Treatment Of Polymicrobial Infections Research Articles

Articles of Significant Interest in This Issue

Pseudomonas aeruginosa and Staphyloccocus aureus are among the most important pathogens in polymicrobial infections, and their co-occurrence is linked to outcomes that are more severe than those of the respective monospecies infections. There is great interest in understanding how these two species interact and the consequences of those interactions for the host. Work by Niggli and Kümmerli (e00962-20) showed that ecological factors such as strain genetic background, relative species frequency, and environmental conditions are important elements governing population dynamics and species coexistence patterns. An improved understanding of what influences these interspecies interactions may provide a basis for better treatment of polymicrobial infections.

Identification of Risk Factors for the Development of Clostridium difficile-Associated Diarrhea Following Treatment of Polymicrobial Surgical Infections

To identify risk factors for Clostridium difficile-associated diarrhea (CDAD) in surgical patients following treatment of polymicrobial infections. Infections among surgical patients are frequently anaerobic or mixed aerobic-anaerobic infections and are therefore subject to polymicrobial antibiotic coverage, including metronidazole. While multiple antibiotics are known to contribute to the development of CDAD, the role of preventive antibiotics is unproven. An 11-year dataset of consecutive infections treated in surgical patients at a single hospital was reviewed. All intra-abdominal, surgical site, or skin/skin structure infections were identified. Each infection was evaluated for antibiotic coverage and subsequent CDAD. Antibiotic usage was assessed using chi analysis. A multiple logistic regression was used to identify independent predictors of CDAD. A total of 4178 intra-abdominal, surgical site, or skin/skin structure infections were identified. Of these infections, 98 were followed by CDAD. Only carbapenem use affected the incidence of CDAD: 3.5% of infections treated with a carbapenem were followed by CDAD, whereas only 2.1% of infections treated without carbapenems were followed by CDAD (P = 0.04). Metronidazole had no association with future CDAD. Only age and Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with CDAD by multiple logistic regression analysis. Older patients with a high severity of illness are at greatest risk for developing CDAD following treatment of polymicrobial infections. No specific antibiotic class, including fluoroquinolones, is associated with an increased incidence of CDAD in this population. Although use of metronidazole in the treatment of polymicrobial infections is appropriate for anaerobic coverage, it does not reduce the risk of future CDAD.

Sertaconazole: updated review of a topical antifungal agent

Sertaconazole is an imidazole-type antifungal agent that has shown considerable in vitro activity against pathogenic fungi. Various studies carried out in animal models, clinical and toxicologic trials have confirmed the value of sertaconazole in the topical treatment of superficial mycoses in dermatology and gynecology. After several years of clinical experience in the topical treatment of dermatophytosis and Tinea versicolor, the substance has been approved for gynecologic candidiasis in Europe. Sertaconazole has a wide action spectrum that includes yeasts and dermatophyte fungi, and it is also active against bacteria, mainly Gram-positive cocci, making it highly efficient in the treatment of polymicrobial infections. The recent approval of the molecule by the US Food and Drug Administration, and the appearance of a new formulation of sertaconazole for the treatment of onychomycoses on a weekly administrative basis, are all data relevant to the process of marketing the product.

Ertapenem: a review of its use in the management of bacterial infections.

Ertapenem, a carbapenem antibacterial, has in vitro activity against many Gram- negative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria that are commonly associated with various infections.Once-daily parenteral (intravenous or intramuscular) ertapenem 1g was as effective as comparator antimicrobial agents (piperacillin/tazobactam or ceftriaxone +/- metronidazole) in patients with bacterial infections in randomised, double-blind, multicentre clinical trials. Response rates with ertapenem were 84% and 87% (combined microbiological and clinical) in patients with complicated intra-abdominal infections (CIAI), 82% (clinical) in patients with complicated skin and skin structure infections (CSSSI), 86% and 92% (microbiological) in patients with complicated urinary tract infections (CUTI), 92% (clinical) in patients with community-acquired pneumonia (CAP) associated with typical pathogens and 94% (clinical) in patients with acute pelvic infection. Respective response rates were statistically equivalent to those with comparators (81-94%). The efficacy of ertapenem was equivalent to that of piperacillin/tazobactam in patients infected with Enterobacteriaceae or anaerobes and to ceftriaxone in patients infected with Enterobacteriaceae. Ertapenem was generally well tolerated by patients with bacterial infections, with most adverse events being mild to moderate in severity. The most common ertapenem-associated adverse events were diarrhoea, infused vein complication, nausea, headache, vaginitis in females, phlebitis and/or thrombophlebitis and vomiting. Ertapenem is a broad-spectrum parenteral antibiotic with activity against many Gram-negative (including Enterobacteriaceae) and Gram-positive aerobic and anaerobic bacteria and is suitable for once-daily administration. Ertapenem has a role in the treatment of CAP associated with typical respiratory pathogens and is of particular value in the treatment of polymicrobial infections (such as CIAI, CSSSI, CUTI and acute pelvic infections), especially where Enterobacteriaceae and anaerobic bacteria are involved.

