imipenem, and the penems under development. It is unclear whether these compounds might be used with aminoglycosides in critically ill, infected patients. It is also unclear what role oral beta-lactamase-stable cephalosporins will have in the therapy of nosocomial infections, since they probably will not be effective against many of the urinary or cutaneous infections that are treated with aminoglycosides. Quinolone agents can be used successfully against many infections. However, the likelihood of bacterial resistance developing and their potential for toxicity are still unknown. Thus, despite the emergence of many new agents, it appears that the time-tested aminoglycosides will continue to play an important role in antimicrobial therapy for some time to come.

Ciprofloxacin is a fluorinated carboxyquinolone that inhibits Enterobacteriaceae, staphylococci, and Pseudomonas at low concentrations. It has poor activity against Bacteroides fragilis. In this study, the effect of administration of ciprofloxacin on bowel flora was determined in patients treated for different infections. Patients, aged 22 to 70 years, were treated with 500 mg of ciprofloxacin every 12 hours or 750 mg every eight hours for seven to 42 days. Some patients had advanced cystic fibrosis; other patients had infections with resistant bacteria. Infecting organisms were Pseudomonas aeruginosa, Staphylococcus aureus, Serratia, and Acinetobacter. Sites of infections were lung, soft tissue, and urinary tract. Stool samples were evaluated initially, during therapy, and after therapy. No resistant gram-negative aerobic species emerged; five patients had yeast colonization, staphylococci were found in three patients, and streptococci were found in one patient. Ciprofloxacin did not select resistant gram-negative bacteria in the stool, although sputum isolates showed increases in minimal inhibitory concentrations. Resistant bacteria were not selected in the fecal flora of patients who had received beta-lactam and aminoglycoside antibiotics before therapy with ciprofloxacin.

This has been an analysis of a number of agents whose clinical use has been approved in the past five years and of several agents that will undoubtedly be available within the next year. By the very nature of time alotted, the analysis had to be superficial. I believe that it is important to view all the agents because they cross each other in uses. I believe that areas of appropriate use exist for all of the compounds that I have discussed, and I also believe that cost and convenience will play increasingly important roles in the selection of what agent is most fitting, the definition of appropriate. In many infections it will not be possible to show a significant difference among drugs in a class, unless extremely large studies are undertaken. From my review of the literature in preparation for this meeting, I doubt these studies will be mounted. The infectious disease clinician must be familiar with all of the agents so that he or she can make judgments about which agent(s) make(s) the most sense for his/her hospital. I believe that it is fitting and proper for the infectious disease physician to appropriate the correct selection, methods of administration, and dose of antibiotic in many clinical situations, particularly ones in which parenteral agents are used. I hope the IDSA will have an impact on the proper use of the quinolones, monobactams, penems, and carbapenems. Our goal in the use of antimicrobial agents should be the selection of agents for prophylaxis, empiric therapy, and therapy for defined infections in a manner that results in cure, with reasonable cost and minimal damage to the microbial ecology.

Of 125 patients treated with ciprofloxacin at the Columbia-Presbyterian Medical Center, New York, 34 had infections due to bacteria other than Pseudomonas aeruginosa. The mean age of the patients was 50 years (19-88 years) and most had significant underlying disease. There were nine lower respiratory infections, eight urinary tract infections, eight soft tissue infections, three osteomyelitis, and three intra-abdominal infections. The pathogens were: Escherichia coli, 7 (mean MIC 0.07 mg/l); Serratia marcescens, 6 (0.2 mg/l); Enterobacter spp., 5 (0.1 mg/l); Klebsiella pneumoniae, 3 (0.1 mg/l); Proteus mirabilis, 3 (0.06 mg/l); Cutrobacter freundii, 2 (0.06 mg/l), Staphylococcus aureus, 3 (0.5 mg/l); and one each of Acinetobacter anitratus. Haemophilus, influenzae, Salmonella enteritidis, Flavobacterium meningosepticum, and Streptococcus faecalis. Of these organisms 81% were resistant to ampicillin, 70% to carbenicillin, 22% to gentamicin, 49% to cefazolin and cephalexin, and 25% to cotrimoxazole. Ten patients had concomitant Ps. aeruginosa infections. Patients were treated orally with 500 mg or 750 mg ciprofloxacin every 12 h. The overall clinical response rate was 88%, and the bacteriological response 76%, and 65% if Ps. aeruginosa is included. Resistance to ciprofloxacin developed in one Staph. aureus and one Ser. marcescens (MIC greater than 2 mg/l). Toxicity was minor. Ciprofloxacin was effective and safe therapy of infections due to Gram-negative bacteria resistant to many of the currently available oral and parenteral agents.

The clinical efficacy and safety of ceftriaxone when administered twice daily was evaluated in the treatment of serious infections, including 9 episodes of bacteremia, 4 of pneumonia, 7 of intra-abdominal or soft tissue infections, 11 of urinary tract infections, 3 of osteomyelitis, and 5 of meningitis. Causative pathogens were Strep. pneumoniae, other hemolytic streptococci, E. coli, P. mirabilis, K. pneumoniae, and species of Enterobacter, Serratia, and Pseudomonas. The overall clinical cure rate was 87 percent and the bacteriologic cure rate was 77 percent. Cures were achieved in infections due to organisms resistant to ampicillin, cefazolin, cefamandole, carbenicillin, and gentamicin. Peak plasma levels were far in excess of the minimal inhibitory concentrations of Enterobacteriaceae. Adverse effects were infrequent, and in only one instance was it necessary to discontinue treatment. Resistance to ceftriaxone developed during therapy with several Enterobacter and Pseudomonas species isolates. Ceftriaxone appears to be a useful agent for treatment of serious gram-negative infections in seriously ill patients.

Knowledge of which microorganisms cause infection in the ear, nose and throat must be coupled with an understanding of the susceptibility patterns of these bacteria as well as knowledge of the pharmacokinetic properties of antimicrobial agents. EVen though many of the bacteria which produce community-acquired infection are susceptible to the older agents, specific problems have developed with regard to species such as Hemophilus influenzae and to Staphylococcus aureus. Hospital-acquired infections due to Enterobacteriaceae may be resistant to the penicillin drugs and to some of the older cephalosporins and aminoglycosides. Use of the new agents often requires an understanding of how rapidly the compounds are cleared from the body or if they will accumulate to toxic levels in the elderly patient with decreased renal function. This article reviews the antimicrobial activity and clinical pharmacology of agents commonly used to treat infections of the ear, nose and throat.

Tetracyclines have a broad range of clinical usefulness because of their broad antimicrobial spectrum of activity. For most routine gram positive and gram negative infections, alternative agents are available, but for Chlamydiae, Rickettsiae, Brucella, and Borrelia they still remain agents of choice. To some extent, gastrointestinal intolerance and inability to use these agents in patients with renal dysfunction have been overcome by the availability of doxycycline. Phototoxicity is a problem with this agent, however. Tetracycline is still useful as a sclerogenic agent for malignant effusions, and demeclocycline often is an agent of choice in therapy of inappropriate antidiuretic hormone secretion.