Fourth Generation Cephalosporins in the Antimicrobial Chemotherapy of Surgical Infections

Surgical infections include a variety of entities such as secondary peritonitis, intra-abdominal abscesses, obstetric and gynecological infections as well as bone-joint and soft-tissue infections. By definition the term “surgical infection” implies that surgery itself plays the major role in therapy, while antimicrobial chemotherapy is only supplementary. Broad-spectrum empirical regimens employed include the combination of a 1st or 2nd generation cephalosporin plus clindamycin or metronidazole ± aminoglycoside (depending on the severity of the condition). Cefepime and cefpirome are new 4th generation parenteral cephalosporins with a spectrum of activity which makes them suitable for the treatment of infections caused by a wide variety of bacteria. They are active against both Gram-positive and Gram-negative organisms, including Staphylococcus aureus and Pseudomonas aeruginosa with activity comparable to or greater than that of cefotaxime or ceftazidime respectively. Cefepime in particular is also very active against strains of Enterobacter and Pseudomonas spp resistant to these two agents. In comparison with 3rd generation cephalosporins, cefepime appears to be less likely to induce resistance, due to a lower rate of hydrolysis by ß-lactamases, a low affinity for these enzymes and more rapid permeation into the cell. Despite the fact that a 4th generation cephalosporin is well-suited for the treatment of polymicrobial infections, the following should be kept in mind: (I) MRSA strains and Bacteroides fragilis group are not included in their spectrum of activity. (II) Cefpirome is the only cephalosporin with in vitro activity against Enterococci. (III) Severe surgical infections of nosocomial origin, and particularly in settings where Enterobacter spp predominate, represent the major indication for empirical use of a 4th generation cephalosporin in combination with a nitroimidazole.

Combination Antimicrobial Therapy for Bacterial Infections

Therapy with antimicrobial combinations has been used as long as antimicrobials have been available. Combinations of antibiotics are often used to take advantage of different mechanisms of action and/or toxicity profiles. Well established indications for combination antimicrobial therapy include: (a) empirical treatment of life-threatening infections; (b) treatment of polymicrobial infections; (c) prevention of the emergence of bacterial resistance; and (d) for synergism. Disadvantages of combination therapy include: (a) increased expense; (b) increased risk of adverse effects; (c) antagonism; and (d) superinfection. Combination antimicrobial therapy should be considered for the treatment of serious Gram-negative infections caused by Enterobacter cloacae, Pseudomonas aeruginosa and Serratia marcescens, and certain Gram-positive infections caused by Enterococcus spp. and Staphylococcus spp. Selection of agents should be dependent upon local susceptibility patterns, clinical experience, site of infection, potential toxicities and cost.

Clinical implications of aminopenicillins with β-lactamase inhibitors

Aminopenicillin/β-lactamase inhibitor combinations (ampicillin/sulbactam and amoxicillin/clavulanic acid) are well established in the therapy of a wide range of infections in both hospital and primary-care settings as a result of their very broad-spectrum activity and good tolerability. These agents are particularly suited to the prophylaxis and treatment of polymicrobial infections. Clinical studies have demonstrated their efficacy in the treatment of diabetic foot infections, intra-abdominal infections, aspiration-related lung infections, brain abscesses and pelvic inflammatory disease, and in the prophylaxis of infections following abdominal, pelvic and head and neck surgery. Recent studies have also revealed that aminopenicillin/β-lactamase inhibitors may provide therapy or prophylaxis which is more cost-effective than with comparative antimicrobial agents.

Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity, and therefore protects piperacillin against Richmond and Sykes types II, III, IV and V beta-lactamases, staphylococcal penicillinase and extended-spectrum beta-lactamases. However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. Piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. Piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections.

Comparative activities of amoxycillin, amoxycillin/clavulanic acid and tetracycline against Chlamydia trachomatis in cell culture and in an experimental mouse pneumonitis

The activity of amoxycillin, amoxycillin/clavulanic acid and two tetracycline antibiotics was investigated against three strains of Chlamydia trachomatis in vitro. McCoy cells were infected and single doses of antibiotic administered 24 h after infection. The percentage of infected cells was calculated at intervals up to 72 h after infection. Amoxycillin and clavulanic acid, alone and in combination, reduced the incidence of inclusion formation of all three strains. Particularly good activity was observed against the laboratory-adapted strain C. trachomatis Sa2f and a clinical isolate C. trachomatis LB1, where a progressive reduction in numbers of inclusions was observed with time. Minocycline and oxytetracycline were the most active agents tested. In an experimental animal model, mice were inoculated intranasally with C. trachomatis MoPn (ATCC VR123) which caused a fatal pneumonia within 16 days, and treated orally for four days commencing at 24 h after infection. At doses producing clinically achievable serum concentrations, amoxycillin (10 mg/kg), amoxycillin/clavulanic acid (10 + 5 mg/kg) and minocycline (5 mg/kg) all protected the mice over a 21-day period. The majority of the animals treated with clavulanic acid alone (20 mg/kg) survived the infection. Treatment with oxytetracycline was less effective, a dose of 160 mg/kg being required to protect 70% of the mice. The results indicate that amoxycillin and amoxycillin/clavulanic acid were more effective against C. trachomatis MoPn in vivo than might be predicted from in-vitro data, suggesting that amoxycillin/clavulanic acid may have potential for the treatment of polymicrobial infections involving C. trachomatis.

Synergy between spiramycin and metronidazole in the treatment of polymicrobial infections.

The in-vitro and in-vivo activity of metronidazole and spiramycin, singly or in combination, was tested in the eradication of infection caused by Bacteroides spp. alone and in combination with Neisseria gonorrhoea, Staphylococcus aureus, Streptococcus pyogenes or Str. faecalis. The in-vitro tests consisted of determinations of the MICs with or without the addition of a constant amount of the other antimicrobials. The MICs of metronidazole for B. melaninogenicus, B. fragilis and B. bivius were significantly reduced by the addition of 0.125 mg/l spiramycin. The in-vivo tests were carried out in mice and consisted of measurements of the effects of the antimicrobial agents on the bacterial contents of abscesses induced by subcutaneous injection of bacterial suspension. Combined therapy of mixed infections showed further significant reduction of the numbers of Bacteroides spp. in seven of 12 combinations and of the aerobic and facultative bacteria in four of 12 combinations. Furthermore, a reduction in the number of facultative anaerobes was noted in mixed infections with Bacteroides spp. which were treated with metronidazole alone. The synergy in vitro and in vivo between metronidazole and spiramycin may have important clinical implications in the treatment of polymicrobial aerobic-anaerobic infections.

Susceptibility profiles of potential aerobic and anaerobic pathogens isolated from hysterectomy patients

A total of 1140 aerobic and anaerobic isolates were recovered from cultures of specimens from the reproductive tracts of 435 uninfected patients who underwent elective hysterectomy. Standard minimum inhibitory concentration susceptibility studies were performed on these isolates to 13 newer penicillins, cephalosporins, and some traditional antimicrobial agents. These data were generated to evaluate the in vitro efficacy of these antibiotics for potential use in prophylaxis or as a single agent for treatment of polymicrobial infections of the female pelvis. The minimum inhibitory concentration data for each antibiotic against 16 genera of aerobic and nine genera of anaerobic bacteria were determined and were used to compare the in vitro antimicrobial activity of newer antibiotics to that of the more traditional antibiotics. Of the antimicrobial agents tested, piperacillin had the highest in vitro activity against these isolates of any antibiotic tested.